Pharmacotherapeutic group: Intestinal anti-inflammatory agent, corticosteroids acting locally. ATC code: A07EA06.
Pharmacology: Pharmacodynamics: The exact mechanism of action of budesonide in the treatment of ulcerative colitis/proctosigmoiditis is not fully understood. Data from clinical pharmacology and controlled clinical trials strongly indicate that the mode of action of budesonide is predominantly based on a local action in the gut. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect.
At a dosage of 2 mg budesonide, applied rectally, which is clinically equieffective with systemically acting glucocorticoids, budesonide leads to practically no suppression of the HPA axis.
Budenofalk 2mg rectal foam investigated up to the daily dosage of 4 mg budesonide showed virtually no influence on the plasma cortisol level.
Pharmacokinetics: General aspects of budesonide: Absorption: After oral application, the systemic availability of budesonide is about 10%. After rectal administration the areas under the concentration time curves are about 1.5-fold higher than in historical controls considering the identical oral budesonide dose. Peak levels are obtained after an average of 2 - 3 hours after administering Budenofalk 2mg rectal foam.
Distribution: Budesonide has a high volume of distribution (about 3 l/kg). Plasma protein binding averages 85-90%.
Biotransformation: Budesonide undergoes extensive biotransformation in the liver (approximately 90%) to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone - both of which are formed via CYP3A - is less than 1% of that of budesonide.
Elimination: The average elimination half-life after oral administration is about 3 - 4 hours. The mean clearance rate is about 10 - 15 L/min for budesonide, determined by HPLC-based methods.
Spread: A scintigraphic investigation with technetium-marked Budenofalk rectal foam in patients with ulcerative colitis showed that the foam spreads out over the entire sigmoid.
Special patient groups (liver disease): Dependent on the type and severity of liver disease the metabolism of budesonide might be decreased.
Toxicology: Preclinical safety data: Preclinical investigations on dogs have shown that Budenofalk 2mg rectal foam is well tolerated locally.
Preclinical data in acute, subchronic and chronic toxicological studies with budesonide showed atrophies of the thymus gland and adrenal cortex and a reduction especially of lymphocytes. These effects were less pronounced or at the same magnitude as observed with other glucocorticosteroids. These steroid effects might also be of relevance in man.
Budesonide had no mutagenic effects in a number of in vitro and in vivo tests.
A slightly increased number of basophilic hepatic foci were observed in chronic rat studies with budesonide, and in carcinogenicity studies there was an increased incidence of primary hepatocellular neoplasms, astrocytomas (in male rats) and mammary tumours (female rats) observed. These tumours are probably due to the specific steroid receptor action, increased metabolic burden on the liver and anabolic effects, effects which are also known from other glucocorticosteroids in rat studies and therefore represent a class effect. No similar effects have ever been observed in man for budesonide, neither in clinical trials nor from spontaneous reports.
In general, preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.
In pregnant animals, budesonide, like other glucocorticosteroids, has been shown to cause abnormalities of foetal development, but the relevance to man has not been established (see also Use in Pregnancy & Lactation).