Source: Υπουργείο Υγείας (CY) Revision Year: 2017 Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids
ATC code: R03BA02
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.
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.
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.
Budesonide has also been shown to decrease airway reactivity to histamine and methacholine in hyper-reactive patients.
Therapy with inhaled budesonide has effectively been used for prevention of exercise-induced asthma.
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 1cm) has been observed. This generally occurs within the first year of treatment (see section 4.4.)
Studies in healthy volunteers with budesonide have shown dose related effects on plasma and urinary cortisol. At recommended doses, budesonide causes less effect on the adrenal function than prednisolone 10mg, as shown by ACTH tests.
Slit lamp examinations were performed in 157 children (5-16 years old), treated with an average daily dose of 504 μg for 3-6 years. Findings were compared with 111 age-matched asthmatic children. Inhaled budesonide was not associated with an increased occurrence of posterior subcapsular cataract.
Studies in healthy volunteers with inhaled budesonide have shown dose-related effect on plasma and urinary cortisol. At recommended doses, budesonide causes significantly less effect on adrenal function than prednisone 10 mg, as shown by ACTH test.
After inhalation via Miat haler about 25-30% of the metered dose is deposited in the lungs.
Of the fraction which is swallowed approximately 90% is inactivated by first pass metabolism in the liver.
The maximal plasma concentration after inhalation of 1 mg budesonide is about 3.5nmol/L and is reached after about 20minutes.
Budesonide undergoes an extensive degree (approximately 90%) of biotransformation in 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 CYP3A4, one of the cytochrome p450 enzymes.
In a study, 100mg ketoconazole taken twice daily, increased plasma levels of concomitantly administered oral budesonide (single dose of 10mg) on average, by 7.8-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected.
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 asthmatic children treated with inhaled budesonide (800 μg single dose), plasma concentration reached Cmax (4.85 nmol/L) at 13.8 minutes after inhalation, and then decreased rapidly; AUC was 10.3 nmol·h/L. The value for AUC is generally comparable to that observed in adults at the same dose, however, the Cmax value tends to be higher in children. Lung deposition in children (31% of the nominal dose) is similar to that measured in healthy adults (34% of nominal dose).
The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference of 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.
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 of 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 behavior at exposures below the teratogenic dose range.
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