BUDESONIDE (ENTERIC COATED) (Page 4 of 8)

8.5 Geriatric Use

Clinical studies of budesonide capsules (enteric coated) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 651 patients treated with budesonide capsules (enteric coated) in clinical studies, 17 (3%) were greater than or equal to 65 years of age and none were greater than 74 years of age. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C, respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure to budesonide [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] . Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism and consider dosage reduction in patients with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration (2.4)] . No dosage adjustment is needed in patients with mild hepatic impairment (Child-Pugh Class A).

10 OVERDOSAGE

Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy.

If corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism and adrenal axis suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily.

Single oral doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema.

11 DESCRIPTION

Budesonide, the active ingredient in budesonide extended-release capsules (enteric coated), is a synthetic corticosteroid. Budesonide is designated chemically as (RS)-11β, 16α, 17,21- tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C 25 H 34 O 6 and its molecular weight is 430.5. Its structural formula is:

Chemical Structure
(click image for full-size original)

Budesonide is a white to off-white, tasteless, odorless powder that is practically insoluble in water and heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 5 is 1.6 × 10 3 ionic strength 0.01.

Budesonide capsules (enteric coated) is formulated as hard gelatin capsules filled with enteric-coated granules that dissolve at pH greater than 5.5. Each capsule for oral administration contains 3 mg of micronized budesonide with the following inactive ingredients: acetyltributyl citrate, ethylcellulose, hypromellose, methacrylic acid copolymer (type C powder), polyethylene glycol, polysorbate 80, sodium lauryl sulfate, sugar spheres (sucrose and corn starch), talc, and triethyl citrate. The capsule shells have the following inactive ingredients gelatin, D&C red #28, D&C red #33, and titanium dioxide. In addition, the black ink S-1-8114/S-1-8115 contains, black iron oxide, D&C yellow #10 aluminum lake, FD&C blue#1 brilliant blue FCF aluminum lake, FD&C blue #2 indigo carmine aluminum lake, FD&C red #40 allura red AC aluminum lake, propylene glycol, and shellac.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Budesonide is an anti-inflammatory corticosteroid and has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to glucocorticoid receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone.

12.2 Pharmacodynamics

Treatment with glucocorticoids, including budesonide capsules (enteric coated) is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. There was a positive correlation between the percent (%) reduction of AUC 0-24 of plasma cortisol and systemic exposure to budesonide both in pediatric and adult patients.

Adults

Plasma cortisol suppression was compared following five days’ administration of budesonide capsules (enteric coated) and prednisolone in a crossover study in healthy volunteers. The mean decrease in the area under the plasma cortisol concentration-time curve over 24 hour (AUC 0-24 ) was greater (78%) with prednisolone 20 mg per day compared to 45% with budesonide capsules (enteric coated) 9 mg per day.

Pediatrics

The effect of budesonide on endogenous cortisol concentrations was compared between pediatrics (n=8, aged 9 to 14 years) and adults (n=6) with active Crohn’s disease following administration of budesonide capsules (enteric coated) 9 mg once daily for 7 days. Compared to baseline values before treatment, the mean decrease in the AUC 0-24 of cortisol was 64% (±18%) in pediatrics and 50% (±27%) in adults after budesonide capsules (enteric coated) treatment [see Warnings and Precautions (5.1), Adverse Reactions (6.1) and Use in Specific Populations (8.4)] .

The responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) was studied in pediatric patients aged 8 to 17 years, with mild to moderate active Crohn’s disease in randomized, double-blind, active control study [see Clinical Studies (14.1)] . After 8 weeks of treatment with 9 mg once daily budesonide capsules (enteric coated) or with prednisolone, administered at tapering doses starting from 1 mg/kg, the proportion of patients with normal response to the ACTH challenge was 6% in the budesonide group compared to none in the prednisolone group; the proportion of patients with morning p-cortisol of greater than 5 mcg/dL was 50% in the budesonide group compared to 22% in the prednisolone group. The mean morning p-cortisol was 6.3 mcg/dL in the budesonide group and 2.6 mcg/dL in the prednisolone group (Table 4).

Table 4. Proportion of Pediatric Patients 8 to 17 years old with Peak Endogenous Cortisol Levels (above 18 mcg/dL) after ACTH Stimulation and Normal Response * to ACTH Challenge Following Administration of budesonide capsules (enteric coated) or Prednisolone for 8 weeks
Budesonide Prednisolone
*
The normal response to ACTH challenge included 3 criteria, as defined in the cosyntropin label:1) morning cortisol level above 5 mcg/dL; 2) increase in cortisol level by at least 7 mcg/dL above the morning (pre-challenge) level following ACTH challenge; and cortisol level of above 18 mcg/dL following ACTH challenge. Cortisol concentration was measured at 30 min after intravenous or intramuscular injection of 0.25 mg cosyntropin at baseline and at week 8 after treatment.
Peak plasma cortisol above 18 mcg/dL
At baseline 91% (20/22) 91% (21/23)
At week 8 25% (4/16) 0% (0/18)
Normal response * to ACTH challenge
At baseline 73% (16/22) 78% (18/23)
At week 8 6% (1/16) 0% (0/18)

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