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- Spencer, C.M. & McTavish, D. Drugs (1995) 50: 854. doi:10.2165/00003495-199550050-00006
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Budesonide is a glucocorticoid with high topical activity, but low systemic bioavailability which results in reduced systemic effects in comparison with other glucocorticoids. To date, it has been evaluated for use in patients with inflammatory bowel disease when administered either orally as a controlled ileal release formulation or rectally as an enema.
In comparative trials, daily treatment with budesonide enema 2 mg/100ml for 4 weeks produced endoscopic remission or improvement in 46 to 84% of patients with active distal ulcerative colitis and/or proctitis and histological remission or improvement in 45 to 68%. In general, this regimen was a effective as regimens of hydrocortisone, methylprednisolone, prednisolone or mesalazine (5-aminosalicylic acid, mesalamine) enemas, but caused less suppression of plasma cortisol levels than the other glucocorticoids.
Oral treatment with controlled release budesonide 9 mg/day for 8 weeks produces clinical remission in 42 to 67% of patients with active Crohn’s disease of the ileum, ileocaecal region and/or ascending colon and significantly reduces Crohn’s disease activity index scores compared with baseline and placebo. Results of a quality-of-life questionnaire reflected these clinical improvements. Budesonide has similar efficacy to prednisolone. Response to budesonide is maintained after dosage tapering at 8 weeks. Compared with placebo, maintenance treatment with oral budesonide 3 or 6 mg/day increases the duration of remission in patients with Crohn’s disease, but does not appear to affect the 1-year relapse rate.
Thus, budesonide, administered rectally to patients with distal ulcerative colitis or proctitis or orally to patients with Crohn’s disease of the ileum, ileocaecal region and/or ascending colon, is a favourable option for the treatment of acute exacerbations of inflammatory bowel disease. Because of the low incidence of adverse glucocorticoid-related effects associated with oral budesonide, it may also be a useful agent for longer term maintenance therapy if further clinical trials confirm its efficacy in this indication.
Budesonide is a glucocorticoid used in the treatment of inflammatory bowel disease. It has greater topical anti-inflammatory activity than many other glucocorticoids, but does not reduce cortisol levels (a measure of systemic effect on adrenal function) to the same extent as methylprednisolone, prednisolone or hydrocortisone when administered orally or rectally. In fact, administration of budesonide 2 mg/100ml enema has no significant effect on basal plasma cortisol levels in patients with ulcerative colitis. Response to corticotrophin (adrenocorticotrophic hormone; ACTH) is also impaired to a lesser extent by rectal treatment with budesonide than with prednisolone. Similarly, oral budesonide 9 mg/day is associated with less impairment of adrenal function than oral prednisolone 40 mg/day (after 2 weeks tapered to 5 mg/day over 7 weeks), but does cause some adrenal suppression compared with placebo. A 1-year placebo-controlled study showed that decreases in ACTH-stimulated plasma cortisol levels induced by oral budesonide did not result in clinically important glucocorticoid-associated adverse effects in 105 patients with Crohn’s disease.
In general, treatment with oral budesonide 9 mg/day reduced mean erythrocyte sedimentation rate in patients with active Crohn’s disease, but did not significantly alter mean serum orosomucoid, C-reactive protein or albumin levels or plasma haptoglobin level. However, in 1 trial, budesonide therapy resulted in a 20% decrease in serum C-reactive protein level. Although both budesonide and prednisolone enema therapy induce small decreases in serum osteocalcin level from baseline, changes are greater in prednisolone recipients. Compared with oral prednisolone 40 mg/day (after 2 weeks tapered to 5 mg/day over 7 weeks), oral budesonide 9 mg/day (after 8 weeks tapered to 6 mg/day) produces smaller decreases in natural killer cell activity (by 22 to 30% vs 25 to 54%) after 2 and 4 weeks in patients with active Crohn’s disease.
