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11/23/2001

Oral Budesonide Approved for Active Crohn's Disease

Cheryl A. Thompson

AstraZeneca LP has received approval from FDA to market oral budesonide capsules (Entocort EC) for the treatment of mild to moderate active Crohn's disease involving the ileum or ascending colon.

When ingested, budesonide acts as a topical glucocorticoid with a high level of anti-inflammatory activity. Budesonide undergoes extensive metabolism, 80–90% of a dose, on the first pass through the liver, with relatively little of the drug reaching the general circulation.

The efficacy of budesonide capsules was evaluated in five eight-week, randomized, double-blind studies involving 994 adults with mild to moderate active Crohn's disease of the ileum or ascending colon. Clinical improvement was measured with the Crohn's Disease Activity Index, a validated instrument that combines a patient's ratings of frequency of liquid or very soft stools, abdominal pain, and general well-being with objective observations of the number of extraintestinal symptoms, need for antidiarrheal drugs, presence of an abdominal mass, body weight, and hematocrit.

A once-daily dose of budesonide 9 mg resulted in clinical improvement for 52–60% of patients, compared with 60–65% for oral prednisolone, which acts systemically, at an initial dosage of 40 mg/day and decreased thereafter. In another study, budesonide 9 mg once daily resulted in clinical improvement for 48% of the patients, which was not significantly different from the 33% response rate for the placebo. The highest response rate for the 9-mg once-daily regimen was 69%; in that study, 45% of the patients assigned to receive the unspecified comparator responded to therapy.

Twice-daily doses of budesonide 4.5 mg resulted in clinical improvement for 42–53% of patients assigned to this regimen. In the only study that compared once-daily budesonide therapy with twice-daily doses, the more frequent dosage schedule came out ahead by five percentage points, but neither regimen was significantly better than placebo. A twice-daily regimen of budesonide 7.5 mg was no better than 4.5 mg twice daily

Each capsule contains budesonide that has been micronized and then coated to prevent dissolution in the stomach. Once in gastrointestinal fluid with a pH of >5.5, budesonide is gradually released from the capsule’s ethylcellulose matrix.

The time from ingestion of a capsule to peak plasma concentration of budesonide can vary in a person from as soon as 30 minutes to as long as 600 minutes. Ingestion of a dose with a high-fat meal delays by two and a half hours the time to peak plasma concentration but does not significantly change systemic exposure.

About 85–90% of the drug in the plasma is bound to protein. Metabolism occurs primarily by cytochrome P-450 (CYP) isoenzyme 3A4, resulting in two major metabolites with <1% of the glucocorticoid activity of budesonide. Intact budesonide does not appear in the urine.

Systemic exposure to budesonide increases eightfold when taken with ketoconazole, a potent inhibitor of CYP 3A4, and twofold with grapefruit juice, an inhibitor of the isoenzyme in the gut mucosa. The labeling for budesonide advises against the consumption of grapefruit juice during therapy. Clinicians should consider reducing the dosage of budesonide during concomitant therapy with drugs that inhibit CYP 3A4 activity.

The most commonly reported adverse reactions among patients who received oral budesonide 9 mg/day in the studies were headache (21%), respiratory infection (11%), and nausea (11%). Symptoms of hypercorticism, such as acne and moon face, occurred less frequently in budesonide-treated patients than those assigned to prednisolone therapy. Benign intracranial hypertension has been reported in three patients since the marketing of budesonide outside the United States.

The product's labeling advises clinicians to follow the general warnings for administering glucocorticoid therapy, despite the relatively small amount of budesonide that reaches the general circulation. As with other glucocorticoids, budesonide is secreted in breast milk.

Replacement of a systemic glucocorticoid with oral budesonide may unmask rhinitis, eczema, and other symptoms of allergies that had been previously controlled.

The recommended dosage of oral budesonide is 9 mg once daily in the morning for up to eight weeks. Another eight-week course may be administered for a recurrent episode of Crohn's disease. The capsules should be swallowed whole. The dosage may be decreased to 6 mg daily during the last two weeks of therapy.

If a patient has been receiving oral prednisolone therapy, that dosage should be decreased when budesonide therapy starts and then gradually stopped. A dosage less than 9 mg/day should be considered for patients with moderate to severe liver disease.

Entocort EC is available as 3-mg capsules, with an opaque light gray body and opaque pink top, in bottles of 100.