Published in:
01-10-2002 | Adis Drug Evaluation
Budesonide (Entocort® EC Capsules)
A Review of its Therapeutic Use in the Management of Active Crohn’s Disease in Adults
Published in: Drugs | Issue 15/2002
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Abstract
Budesonide (Entocort® EC Capsules) is an oral corticosteroid with a high degree of topical activity and low systemic bioavailability (≈11%). This action is achieved by a high affinity for the glucocorticoid receptor and an extensive first-pass hepatic metabolism. The budesonide capsule has been formulated to dissolve in a pH dependent manner, delivering most of the drug to the ileum and ascending colon, areas of the intestine most commonly affected by Crohn’s disease.
In large (n ≥ 176), well designed clinical trials of 10 to 12 weeks’ duration in patients with active, mild to moderate Crohn’s disease, budesonide (9 mg/day) was significantly more effective in inducing remission than placebo or mesalazine (mesalamine) slow release, and demonstrated similar efficacy to recommended dosages of prednisolone. Results of health-related quality-of-life assessments support clinical data, showing a significantly greater improvement among patients treated with budesonide than with placebo or mesalazine slow release.
Oral budesonide was well tolerated in clinical trials of up to 16 weeks’ duration. In these studies, the incidence of adverse events associated with budesonide (9 mg/day) was similar to that seen with placebo and mesalazine slow release. The rate of glucocorticoid-related adverse effects observed with budesonide was significantly less than that reported with prednisolone.
Conclusion: Oral budesonide 9 mg/day offers efficacy that is superior to mesalazine slow release and placebo, and similar to prednisolone in the treatment of patients with active mild to moderate Crohn’s disease involving the ileum and/or ascending colon. Budesonide is generally well tolerated and the incidence of adverse events is similar to that seen with placebo or mesalazine slow release. Glucocorticoid-related adverse effects are significantly less frequent during short-term therapy with budesonide than with prednisolone. Thus, for the medical management of patients with active mild to moderate Crohn’s disease, oral budesonide has superior efficacy to mesalazine slow release and a more favourable tolerability profile than prednisolone.
Pharmacodynamic Properties
Budesonide is a nonhalogenated corticosteroid with a high affinity for the glucocorticoid receptor (15-fold greater than prednisolone). The drug undergoes extensive first-pass hepatic metabolism (about 90%) to form compounds with negligible corticosteroid activity; the resultant systemic bioavailability is, therefore, low.
Budesonide (administered as a solution) was about twice as active as beclomethasone dipropionate and more than 1000 times more active than prednisolone and hydrocortisone in inducing cutaneous vasoconstriction after topical application.
In general, the effect on erythrocyte sedimentation rate (ESR), C-reactive protein and serum orosomucoid concentrations was not significantly different after treatment with budesonide (Entocort® EC Capsules) 9 mg/day or prednisolone 40 mg/day. After 12 weeks of treatment, the mean leucocyte count increased significantly in patients receiving prednisolone 40 mg/day, but decreased slightly with budesonide 9 mg/day.
In short-term studies (up to 12 weeks) in patients with mild to moderate, active Crohn’s disease, tapered dosages of prednisolone caused a significantly greater decrease in morning cortisol concentrations and response to corticotropin stimulation than budesonide at dosages of up to 15 mg/day. Compared with mesalazine (mesalamine) slow release 2g twice daily, budesonide 9mg once daily decreased plasma cortisol concentrations to a greater degree, but the difference was not statistically significant. A dose-dependent suppression of morning plasma cortisol concentrations and response to corticotropin stimulation was demonstrated with budesonide, and dosages of 9 and 15mg decreased plasma cortisol concentrations significantly more than placebo.
Compared with prednisolone, budesonide caused a significantly lower increase in mean fasting blood glucose concentrations and mean serum creatinine concentrations after 4 and 8 weeks of treatment. Budesonide did not impair osteoblast activity in patients with active Crohn’s disease, whereas methylprednisolone did.
Pharmacokinetic Properties
Budesonide capsules contain granules that are coated to prevent dissolution in gastric pH. At a pH >5.5, budesonide is slowly released from a matrix of ethylcellulose during its passage through the small intestine.