Budesonide enema achieves adequate maximum retrograde colonic spread within 15 minutes in patients with distal ulcerative colitis. The drug has a systemic bioavailability of 9.3 to 15% and a mean absorption time of about 6 and 1.4 hours, respectively, when administered orally or rectally to healthy volunteers. In healthy volunteers and patients with ulcerative colitis, maximum plasma concentrations of 2.1 to 3 nmol/L are achieved 1.2 to 1.5 hours after rectal administration of budesonide 2 mg/100ml. Area under the plasma concentration-time curve increased after 28 days’ therapy, but other assessments showed that the drug did not accumulate with repeated administration. The controlled ileal release formulation of oral budesonide is predominantly absorbed in the ileum and ascending colon. Budesonide undergoes extensive first-pass metabolism via oxidative and reductive pathways in the liver to 2 major metabolites 6β-hydroxy-budesonide and 16α-hydroxy-prednisolone, which have considerably less glucocorticoid activity than the parent drug.
Budesonide has been incorporated into formulations for oral (controlled release) or rectal (enema) treatment of patients with inflammatory bowel disease, most commonly Crohn’s disease (affecting the ileum, ileocaecal region and/or ascending colon) or ulcerative colitis, respectively. Budesonide enema 2 mg/100ml generally has similar efficacy to hydrocortisone, methylprednisolone, prednisolone or mesalazine enemas and greater efficacy than placebo after 4 weeks of treatment. General well-being is also improved after 2 weeks’ treatment with budesonide enema in comparison with placebo. Budesonide enema produced endoscopic improvement faster than prednisolone enema in one of the larger studies, but not in another. Endoscopic remission or improvement occurred in 46 to 84% of patients treated with budesonide enema, while histological remission or improvement was achieved by 45 to 68% of patients enrolled in comparative trials.
Clinical remission is achieved by 42 to 67% of patients with active Crohn’s disease of the ileum, ileocaecal region and/or ascending colon following treatment with oral controlled ileal release budesonide 9 mg/day for 8 weeks. This drug regimen also significantly reduces Crohn’s disease activity index scores compared with baseline and placebo. Results of a quality-of-life questionnaire reflected these clinical improvements. Oral budesonide has a rapid effect in comparison with placebo, but results of comparisons with prednisolone were equivocal. However, oral budesonide generally has efficacy similar to that of prednisolone. Prior treatment with steroidal agents does not have a detrimental effect on response to oral budesonide. Budesonide dosages were generally tapered after 8 weeks of oral therapy and responses were maintained after dosage reductions. Maintenance treatment with budesonide 3 to 6 mg/day increases the duration of remission in patients with Crohn’s disease, but does not appear to significantly reduce the proportion of patients experiencing relapse after 1 year of treatment.
Budesonide enema is generally well tolerated: the most frequently experienced events (reported in ≤5% of patients) are gastrointestinal and include increased bowel frequency and colorectal bleeding. Haematuria, thromboembolism, acne and villous adenoma have been reported in 1 patient each. Laboratory abnormalities do not usually develop and no signs of significant adrenal suppression have been detected during treatment with budesonide enema.
In a large trial (n = 258) comparing oral controlled ileal release budesonide 3, 9 or 15 mg/day and placebo, similar proportion of patients in the active treatment and placebo groups experienced an adverse event or discontinued treatment because of these events. 41% of adverse events were gastrointestinal in nature, with dyspepsia and nausea being most commonly reported. Glucocorticoid-associated effects developed in a similar proportion of patients in each group (15 to 38%), but cushingoid facial features were more common with budesonide (7%) than with placebo (2%). Glucocorticoid-associated adverse effects, particularly cushingoid facial features, appear to occur more commonly during prednisolone therapy than during treatment with oral budesonide. Oral budesonide therapy does not appear to affect liver function tests, or to produce haematological and biochemical abnormalities when compared with placebo. In general, 6 to 12 months’ maintenance therapy with oral budesonide was not associated with significant adverse events. However, longer term trials are necessary to fully define the tolerability profile of budesonide.
Dosage and Administration
Budesonide enema 2 mg/100ml should be inserted rectally once daily at bedtime for the treatment of acute distal ulcerative colitis or proctitis. In most studies treatment was continued for 4 weeks. Clinical studies indicate that oral budesonide should be administered at a daily dose of 9mg for about 8 weeks for the treatment of active Crohn’s disease of the ileum, ileocaecal region and/or ascending colon.