Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Dr. Falk Pharma GmbH, Leinenweberstr. 5, 79108, Freiburg, Germany
Pharmacotherapeutic group: Glucocorticosteroid
ATC code: A07EA06
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 Budenofalk 3mg capsules is predominantly based on a local action in the gut. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. At doses clinically equivalent to systemically acting glucocorticosteroids, budesonide gives significantly less HPA axis suppression and has a lower impact on inflammatory markers.
Budenofalk 3mg capsules show a dose-dependent influence on cortisol plasma levels which is at the recommended dose of 9 mg budesonide/day significantly smaller than that of clinically equivalent effective doses of systemic glucocorticosteroids.
In a randomized, double-blind, double-dummy trial in patients with mild to moderate Crohn’s disease (200 < CDAI < 400) affecting the terminal ileum and/or the ascending colon the efficacy of 9 mg budesonide in a single daily dose (9 mg OD) was compared to the treatment with 3 mg budesonide given three times daily (3 mg TID).
The primary efficacy endpoint was the proportion of patients in remission (CDAI<150) at week 8.
A total of 471 patients were included in the study (full analysis set, FAS), 439 patients were in the per protocol (PP) analysis set. There were no relevant differences in the baseline characteristics in both treatment groups. At the confirmatory analysis, 71.3% of the patients were in remission in the 9 mg OD group and 75.1% in the 3 mg TID group (PP) (p=0.01975) demonstrating the non-inferiority of 9 mg budesonide OD to 3 mg budesonide TID.
No drug-related serious adverse events were reported.
In a prospective, double-blind, randomised, multicentre trial, 207 patients with autoimmune hepatitis (AIH) without cirrhosis were treated with initial daily doses of 9 mg/d budesonide (n=102) for up to 6 months or 40 mg/d prednisone (tapered to 10 mg/d, n=105). Upon biochemical remission, the budesonide dose was reduced to 6 mg/d. Patients also received 1-2 mg/kg/d azathioprine throughout the study. The composite primary endpoint was complete biochemical remission (i.e. normal serum levels of aspartate- and alanine-aminotransferase) without occurrence of predefined steroid-specific side effects at 6 months. This primary endpoint was achieved in 47% of the patients in the budesonide group and 18% of the patients in the prednisone group (p<0.001).
Regarding secondary efficacy variables, at 6 months, complete biochemical remission occurred in 60% and 39% of the patients in the budesonide group and in the prednisone group, respectively (p=0.001). 72% and 47% of the patients in the budesonide group and in the prednisone group, respectively, did not develop steroid- specific side-effects (p<0.001). The mean decrease in IgG and γ-globulin concentrations and the decrease in the rates of patients with elevated IgG and - γ-globulin concentrations did not show any differences between treatment groups.
An open-label, follow-up treatment of additional 6 months was offered to all patients after the controlled, double-blind phase. A total of 176 patients proceeded to this open-label phase and received 6mg/d budesonide in combination with 1-2 mg/kg/d azathioprine. Rates of patients with biochemical remission and rates of patients with complete response (not statistically significant) were still higher in the original budesonide group (complete response rate 60% and biochemical remission 68.2% at the end of the open label phase) than in the original prednisone group (complete response rate 49% and biochemical remission 50.6% at the end of the open label phase).
The safety and efficacy of budesonide in 46 paediatric patients (11 males and 35 females) aged 9 to 18 years were studied as a subset of patients of the above mentioned clinical study. 19 paediatric patients were treated with budesonide and 27 received the active control (prednisone) for induction of remission with a daily dose of 9 mg budesonide. After 6 months in the study, 42 paediatric patients continued for a further 6 months on open label, follow up treatment with budesonide.
The rate of complete responders (defined as biochemical response, i.e. normalisation of liver transaminases (ASAT, ALAT) and lack of steroid-specific side-effects) in patients aged ≤ 18 years was considerably lower compared to adult patients. There was no significant difference seen between the treatment groups. After follow up treatment with budesonide for a further 6 months, the rate of paediatric patients with complete response was still slightly lower compared to adult patients but the difference between the age groups was much smaller. There was no significant difference in the rate of complete responders between those originally treated with prednisone and those treated continuously with budesonide.