Plasma concentrations of budesonide increased linearly in response to doses of 3 to 15 mg/day. After a single oral dose of budesonide 9mg, the maximum plasma concentration (Cmax) is approximately 4 nmol/L and is attained at about 3 hours.
The mean systemic bioavailability following oral administration of budesonide is approximately 11%, indicating an extensive first-pass metabolism. Food did not significantly affect the systemic availability and Cmax of orally administered budesonide, however, absorption was delayed, probably due to delayed gastric emptying.
Excretion is mainly via the kidneys, but patients with renal impairment are not expected to be at an increased risk of adverse effects. The systemic availability of oral budesonide in patients with liver cirrhosis is increased by approximately 2.5-fold compared with that in healthy volunteers.
Clinical Efficacy
Oral budesonide induced remission in patients with active mild to moderate Crohn’s disease significantly more than placebo or mesalazine slow release, and at a rate similar to that of prednisolone, in controlled clinical trials. Clinical remission was achieved by approximately 50 to 60% of patients after 8 to 10 weeks of treatment with budesonide 9 mg/day.
In two placebo-controlled trials, patients receiving budesonide 9 mg/day showed a higher rate of remission than those receiving placebo after 8 weeks of treatment; however, the difference was only significant in one study (51 vs 20%, p < 0.001). In the other study, remission rates were 48, 53 and 33% in patients receiving budesonide 9mg once daily, 4.5mg twice daily or placebo, respectively.
In a randomised, controlled trial comparing mesalazine slow release 2g twice daily with budesonide 9mg once daily, remission rates in patients treated with budesonide were significantly higher at 8, 12 and 16 weeks. In studies comparing budesonide with prednisolone 40mg daily (tapered after 2 weeks), prednisolone induced remission in 60 and 65% of patients after 8 weeks of treatment; these response rates were not significantly different to those seen with budesonide 9mg once daily (52 and 60%).
Results from a recent meta-analysis support the results of clinical trials by indicating that oral budesonide is significantly more effective than placebo, and in one study, more effective than mesalazine slow release, in inducing remission of mild to moderate Crohn’s disease. Meta-analysis results also indicate that budesonide induced remission at a similar rate to prednisolone in patients with a Crohn’s Disease Activity Index (CDAI) score ≤300, but appeared less likely to induce remission than conventional steroids in patients with a CDAI score >300.
Budesonide once daily improved health-related quality of life significantly more than placebo and mesalazine slow release in patients with active mild to moderate Crohn’s disease.
Tolerability
Oral budesonide is well tolerated and a similar proportion of patients receiving budesonide 9 mg/day or placebo experienced adverse effects or withdrew from placebo-controlled trials because of adverse effects. The most common adverse events reported in clinical trials were headache (21%), respiratory infection (11%), nausea (11%) and symptoms of hypercorticism.
The incidence of adverse events was similar in patients receiving budesonide 9mg once daily or mesalazine slow release 2g twice daily. However, patients randomised to budesonide had fewer severe adverse events than those in the mesalazine group.
Compared with prednisolone in controlled, short-term clinical trials, budesonide 9mg once daily caused significantly fewer glucocorticoid-related adverse effects.
Haematological and biochemical variables did not differ significantly between treatment groups receiving budesonide 3, 9 or 15 mg/day or placebo.
Dosage and Administration
Oral budesonide is indicated for the treatment of adults with mild to moderate, active Crohn’s disease of the ileum and/or ascending colon. The recommended dosage is 9mg once daily, taken in the morning, for a period of up to 8 weeks. The capsule should be swallowed whole, not chewed or broken. Tapering of dosage, to 6 mg/day for 2 weeks, can be implemented before complete cessation of the drug. A repeat 8-week course can be given for recurring episodes of active Crohn’s disease.
A reduction in the dose of budesonide should be considered in patients with moderate to severe liver disease and if concomitant therapy with cytochrome P450 3A4 inhibitors is indicated. Grapefruit juice should be avoided during therapy. Although budesonide has a lower systemic effect than conventional steroids and causes less suppression of adrenal function, general warnings concerning corticosteroids should be followed.