Each actuation contains: Budesonide BP 200 mcg.
Budesonide aerosol for inhalation is a CFC-free metered dose inhaler preparation of Budesonide that delivers 200 mcg of the drug with every actuation.
Budesonide is a non-halogenated glucocorticoid structurally related to 16-alphahydroxyprednisolone. The drug is a 1:1 mixture of the 22R and 22S epimers. The 22R epimer is 2 to 3 times more potent than the 22S epimer and has a different pharmacokinetic profile.
Thus chemically, Budesonide is an epimeric mixture of the alpha- and beta-propyl forms of 16-alpha, 17-alpha-butylidenedioxy-11-beta, 21-dihydroxypregna-1,4-diene-3,20-dione. Its molecular formula is C25H34O6 while its molecular weight is 430.5.
Corticosteroid.
Pharmacology: Pharmacodynamics: Budesonide is a non-halogenated glucocorticoid corticosteroid structurally related to 16-alphahydroxyprednisolone.
Corticosteroids have multiple mechanisms of action including anti-inflammatory activity, immunosuppressive properties, and antiproliferative actions. Anti-inflammatory effects result from decreased formation, release, and activity of the mediators of inflammation (e.g., kinins, histamine, liposomal enzymes, prostaglandins, and leukotrienes). These effects reduce the initial manifestations of the inflammatory process. Corticosteroids inhibit margination and subsequent cell migration to the area of injury, and also reverse the dilation and increased vessel permeability in the area, resulting in decreased access of cells to the sites of injury. This vasoconstrictive action decreases serum extravasation, swelling, and discomfort. The immunosuppressive properties decrease the response to delayed and immediate hypersensitivity reactions (e.g., type III and type IV). This results from inhibition of the toxic effect from antigen and antibody complexes that precipitate in vessel walls creating cutaneous allergic vasculitis, and by inhibiting the action of lymphokines, target cells, and macrophages which together produce allergic contact dermatitis reactions. Additionally, the access of sensitized T lymphocytes and macrophages to target cells may also be prevented by corticosteroids.
The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions, such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important.
A clinical study in asthmatics comparing inhaled and oral budesonide at doses calculated to achieve similar systemic bioavailability demonstrated statistically significant evidence of efficacy with inhaled but not oral budesonide compared with placebo. Thus, the therapeutic effect of conventional doses of inhaled budesonide may be largely explained by its direct action on the respiratory tract.
In a provocation study pre-treatment with budesonide for four weeks has shown decreased bronchial constriction in immediate as well as late asthmatic reactions.
Onset of effect: After a single dose of orally inhaled budesonide, delivered via dry powder inhaler, improvement of the lung function is achieved within a few hours. After therapeutic use of orally inhaled budesonide delivered via dry powder inhaler, improvement in lung function has been shown to occur within 2 days of initiation of treatment, although maximum benefit may not be achieved for up to 4 weeks.
Airway reactivity: Budesonide has also been shown to decrease airway reactivity to histamine and methacholine in hyper-reactive patients.
Exercise-induced asthma: Therapy with inhaled budesonide has effectively been used for prevention of exercise-induced asthma.
Growth: Limited data from long term studies suggest that most children and adolescents treated with inhaled budesonide ultimately achieve their adult target height. However, an initial small but transient reduction in growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment.
Pharmacokinetics: Absorption: After oral inhalation of budesonide, substantial absorption occurs from the lung (nearly 73%), peak plasma concentrations being attained within about 30 minutes. Onset of action occurs within 24 hours and the effect lasts for 12-24 hours. Peak response is seen within 1-2 weeks of drug treatment.
Distribution: The drug is 85% to 90% protein-bound and has a volume of distribution (Vd) of 3 L/kg.
Metabolism: Budesonide undergoes substantial hepatic first-pass metabolism mainly by the cytochrome P450, isoenzyme CYP3A4. The major metabolites, 6-betahydroxybudesonide and 16-alphahydroxyprednisolone have less than 1% of the glucocorticoid activity of unchanged budesonide. Metabolism is minimal in the lung which results in higher systemic bioavailability.
Excretion: Metabolites of Budesonide are eliminated by kidney. Budesonide is reported to have a terminal half-life of about 2 to 4 hours. Metabolism is minimal in the lung.