Two randomised controlled studies with Budenofalk 3 mg capsules included patients in the age range of 8 to 19 years with mildly to moderately active Crohn’s disease (PCDAI [paediatric CD activity index] 12.5–40) with ileal, ileocolonic or isolated colonic inflammation.
In one study a total of 33 patients were treated with 9 mg budesonide (3 mg TID) daily for 8 weeks followed by 6 mg budesonide daily during week 9 and 3 mg budesonide daily in week 10 or with prednisone (40 mg/d for two weeks, tapered to zero in steps of 5 mg/week). Remission (PCDAI ≤ 10) was achieved in 9/19 (47.3%) of the patients in the budesonide group (both at week 4 and 12) and 8/14 (57.1%, at week 4) and 7/14 (50%, at week 12) of the patients in the prednisone group.A second study including 70 children with CD compared two dosing schedules of budesonide: Patients in group 1 were treated for 7 weeks with 9 mg /day budesonide (3 mg TID) followed by 6 mg/day budesonide (3 mg BID) for additional 3 weeks. In group 2, patients were treated for 4 weeks with 12 mg/day budesonide (3 mg TID and 3 mg OD) and thereafter for each of 3 weeks with 9 mg/day budesonide (3 mg TID) and 6 mg/day budesonide (3 mg BID), respectively. Mean decrease of PCDAI at week 7 was defined as primary efficacy end point. There was a relevant decrease in the PCDAI in both treatment groups. The decrease was more pronounced in group 2 but the difference between the groups did not reach statistical significance (n.s.).
Secondary efficacy endpoints: Improvement (defined as a decrease of PCDAI ≥10 points) was seen in 51.4% of the patients in group 1 and 74.3% of the patients in group 2 (n.s.); remission (PCDAI ≤12.5) was found in 42.9% of the patients in the first group versus 65.7% in the second group (n.s.).
Budenofalk 3mg capsules, which contain gastric juice resistant granules, have – due to the specific coating of the granules – a lag phase of 2-3 hours. In healthy volunteers, as well as in patients with Crohn’s disease, mean maximal budesonide plasma concentrations of 1-2 ng/ml were seen at about 5 hours following an oral dose of Budenofalk 3mg capsules at a single dose of 3 mg, taken before meals. The maximal release therefore occurs in the terminal ileum and caecum, the main area of inflammation in Crohn’s disease.
In ileostomy patients release of budesonide from Budenofalk 3mg is comparable to healthy subjects or Crohn’s disease patients. In ileostomy patients it was demonstrated that about 30–40% of released budesonide is still found in the ileostomy bag, indicating that a substantial amount of budesonide from Budenofalk 3mg will be transferred normally into the colon.
Concomitant intake of food may delay release of granules from stomach by 2-3 hours, prolonging the lag phase to about 4-6 hours, without change in absorption rates.
Budesonide has a high volume of distribution (about 3 l/kg). Plasma protein binding averages between 85 and 90%.
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 16ɑ-hydroxyprednisolone, is less than 1 of that of budesonide.
The average elimination half-life is about 3-4 hours. The systemic availability in healthy volunteers as well as in fasting patients with Crohn’s disease is about 9-13 %. The clearance rate is about 10-15 l/min for budesonide, determined by HPLC-based methods.
A relevant proportion of budesonide is metabolised in the liver. The systemic exposure of budesonide might be increased in patients with impaired hepatic functions due to a decrease in budesonide metabolism by CYP3A4. This is dependent on the type and severity of liver disease.
Pharmacokinetics of budesonide were evaluated in 12 paediatric patients with Crohn’s disease (age: 5 to 15 years). Following multiple dose administration of budesonide (3 × 3 mg of budesonide for one week) mean AUC of budesonide during the dosing interval was about 7 ng h/ml, and Cmax about 2 ng/ml. Disposition of oral budesonide (3 mg, single dose) in paediatric patients was similar to that in adults.
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. Like with other glucocorticosteroids, and in dependence of the dose and duration and in dependence of the diseases 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 an increased incidence of primary hepatocellular neoplasms, astrocytomas (in male rats) and mammary tumours (female rats) were 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 fetal development. But the relevance to man has not been established (see also section 4.6).
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