Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids.
ATC Code: RO3BA02.

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.

Topical anti-inflammatory effect

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

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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 hyperreactive patients.

Exercise-induced asthma
Therapy with inhaled budesonide has effectively been used for prevention of exercise- induced asthma.

Growth

In short term studies a small and generally transient reduction in growth has been observed, which usually occurs within the first year of treatment. Long-term observational studies suggest that children and adolescents treated with inhaled corticosteroids on average achieve their adult target height. However, in one study children who had been treated with high dose inhaled budesonide via a dry powder inhaler (400 micrograms daily) for up to 6 years without titration to the lowest effective dose were found on average to be 1.2 cm shorter as adults than those treated with placebo over the same period. See section 4.4 about titration to the lowest effective dose and about monitoring the growth in children.

Influence on plasma cortisol concentration

Studies in healthy volunteers with Budicort Respules have shown dose-related effect on plasma and urinary cortisol. At recommended doses, Budicort Turbuhaler, causes significantly less effect on adrenal function than prednisone 10 mg, as shown by ACTH test.

Paediatric population

Clinical – asthma
The efficacy of Budicort Respules has been evaluated in a large number of studies, and it has been shown that Budicort Respules 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.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
In adults the systemic availability of budesonide following administration of Pulmicort 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.
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Distribution

Budesonide has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85 - 90%.

Biotransformation

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.

Elimination

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.

Linearity
The kinetics of budesonide are dose-proportional at clinically relevant doses.
In a study, 100 mg ketoconazole taken twice daily, increased plasma levels of concomitantly administered oral budesonide (single dose of 10 mg) on average, by 7.8-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected.


Paediatric population:
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 Budicort Respules, 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.
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