Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Ferring Pharmaceuticals Ltd, Drayton Hall, Church Road, West Drayton, UB7 7PS
Pharmacotherapeutic group: Intestinal anti-inflammatory agents, Corticosteroids acting locally
ATC code: A07EA06
The exact mechanism of action of budesonide in the treatment of UC and MC is not fully understood. In general, budesonide inhibits many inflammatory processes including cytokine production, inflammatory cell activation and expression of adhesion molecules on endothelial and epithelial cells. At doses clinically equivalent to prednisolone, budesonide gives significantly less HPA axis suppression and has a lower impact on inflammatory markers.
Data from clinical pharmacology and pharmacokinetic studies indicate that the mode of action of Cortiment tablets is based on a local action in the gut.
MMX extended release technology is characterised by a multi-matrix structure covered by a gastro-resistant coating that dissolves in intestinal fluids having a pH greater than 7.
When the dosage form is administered, the gastro-protective layer protects the dosage form during transit through the stomach and duodenum up to the lower part of the intestine. When the protective layer is lost, the intestinal fluid then comes into contact with the hydrophilic matrix polymers, which start to swell until a viscous gel matrix is formed. The solvent that penetrates into the gel matrix dissolves the active ingredient from the lipophilic matrices. Budesonide is then released into the intestinal tract at a controlled rate throughout the colon.
Budesonide is a glucocorticoid used in the treatment of inflammatory bowel disease. It has a topical anti-inflammatory activity but does not reduce cortisol levels to the same extent as systemic glucocorticoids.
Two randomised, controlled phase III clinical trials including 1022 patients with mild to moderate active UC have been performed in adult patients. Two hundred fifty five (255) patients were treated for 8 weeks with Cortiment 9 mg per day. Patients included were either treatment naïve (42% ITT) or had failed on 5-ASA (58% ITT). Both studies included a reference arm, mesalazine (Asacol) and budesonide (Entocort), respectively to show assay sensitivity. The definition of remission applied in both studies was UCDAI score of ≤1, with 0 score for rectal bleeding and stool frequency, normal mucosa (no friability) and ≧1 point reduction in endoscopy score.
Effect of Cortiment 9mg tablet on Primary Endpoint:
| Study | Cortiment 9 mg Remission (%) | Placebo Remission (%) | P= |
| Study CB-01-02/01 | 17.9 | 7.4 | 0.0143 |
| Study CB-01-02/02 | 17.4 | 4.5 | 0.0047 |
Statistical difference versus placebo was reached for Cortiment 9 mg for both studies and the difference versus placebo was 10.4% and 12.9% respectively.
5-ASA is the Standard of Care for treatment of mild to moderate disease. Results of a head to head comparison with Cortiment and 5-ASA were not available. Therefore, the place in the therapeutic work-up remains to be established. Some patients may benefit from treatment initially with Cortiment.
Evidence for the indication microscopic colitis (collagenous colitis and lymphocytic colitis) is presented below. This evidence comes from studies on budesonide product Entocort. The systemic availability of this product is similar to that of budesonide product Cortiment (see section 5.2).
Two randomised, double-blind, placebo-controlled induction studies of six and eight weeks duration investigated the clinical and histological effects of budesonide 9 mg/day in the treatment of collagenous colitis. In the first study, 23 patients were randomised to budesonide 9 mg/day and 22 patients to placebo for 6 weeks. The rate of clinical remission was significantly higher (p<0.001) in the budesonide group than in the placebo group 86.9% vs. 13.6%. Histologic improvement was observed in 14 patients of the budesonide group (60.9%) and in one patient of the placebo group (4.5%; p<0.001). In the second study, 10 patients were randomised to budesonide for 8 weeks (9 mg/day 4 weeks, 6 mg/day 2 weeks, and 3 mg/day 2 weeks) and ten to placebo. All 10 patients receiving budesonide had a clinical response compared with two in the placebo group (p<0.001).
Two open-label studies (run-in phase of randomised, double-blind, placebo-controlled maintenance studies) investigated the efficacy of budesonide 9 mg/day during 6 weeks. In the first study, 46 patients (96%) achieved clinical remission within 2–30 (mean 6.4) days, with marked improvements in stool consistency. In the second study, of the 42 patients who commenced the study, 34 patients (81%) were in clinical remission (mean stool frequency of three or fewer per day) at week 6.
Evidence for this indication is limited. One randomised, double-blind placebo-controlled study was carried out in 15 lymphocytic colitis patients. Eleven subjects were treated with budesonide 9 mg/day and four patients received placebo for 8 weeks. A clinical response (defined as at least 50% improvement in the frequency of bowel movements) was seen in 25% of the placebo group vs. 91% in the budesonide group (p=0.03).
Cortiment was not studied in the paediatric population.
After oral dosing of plain micronised compound, absorption seems to be complete. A large proportion of the unformulated drug is absorbed from the ileum and ascending colon.
Systemic availability of Budesonide following a single administration of Cortiment tablets in healthy volunteers was compared to that of Entocort and the result was similar, about 10%, due to first pass metabolism in the liver. Maximum plasma concentrations of budesonide are approximately 1.3-1.8 ng/ml at 13-14 hours post administration. Concomitant administration of Cortiment tablets with food had no clinically relevant effect on absorption. It has been shown that there is no potential for drug accumulation on repeated dosing.
Budesonide has a high volume of distribution (about 3 L/kg). Plasma protein binding averages 85–90%.
Budesonide undergoes extensive biotransformation in the liver to metabolites of low glucocorticoid activity. The glucocorticoid 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 of budesonide is rate limited by absorption. Budesonide has a high systemic clearance (about 1.2 L/min).
No data or experience is available with respect to the pharmacokinetics of Cortiment tablets in the paediatric population.
A preclinical toxicology and toxicokinetic bridging study, comparing Cortiment tablets with an existing prolonged release budesonide formulation (Entocort EC 3 mg capsules, AstraZeneca) in cynomolgous monkeys has confirmed that Cortiment tablets result in a delayed peak exposure and reduced total exposure compared to the existing formulation of budesonide, while maintaining a superimposable toxicological profile.
Preclinical data have shown that budesonide produces effects less severe or similar to other glucocorticoids, such as weight increase, atrophy of the adrenal glands and thymus and effects on the leucocyte count. As with other glucocorticosteroids, and dependent on the dose and duration and the diseases concerned, these steroid effects may also be relevant in man.
Budesonide had no effect on fertility in rats. In pregnant rats and rabbits, budesonide, like other glucocorticosteroids, has been shown to cause foetal death and abnormalities of foetal development (smaller litter size, intrauterine foetal growth retardation and skeletal abnormalities). Some glucocorticoids have been reported to produce cleft palate in animals. The relevance of these findings to man has not been established (see also section 4.6).
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 (in female rats) were observed. These tumours are probably due to the specific steroid receptor action, increased metabolic burden and anabolic effects on the liver, effects which are also known from rat studies with other glucocorticosteroids and therefore represent a class effect in this species.
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