Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Breath Limited, Whiddon Valley, Barnstaple, North Devon, EX32 8NS, United Kingdom
Pharmacotherapeutic group: Other drugs for obstructive airways diseases, inhalant, Glucocorticoids
ATC code: R03 BA 02
Budesonide is a glucocorticosteroid with a powerful local anti-inflammatory action.
The precise mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory effects (including T-cells, eosinophilic cells and mast cells) such as inhibition of the release of inflammatory mediators and inhibition of cytokine-mediated immune response, are probably important. The strength of budesonide, measured as affinity for glucocorticoid receptors, is approximately 15 times stronger than that of prednisolone.
A clinical trial with asthma patients in which inhaled and oral budesonide was compared with placebo, showed statistically significant effects of inhaled budesonide, but not of oral budesonide. The therapeutic effect of normally used doses of inhaled budesonide may therefore chiefly be explained by a direct effect on the airways.
Budesonide has demonstrated an anti-anaphylactic and anti-inflammatory effect in challenge tests in experimental animals and in patients. This effect has manifested itself as reduced bronchial obstruction in both the immediate and the later allergic reaction.
It was also demonstrated that budesonide reduces the airways' reactivity to histamine and metacholine in hyperreactive patients. Treatment with inhaled budesonide has been used to effectively prevent exercise-induced asthma.
Studies in healthy volunteers with inhaled budesonide have shown dose-related effect on plasma and urinary cortisol. At recommended doses, inhaled budesonide causes significantly less effect on adrenal function than prednisone 10 mg, as shown by ACTH test. No clinically relevant changes in the plasma cortisol values or response to ACTH stimulation were observed when budesonide was given in doses up to 1600 µg daily for 3 months to adults and up to 800 µg daily to children. Long-term monitoring for up to 52 weeks confirmed that the HPA axis was not suppressed.
The efficacy of budesonide nebuliser suspension has been evaluated in a large number of studies, and it has been shown that budesonide nebuliser suspension is effective both in adults and children as once- or twice-daily medication for prophylactic treatment of persistent asthma. Some examples of representative studies are given below.
A number of studies in children with croup have compared budesonide nebuliser suspension with placebo. Examples of representative studies evaluating the use of budesonide for the treatment of children with croup are given below.
A randomized, double-blind placebo-controlled trial in 87 children (aged 7 months to 9 years), admitted to hospital with a clinical diagnosis of croup, was conducted to determine whether budesonide nebuliser suspension improves croup symptom scores or shortens the duration of stay in hospital. An initial dose of budesonide nebuliser suspension (2 mg) or placebo was given followed by either budesonide 1 mg or placebo every 12 hours. Budesonide nebuliser suspension statistically significantly improved croup score at 12 and 24 hours and at 2 hours in patients with an initial croup symptom score above 3. There was also a 33% reduction in the length of stay.
A randomized, double-blind, placebo-controlled study compared the efficacy of budesonide nebuliser suspension and placebo in the treatment of croup in 83 infants and children (aged 6 months to 8 years) admitted to hospital for croup. Patients received either budesonide 2 mg nebuliser suspension or placebo every 12 h for a maximum of 36 h or until discharge from hospital. The total croup symptom score was assessed at 0, 2, 6, 12, 24, 36 and 48 hours after the initial dose. At 2 hours, both the budesonide nebuliser suspension and placebo groups showed a similar improvement in croup symptom score, with no statistically significant difference between the groups. By 6 hours, the croup symptom score in the budesonide nebuliser suspension group was statistically significantly improved compared with the placebo group, and this improvement versus placebo was similarly evident at 12 and 24 hours.
Both asthma and inhaled glucocorticosteroids may affect the growth in length. The effect of Budesonide Nebuliser Suspension on the growth in length was studied in 519 children (from 8 months to 9 years) in three prospective, randomised, open, non-blinded studies. The studies did not show any significant difference in the growth in length of children treated either with Budesonide Nebuliser Suspension or with conventional asthma therapy. Two studies (N=239 and 72 patients, respectively) showed 7 mm and 8 mm greater growth after one year of treatment with Budesonide Nebuliser Suspension compared with traditional asthma therapy (not statistically significant), while one study (N=208) showed a growth in length that after one year was 8 mm smaller in the Budesonide Nebuliser Suspension group than in the group of conventional asthma treatment (statistically significant difference).
In adults the systemic availability of budesonide following administration of Budesonide Nebuliser Suspension via a jet nebuliser is approximately 15% of the nominal dose and 40% to 70% of the dose delivered to the patients. A minor fraction of the systemically available drug comes from swallowed drug. The maximal plasma concentration, occurring about 10 to 30 min after start of nebulisation is approximately 4 nmol/L after a single dose of 2 mg.
Budesonide has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85-90%.
Budesonide undergoes an extensive degree (~90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.
The metabolites of budesonide are excreted as such or in conjugated form mainly via the kidneys. No unchanged budesonide has been detected in the urine. Budesonide has high systemic clearance (approximately 1.2 L/min) in healthy adults, and the terminal half-life of budesonide after iv dosing averages 2-3 hours.
The kinetics of budesonide are dose-proportional at clinically relevant doses.
Budesonide has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults. In 4-6 years old asthmatic children, the systemic availability of budesonide following administration of Budesonide Nebuliser Suspension via a jet nebuliser (Pari LC Jet Plus with Pari Master compressor) is approximately 6% of the nominal dose and 26% of the dose delivered to the patients. The systemic availability in children is about half of that in healthy adults. The maximal plasma concentration, occurring approximately 20 min after start of nebulisation is approximately 2.4 nmol/L in 4-6 years old asthmatic children after a 1 mg dose. The exposure (Cmax and AUC) of budesonide following administration of a single 1 mg dose by nebulisation to 4-6 year old children is comparable to that in healthy adults given the same delivered dose by the same nebuliser system.
Preclinical data revealed no special hazard for humans in the therapeutic dose range based on studies of chronic toxicity, genotoxicity and carcinogenicity.
Glucocorticoids, including budesonide, have produced teratogenic effects in animals, including cleft palate and skeletal abnormalities. Similar effects are considered unlikely to occur in humans at the recommended dose levels.
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