Renal excretion accounts for 60% of the total excretion of the drug and its metabolites. Only metabolites and not unchanged drug are eliminated via the kidney that accounts for 60% of the excretion. Biliary excretion is minimal and fecal elimination accounts for 15.1% to 29.6% of the excretion. Renal and fecal elimination is greater after oral administration than after oral inhalation.
Toxicology: 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.
No deaths occurred when budesonide was administered in the inhalation dose of 68 mg/kg in rats (approximately 430 times the maximum recommended daily inhalation dose in adults and approximately 510 times the maximum recommended daily inhalation dose in children on a mcg/m2 basis). The minimal inhalation lethal dose in mice was 100 mg/kg (approximately 320 times the maximum recommended daily inhalation dose in adults and approximately 380 times the maximum recommended daily inhalation dose in children on a mcg/m2 basis). The minimal oral lethal dose was 200 mg/kg in mice (approximately 630 times the maximum recommended daily inhalation dose in adults and approximately 750 times the maximum recommended daily inhalation dose in children on a mcg/m2 basis) and less than 100 mg/kg in rats (approximately 630 times the maximum recommended daily inhalation dose in adults and approximately 750 times the maximum recommended daily inhalation dose in children based on a mcg/m2 basis).
Carcinogenesis, Mutagenesis and Impairment of Fertility: The carcinogenicity of budesonide was evaluated in mice which were exposed for a total of 91 weeks, at doses up to 200 mcg/kg/day (approximately ½ the maximum recommended daily inhalation dose in adults and children on a mcg/m2 basis). There was no evidence of carcinogenicity in this study. Budesonide demonstrated a statistically significant increase in the incidence of gliomas at oral dose of 50 mcg/kg/day (approximately ¼ the maximum recommended daily inhalation dose on a mcg/m2 basis) for 104 weeks in Sprague-Dawley rats; no such changes were seen in male rats receiving oral doses of 10 and 25 mcg/kg/day (approximately 1/20 and 1/8 the maximum recommended daily inhalation dose on a mcg/m2 basis) or in female rats at oral doses up to 50 mcg/kg/day (approximately ¼ the maximum recommended human daily inhalation dose on a mcg/m2 basis). There was no evidence of carcinogenicity in two other 104-week carcinogenicity studies (conducted with same dose in previous study) in male Sprague-Dawley and Fischer rats. Compared with concurrent controls, a statistically significant increase in the incidence of hepatocellular tumors was observed in all three steroid groups (budesonide, prednisolone, triamcinolone acetonide) in these studies.
Budesonide did not demonstrate any mutagenic or clastogenic effect in 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.
Decreases in maternal body weight gain, prenatal vialibility, and viability of the young at birth and during lactation were observed following treatment with a dose of 20 mcg/kg/day (approximately 1/8 the maximum recommended daily inhalation dose in adults on a mcg/m2 basis).
An increased incidence of brain gliomas in male rats, in a carcinogenicity study, could not be verified in a repeat study in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.
Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.
Available clinical experience shows no indication that budesonide, or other glucocorticosteroids, induce brain gliomas or primary hepatocellular neoplasms in man.
In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not appear to be relevant in humans at the recommended doses.
Animal studies have also identified an involvement of excess prenatal glucocorticosteroids, in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.
For the management of bronchial asthma. Seasonal allergic and allergic/non allergic perennial rhinitis. Treatment and prevention of nasal polyps after polypectomy.
Budesonide aerosol is for oral inhalation.
When transferring patients to Budesonide from other devices, treatment should be inidividualised, whether once or twice daily dosing is being used. The drug and method of delivery should be considered.
Divided doses (twice daily): The dosage should be individualised.
The dose should always be reduced to the minimum needed to maintain good asthma control.
Adults (including elderly) and children over 12 years of age: When starting treatment, during periods of severe asthma and while reducing or discontinuing oral glucocorticoids, the dosage in adults should be 200-1,600 micrograms daily, in divided doses.
In less severe cases and children over 12 years of age, 200-800 micrograms daily, in divided doses, may be used. During periods of severe asthma, the daily dosage can be increased to up to 1,600 micrograms, in divided doses.
Children 12 years of age and under: 200-800 micrograms daily, in divided doses. During periods of severe asthma, the daily dose can be increased up to 800 micrograms.
Once daily dosage: The dosage should be individualized.
The dose should always be reduced to the minimum needed to maintain good asthma control.
Adults (including elderly) and children over 12 years of age: 200 micrograms to 400 micrograms may be used in patients with mild to moderate asthma who have not previously received inhaled glucocorticoids.
