Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Tillotts Pharma UK Limited., Wellingore Hall, Wellingore, Lincolnshire, LN5 0HX, United Kingdom
Pharmacotherapeutic group: Corticosteroids acting locally
ATC code: A07EA06
Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect.
The exact mechanism of budesonide in the treatment of Crohn’s disease is not fully understood.
Data from clinical pharmacology studies and controlled clinical trials strongly indicate that the mode of action of Entocort CR Capsules is based, at least partly, on a local action in the gut. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. At doses clinically equivalent to prednisolone, budesonide gives significantly less HPA axis suppression and has a lower impact on inflammatory markers.
At recommended doses, Entocort CR Capsules caused significantly less effect than prednisolone 20–40 mg daily on morning plasma cortisols; on 24 hour plasma cortisol (AUC0–24h) and on 24 hour urine cortisol levels.
ACTH tests have shown Entocort CR Capsules to have significantly less effect than prednisolone on adrenal functions.
HPA axis function. At recommended doses, Entocort CR Capsules cause significantly less effect than prednisole 20-40 mg daily on morning plasma cortisol, on 24-hour plasma cortisol (AUC 0-24 h) and on 24-hour urine cortisol. Also ACTH tests have shown that Entocort CR Capsules, compared with prednisolone, have significantly less impact on the adrenal function. Children with Crohn’s disease have a slightly higher systemic exposure and cortisol suppression than adults with Crohn’s disease.
Long-term studies have not been performed in children treated with Entocort CR Capsules. In a study evaluating the effect of Entocort CR Capsules on cortisol suppression in 8 children (range 9–14 years) and 6 adults , the oral administration of 9 mg Entocort CR Capsules for 7 days induced a mean cortisol suppression (± SD) of 64% (±18%) in children and 50% (±27%) in adults with respect to baseline values. No clinically relevant findings in terms of safety have been reported. (Study 08-3044)
A study performed in children with mild to moderate Crohn’s disease (CDAI ≥ 200) compared the activity of Entocort CR Capsules at the dose of 9 mg once daily with that of prednisolone, administered at tapering doses, starting from 1 mg/kg. 22 patients were treated with Entocort CR Capsules and 26 patients were treated with the reference drug prednisolone. After 8 weeks of treatment, 70.8% of patients treated with prednisolone reached the endpoint (CDAI ≤ 150), as compared to 54.5% of subjects treated with Entocort CR Capsules, the difference was not statistically significant (p = 0.13). In the course of the study, adverse events were observed in 96% of patients treated with prednisolone and 91% of patients treated with Entocort CR Capsules. The nature of these adverse events was similar in both study arms, but the incidence of glucocorticoid-related side-effects (such as acne and moon face) was lower in patients treated with Entocort CR Capsules. (Study SD-008-3037)
Study D9422C0001 was an open-label, uncontrolled study designed to evaluate Entocort in 108 pediatric patients (children and adolescents aged 5 to 17 years) diagnosed with mild to moderate Crohn’s disease of the ileum and/or ascending colon. The median duration of treatment exposure of Entocort of 58 days (range: 5 days to 90 days). Patients were dosed with oral Entocort once daily according to bodyweight, patients weighing ≤25 kg received 6 mg once daily for 8 weeks; patients weighing >25 kg received 9 mg once daily for 8 weeks. During the 8 weeks of treatment there was a reduction in the mean (±SD) PCDAI score from 19.1 (±10.1) to 9.1 (±8.5), indicating an improvement in disease activity; with an improvement in mean (±SD) IMPACT 3 score from 132.1 (±18.8) to 140.9 (±16.9). AEs were observed at a similar frequency and severity as seen in adults, and were mostly related to Crohn’s disease, puberty and possible GCS related side effects.
Study D9422C00002 was an open-label, un-comparative study designed to evaluate Entocort 6 mg once daily as maintenance treatment in 50 pediatric patients (children and adolescents aged 5 to 17 years) with a diagnosis of mild to moderate Crohn’s disease of the ileum and/or ascending colon who were in clinical remission (PCDAI ≤10). Treatment consisted of a 12-week maintenance treatment phase of 6 mg once daily, a 2-week taper phase to 3 mg once daily. The median duration of treatment exposure of Entocort was 98.5 days (range: 11 days to 135 days). Most patients remained in the clinical remission stage, as there were no major changes in the mean PCDAI composite score or IMPACT 3 score. Mean (SD) PCDAI was 4.85 (3.62) at baseline and 6.89 (8.08) after 12 weeks of maintenance treatment with Entocort 6 mg daily. At the same points in time the mean IMPACT3 score was 145.62 (12.43) and 146.98 (15.48), respectively. AEs were observed at a similar frequency and severity as seen in adults, and were mostly related to Crohn’s disease, puberty and possible GCS related side effects.
After oral dosing of plain micronised compound, absorption is rapid and seems to be complete. A large proportion of the drug is absorbed from the ileum and ascending colon. Systemic availability in healthy subjects is approximately 9–12% for Entocort CR Capsules. This is similar to the systemic availability of plain micronised budesonide, indicating complete absorption. In patients with active Crohn’s disease systemic availability is approximately 12–20% at the start of treatment.
Budesonide has a high volume of distribution (about 3 L/kg). Plasma protein binding averages 85–90%. In healthy volunteers mean maximal plasma concentrations of 5–10 nmol/L were seen at 3–5 hours following a single oral dose of Entocort CR Capsules 9 mg.
Budesonide then undergoes extensive biotransformation in the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxy-prednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.
Elimination is rate limited by absorption. The average terminal half-life is 4 hours. Budesonide has a high systemic clearance (about 1.2 L/min).
In a study comparing the pharmacokinetics of Entocort CR Capsules in 8 children (range 9–14 years) and 6 adults, Entocort CR Capules 9 mg for 7 days induced a systemic exposure (AUC) that was 17% higher in children than in adults, with maximum concentrations (Cmax) 50% higher in children than in adults (mean AUC ± SD: children 41.3 nmol/L ± 21.2; adults 35.0 nmol/L ± 19.8. Mean Cmax ± SD: children 5.99 nmo/L ± 3.45; adults 3.97 nmo/L ± 2.11.) (Study 08-3044).
Results from acute, subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe or similar to those observed after administration of other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.
Budesonide, evaluated in six different test systems, did not show any mutagenic or clastogenic effects.
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 on 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 the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.
Available clinical experience shows that there are no indications that budesonide or other glucocorticosteroids induce brain gliomas or primary hepatocellular neoplasms in man.
The toxicity of Entocort CR Capsules, with focus on the gastro-intestinal tract, has been studied in cynomolgus monkeys in doses up to 5 mg/kg after repeated oral administration for up to 6 months. No effects were observed in the gastrointestinal tract, neither at gross pathology nor in the histopathological examination.
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