Pharmacology Update

Entocort EC—A New Treatment for Crohn’s Disease

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Astrazeneca has received FDA approval to market an oral form of budesonide to treat Crohn’s disease. Budesonide is a corticosteroid with potent topical anti-inflammatory activity. AstraZeneca has formulated the capsules to deliver budesonide in the intestine (pH > 5.5) in a time-dependent manner. Corticosteroid-related side effects appear to be lower with budesonide than conventional corticosteroids (eg, prednisone, prednisolone). It will be marketed by AstraZeneca as Entocort EC.

Indications

Budesonide capsules are indicated for the treatment of mild-to-moderate active Crohn’s disease involving the ileum and/or the ascending colon.1

Dosage

The recommended dose is 9 mg once daily in the morning for up to 8 weeks. The dose may be tapered to 6 mg per day 2 weeks before completion of therapy. The capsules should be swallowed whole. An 8-week course can be given for recurring episodes of Crohn’s disease. In patients with hepatic impairment, dose reduction should be considered and signs of hypercorticism monitored. Grapefruit should be avoided as it inhibits the metabolism of budesonide via CYP3A4 and may double systemic exposure.1

Budesonide capsules are available as 3 mg capsules.

Potential Advantages

Corticosteroid-related side effects are significantly less with budesonide than with conventional steroids such as prednisolone. A meta-analysis involving 4 studies (n = 341) showed a rate difference of -22.4% (95% CI, -32 to -12.8%; P < 0.001).2 Compared to prednisolone, the proportion of patients with normal plasma cortisol was higher in the budesonide group, 60-66% vs. 26-28%.1 In one study (n = 182), budesonide 9 mg once daily was reported to be more effective than mesalamine (Pentasa) 2 g twice daily. The rate of remission after 8 weeks was 69% for budesonide and 45% for mesalamine (P = 0.001).3

Potential Disadvantages

Budesonide appears to be less effective in inducing remission compared to conventional corticosteroids. The pooled-rate difference from 6 trials was -8.5% (95% CI, -16.4-0.7%; P = 0.02). While corticosteroid-associated side effects were significantly lower with budesonide than that of conventional corticosteroid about one third of patients still showed signs of adrenal suppression.3 Budesonide is not generally effective for the long-term prevention of relapse of Crohn’s disease.4 Relapse rates were similar between budesonide and placebo in medically induced remission or surgically induced remission Crohn’s disease.2 Budesonide is not approved for use in the maintenance of Crohn’s disease.

Comments

Budesonide is a potent topical corticosteroid with a significant first pass effect. Entocort EC are capsules containing acid-stable granules coated to dissolve at pH > 5.5. This combination allows for delivery of the drug in the intestine with minimal systemic exposure. FDA approval was based on 5 randomized trials (n = 994) in patients with mild-to-moderate disease. Success was based on the Crohn’s Disease Activity Index (CDAI). The index assesses 8 variables including number of liquid stools, extent of abdominal pain, general well being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. The scores ranged from 0-700. The primary end point for clinical success was a CDAI score < 150. Clinical success of budesonide ranged from 48-69% compared to 20-33% for placebo.1 The success (clinical improvement or remission) of mesalamine products from controlled trials have ranged from 40-60%.5 One study reported that budesonide was more efficacious than mesalamine.3 A recent short-term study (n = 120) assessed the effectiveness of switching steroid-dependent patients with inactive disease affecting the ileum and/or ascending colon from prednisolone to budesonide 6 mg daily or placebo. About two thirds of the budesonide patients remained in remission at 13 weeks with a 50% reduction in steroid-related side effects compared to one third for those who received placebo.6 Budesonide is generally well tolerated. Common side effects (vs placebo) were headache (21% vs 18%), respiratory infection (11% vs 7%), and nausea (11% vs 9%).1

The cost for Entocort EC (9 mg daily) is about $6.50 per day.

Clinical Implications

Crohn’s disease is a chronic immunologically mediated inflammatory disorder of the bowel. The incidence is 7 per 100,000 and the male to female ratio is 1.1-1.8: 1. The use of oral contraceptives is linked to Crohn’s disease. The relative risk for users is about 1.9.5 For mild-to-moderate disease, mesalamine products are first-line choices. For more serious disease or inadequate response to mesalamine, corticosteroids or immunosuppressives such as azathioprine or 6-mercaptopurine or infliximab are options. Budesonide provides a reasonable transition between mesalamine and oral corticosteroids or immunosuppressants. It approaches the corticosteroids in efficacy but with fewer corticosteroid-associated side effects.

Dr. Elliott, Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California-San Francisco; and Dr. Chan, Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA, are Associate Editors of Internal Medicine Alert.

References

1. Entocort EC Product Information. AstraZeneca. 2001.

2. Papi C, et al. Aliment Pharmacol Ther. 2000;14: 1419-1428.

3. Thomsen O, et al. N Engl J Med. 1998;339:370-374.

4. Simms L, Steinhart AH. Cochrane Database Syst Rev. 2001;CD002913.

5. Friedman S, Blumberg RS. Harrison’s Principles of Internal Medicine. New York, NY: McGraw-Hill; 2001:1679-1691.

6. Cortot A, et al. Gut. 2001;48(2):186-190.