Up to 800 micrograms may be used by patients with mild to moderate asthma already controlled on inhaled steroids (e.g., budesonide or beclomethasone dipropionate), administered twice daily.
Children 12 years of age and under: 200 micrograms to 400 micrograms may be used 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), administered twice daily.
The patient should be transferred to once daily dosing at the same equivalent total daily dose; the drug and method of delivery should be considered. The dose should subsequently be reduced to the minimum needed to maintain good asthma control.
Patients should be instructed to take the once daily dose in the evening. It is important that the dose is taken consistently and at similar time each evening.
There are insufficient data to make recommendations for the transfer of patients from newer inhaled steroids to once daily Budesonide.
Patients, especially those receiving once daily treatment, should be advised that in case their asthma deteriorates (e.g., increased frequency of bronchodilator use or persistent respiratory symptoms), they should double their steroid dose by administering it twice daily, and should contact their doctor as soon as possible.
In patients where an increased therapeutic effect is desired, an increased dose of Budesonide is recommended because of the lower risk of systemic effects as compared with a combined treatment with oral glucocorticosteroids.
Note for Children: The growth and development of infants and children who are receiving prolonged treatment with inhaled or systemic corticosteroids should be followed carefully; use the lowest effective dose.
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 with Budesonide should be continued at the recommended dose to control the asthma.
Budesonide inhaler is contraindicated in the following cases: As primary treatment of status asthmaticus or other acute episodes/exacerbations of asthma or in patients with moderate to severe bronchiectasis.
Hypersensitivity to Budesonide, other steroids or any other ingredients of this product.
Not recommended for use in concomitant untreated active or quiescent pulmonary tuberculosis and in untreated fungal, bacterial, or systemic viral infections.
Risk of adrenal insufficiency while change from systemic to inhalation therapy: It is essential to be precautious when patients are transferred from systemically active corticosteroids to inhaled Budesonide, because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to aerosol Budesonide. Recovery of hypothalamic-pituitary-adrenal (HPA) function after withdrawal from systemic corticosteroids requires a number of months. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery or infections, particularly gastroenteritis. Although inhaled Budesonide may provide control of asthmatic symptoms during these episodes, it does not provide the systemic steroid which is necessary for coping with these emergencies.
During periods of stress or a severe asthmatic attack, patients, who have been withdrawn from systemic corticosteroids, should be instructed to immediately resume systemic steroids in dosages that were previously effective and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack. To assess the risk of adrenal insufficiency in emergency situations, routine tests of adrenal cortical function, including measurement of early morning and evening cortisol levels, should be performed periodically in all patients. An early morning resting cortisol level may be accepted as normal only if it falls at or near the normal mean level. In the majority of patients no significant adrenal suppression occurs until doses of 1,500 μg/day, by inhalation, are exceeded. Reduction of plasma cortisol levels has been reported in some patients who received 2,000 μg/day of inhaled Budesonide. In such patients the risks of developing adrenal suppression should be balanced against the therapeutic advantages and precautions should be taken to provide systemic steroid cover in situations of prolonged stress. Prolonged suppression of the HPA axis may eventually lead to systemic effects including growth retardation in children and adolescents.
Transfer of patients from systemic steroid therapy to Budesonide may unmask allergic conditions previously suppressed by the systemic steroid therapy, e.g., rhinitis, conjunctivitis, and eczema. These allergies should be symptomatically treated with antihistamine and/or topical preparations, including topical steroids.
Studies have shown that the combined administration of alternate-day prednisone systemic treatment and orally inhaled Budesonide increases the likelihood of HPA suppression compared to a therapeutic dose of either one alone. Therefore, Budesonide treatment should be used with caution in patients already on alternate-day prednisone regimens for any disease.
Systemic Absorption of Orally Inhaled Steroids: Because of the possibility of systemic absorption of orally inhaled corticosteroids, including Budesonide, patients should be monitored for symptoms of systemic effects such as mental disturbances, increased bruising, weight gain, cushingoid features, acneiform lesions and cataracts. If such changes occur, Budesonide should be discontinued slowly, consistent with accepted procedures for discontinuing oral steroids.
Candidiasis: The development of pharyngeal and laryngeal candidiasis is a cause of concern because the extent of its penetration into the respiratory tract is unknown. These infections may require treatment with appropriate antifungal therapy and/or discontinuation of treatment with Budesonide, depending on the severity of the infections.
