Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Sandoz Limited, Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR, United Kingdom
Pharmacotherapeutic group: Decongestants and other nasal preparations for topical use, Corticosteroids
ATC Code: R01AD05
Budesonide is a glucocorticosteroid with a strong topical anti-inflammatory effect on the nasal mucosa and weak systemic effects after topical administration.
Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (e.g. mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g. histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic mediated inflammation. They also reduce cytokines, leukotrienes and chemokines (e.g. IL-1 to IL-6, RANTES, TNF-α, IFN-γ and GM-CSF) which are secreted by inflammatory cells. Budesonide binds to glucocorticoid receptors resulting in a complex which acts as a transcription factor by either down-regulating proinflammatory mediators or up-regulating anti-inflammatory mediators. There are believed to be approximately 10–100 steroid-responsive genes per cell.
The therapeutic efficacy of budesonide Nasal Spray has been evaluated in several thousand adults and children. Most studies were conducted with delivered doses of budesonide of 32 to 256 μg intranasal once daily. Examples of representative studies evaluating the use of budesonide for the treatment of children with seasonal and perennial allergic rhinitis studies are provided below. The primary efficacy variable was the combined nasal symptoms score (CNSS), which is the sum of the individual nasal symptom scores for three nasal symptoms (congestion, runny nose and sneezing, each rated on a scale of 0-3).
A 2-week randomized double-blind, placebo-controlled, parallel-group study evaluated the efficacy and safety of budesonide nasal spray 16, 32 and 64 μg once daily in 400 children (aged 2 to 5 years) with allergic rhinitis (seasonal or perennial). There was a marked reduction from baseline CNSS in all treatment groups, including placebo. The difference between budesonide nasal spray 64 μg and placebo treatment was not statistically significant.
A 6-week randomized double-blind, placebo-controlled, parallel-group study evaluated the efficacy and safety of budesonide nasal spray 128 μg once daily in 202 children (aged 6-16 years) with perennial allergic rhinitis. Primary efficacy variables were CNSS and values of peak nasal inspiratory flow (PNIF) measurements. Budesonide nasal spray improved the CNSS and PNIF statistically significantly more than placebo. Onset of action for budesonide nasal spray was 12 hours after first dose for CNSS and 48 hours for PNIF.
In a randomized, double-blind, placebo-controlled growth study, 229 pre-pubertal children ages 4 years to 8 years received budesonide nasal spray 64 mcg once daily or placebo for 12 months after a 6-month baseline period. In this study, growth velocity was similar between budesonide nasal spray and placebo treatment groups after 12 months of therapy: the mean difference in growth velocity (placebo-budesonide nasal spray) was 0.27 cm/year (95% confidence interval: –0.07 to 0.62).
In the recommended dosages budesonide nasal spray does not cause clinical relevant changes in basal plasma cortisol concentrations or to ACTH stimulation. In healthy volunteers a dose dependent suppression of plasma cortisol- and urinary cortisol concentrations were seen after short term administration of budesonide nasal spray.
The systemic availability of budesonide from RHINOCORT AQUA, with reference to the metered dose, is 33%. In adults, the maximal plasma concentration after administration of 256 micrograms budesonide from RHINOCORT AQUA is 0.64 nmol/L and is reached within 0.7 hours. The Area Under Curve (AUC) after administration of 256 micrograms budesonide from RHINOCORT AQUA is 2.7 nmol*h/L in adults.
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. Budesonide does not undergo local metabolic inactivation in the nose.
The metabolites are excreted as such or in conjugated form mainly via the kidneys. No intact budesonide has been detected in the urine. Budesonide has a high systemic clearance (approximately 1.2 L/min) and the plasma half-life 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. The Area Under Curve (AUC) after administration of 256 micrograms budesonide from RHINOCORT AQUA is 5.5 nmol*h/L in children, indicating a higher systemic glucocorticosteroid exposure in children than in adults. At clinically recommended doses, the pharmacokinetics of budesonide are dose-proportional and plasma exposure is correlated to the weight of the patient. Therefore this should be taken into account when establishing paediatric doses.
Non-clinical data reveal no special hazard for humans at therapeutic doses based on studies of chronic toxicity, genotoxicity and carcinogenicity.
Glucocorticosteroids including budesonide have produced teratogenic effects in animals, including cleft palate and skeletal abnormalities. Similar effects are considered unlikely to occur in humans at therapeutic doses.
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