Monitoring Asthma Control: Budesonide is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm. Patients will require a fast and short acting inhaled bronchodilator (e.g., salbutamol) to relieve acute asthmatic symptoms.
Patients should be instructed to contact their physicians immediately when episodes of asthma which are not responsive to bronchodilators occur during the course of treatment with Budesonide. During such episodes, patients may require therapy with systemic corticosteroids. There is no evidence that control of bronchial asthma can be achieved by the administration of Budesonide in amounts greater than the recommended dosages.
General: Proper Use of Drug: The patients should be instructed that Budesonide is a preventative agent which must be taken daily at the intervals recommended by their doctor and is not to be used as treatment for an acute asthmatic attack. Treatment with Budesonide inhalation aerosol should not be stopped abruptly, but tapered off gradually (as with other steroids). Patients should be advised to inform subsequent physicians of the prior use of corticosteroids.
Steroid Replacement: The replacement of a systemic steroid with Budesonide has to be gradual and carefully supervised by the physician since upon withdrawal, systemic symptoms (e.g., joint and/or muscle pain, lassitude, depression) may occur despite maintenance or improvement of respiratory function. The guidelines under Dosage & Administration should be followed in all such cases.
Long-term Effects: The long-term effects of Budesonide in human subjects are still unknown. In particular, the local effects of the agent on developmental or immunologic processes in the mouth, pharynx, trachea and lungs are unknown. There is also no information about the possible long-term systemic effects of the agent. During long-term therapy, HPA axis function and hematological status should be assessed periodically.
Pulmonary Infiltration by Eosinophils: Pulmonary infiltrates with eosinophils may occur in patients on Budesonide therapy. Although, it is possible that in some patients this state may become manifest because of systemic steroid withdrawal when inhalational steroids are administered, a causative role for Budesonide and/or its vehicle cannot be ruled out.
Effect on Infection: Patients on immunosuppressant drugs are more susceptible to infections than healthy individuals. Illnesses like chickenpox and measles can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. The mechanism of modulation of the risk of developing a disseminated infection with respect to the dose, route, and duration of corticosteroid administration is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled I.V. immunoglobulin (IVIG), as appropriate, may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.
Corticosteroids may mask some signs of infections and new infections may appear. A decreased resistance to localized infection has been observed during corticosteroid therapy. During long-term therapy, pituitary-adrenal function and hematological status should be periodically assessed. Exacerbation of asthma caused by infections is usually controlled by appropriate antibiotic treatment, by increasing the dose of inhaled Budesonide and if necessary, by giving a systemic steroid.
Hypothyroidism and Cirrhosis: There is an enhanced effect of corticosteroids on patients with hypothyroidism and in those with cirrhosis.
Concomitant Aspirin: Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.
Use in Pregnancy: Pregnancy and Teratogenic Effects: Glucocorticoids are known teratogens in rodent species and Budesonide is no exception. Teratogenicity studies have been carried out by the inhaled and oral routes in mice, rats and rabbits. In mice and rabbits, Budesonide showed effects at high dose levels typical of a potent corticosteroid, e.g., retardation of fetal growth and cleft palate. Similarly in rats Budesonide induced early embryonic death and fetal growth retardation at very high dose levels; however, no fetus with cleft palate was detected. Well-controlled trials relating to fetal risk in humans are not available. Administration during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus.
Pregnancy: US FDA Pregnancy Category B: Data on approximately 2,000 exposed pregnancies indicate no increased teratogenic risk associated with the use of inhaled budesonide. In animal studies, glucocorticosteroids have been shown to induce malformations (Refer to Pharmacology: Toxicology: Carcinogenesis, Mutagenesis and Impairment of Fertility under Actions).
This is not likely to be relevant for humans at the given recommended doses, but therapy with inhaled budesonide should be regularly reviewed and maintained at the lowest effective dose.
Budesonide should be administered only after weighing the potential benefits of the therapy against the potential risks to the mother and the fetus.
Inhaled glucocorticoids should be considered in preference to oral glucocorticoids because of the lower systemic effects at the doses required to achieve similar pulmonary responses. The general consensus view is that the management of asthma in pregnant patients should be the same as that of non-pregnant patients, and that poor oxygenation due to uncontrolled asthma represents a greater danger to the fetus than any potential harm associated with the drugs used to treat the disease. Asthma in pregnant women is generally treated with the same agents and regimens as in non-pregnant women with asthma. Infants of mothers treated with corticosteroids during pregnancy should be carefully monitored for hypoadrenalism.
Lactation: No reports describing the use of Budesonide during human lactation are available and the effects on the nursing infant from exposure to the drug in milk are unknown. The use of Budesonide, in nursing mothers, warrants caution because other corticosteroids are known to enter breast milk and it is assumed that Budesonide does so as well.
General: In general, inhaled corticosteroid therapy may be associated with dose dependent increases in the incidence of ocular complications, reduced bone density, suppression of HPA axis responsiveness to stress, and inhibition of growth velocity in children.
Inhaled corticosteroid treatment for asthma or rhinitis may exacerbate glaucoma. In patients with established glaucoma, who require long-term inhaled corticosteroid treatment, it is advisable to measure intraocular pressure before commencing the inhaled corticosteroid and to monitor it subsequently. In patients without established glaucoma, but with a potential for developing intraocular hypertension (e.g., the elderly), intraocular pressure should be monitored at appropriate intervals.
The prevalence of posterior sub-capsular and nuclear cataracts is probably low in elderly patients treated with inhaled corticosteroids, but increased in relation to the daily and cumulative lifetime dose. Co-factors such as smoking, ultraviolet B exposure, or diabetes may increase the risk. Children may be less susceptible.
A reduction in 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 adolescents taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression if any adolescent's growth appears slowed.
Osteoporosis and fractures are the major complications of long-term asthma treatment with parenteral or oral steroids. Inhaled corticosteroid therapy is also associated with dose dependent bone loss although the degree of risk is very much lesser than with oral steroid. This risk may be offset by estrogen replacement in postmenopausal women, and by titrating the daily dose of inhaled steroid to the minimum required to maintain optimal asthma control. It is not known yet whether the peak bone density achieved during youth is adversely affected, if substantial amounts of inhaled corticosteroid are administered prior to 30 years of age. Failure to achieve maximal bone density during youth could increase the risk of osteoporotic fracture when these individuals reach 60 years of age and older.
Paradoxical Bronchospasm: Similar to other inhalation therapy, the potential for paradoxical bronchospasm should be kept in mind. If it occurs, immediately discontinue the therapy and institute alternate treatment.
Adrenal Suppression: In the majority of patients, no significant adrenal suppression occurs until one exceeds doses of 1,500 μg/day by inhalation. Reduction of plasma cortisol levels has been reported in some patients who received 2,000 μg/day of inhaled Budesonide.
Gastrointestinal Tract: Therapeutic dosages may lead to growth of
C. albicans in the mouth and throat. Long-term studies have shown a dosage-dependent effect. Positive cultures for oral Candida may be present in up to 75% of patients, although the frequency of clinically apparent infection is considerably lower, varying between 0 and 43% with an average of 15%. In children, the incidence of oropharyngeal candidiasis is lower than in adults. In some studies, an overgrowth of
A. niger has been found in conjunction with
C. albicans. Such affected patients may find it helpful to rinse their mouths with water after using Budesonide.
A few patients on Budesonide have complained of hoarseness, dry mouth or throat irritation. It may be helpful to rinse out the mouth with water immediately after inhalation.
Immunologic Reactions: The replacement of systemic steroids with Budesonide may unmask symptoms of allergies which were previously suppressed by the systemic drug. Conditions such as allergic rhinitis and eczema may thus become apparent during Budesonide therapy after the withdrawal of systemic corticosteroids.
Rare cases of immediate and delayed hypersensitivity reactions, including urticaria, angioedema, rash and bronchospasm, have been reported after the use of Budesonide oral or intranasal inhalers; pruritus, erythema, and edema of the eyes, face, lips and throat also have been reported.
Other Effects: Reports of headache, light-headedness, dryness and irritation of the nose and throat, and unpleasant taste and smell have been received. Rarely there may be a loss of taste and smell sensations.
Dosage adjustments with concomitant systemic steroids must be considered in individual cases as per the regime and patient's response. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. Further data regarding other concomitant therapy with Budesonide inhaler are not available.
Store at temperatures not exceeding 30°C. Do not freeze.
R03BA02 - budesonide ; Belongs to the class of other inhalants used in the treatment of obstructive airway diseases, glucocorticoids.
Budesma MDI 200 mcg/actuation
300 metered dose x 1's
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