budesonide 3 mg Capsule, Coated Pellets, 100-count — NDC 68382-720-01 (Billing 68382-0720-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics Treatment with glucocorticoids, including budesonide delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 Delayed-Release Capsules or Prednisolone for 8 weeks *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. Budesonide Prednisolone 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)

12.3Pharmacokinetics Absorption Mean oral bioavailability of budesonide ranged from 9% to 21% both in patients and in healthy subjects, demonstrating a high first-pass elimination of the drug. Budesonide pharmacokinetics were dose-proportional following repeated administration in the dose range of 3 to 15 mg. No accumulation of budesonide was observed following repeated dosing.

Following oral administration of a single dose of… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics Absorption Mean oral bioavailability of budesonide ranged from 9% to 21% both in patients and in healthy subjects, demonstrating a high first-pass elimination of the drug. Budesonide pharmacokinetics were dose-proportional following repeated administration in the dose range of 3 to 15 mg. No accumulation of budesonide was observed following repeated dosing.

Following oral administration of a single dose of 9 mg budesonide delayed-release capsules in healthy subjects under fasting condition, the mean peak plasma concentration (C max ) and the area under the plasma concentration time curve (AUC) for budesonide were 1.50 ± 0.79 ng/mL and 14.13 ± 7.33 ng•hr/mL, respectively. The time to peak concentration (T max ) varied between 2 and 8 hours with a median value of 3.5 hours. In a different study, following oral administration of 9 mg budesonide delayed-release capsules for five days in healthy subjects, the mean C max and the steady state AUC for budesonide were 2.28 ± 0.77 ng/mL and 15.93 ± 6.29 ng•hr/mL, respectively.

Following administration of 9 mg budesonide delayed-release capsules once daily in patients with active Crohn's disease, the mean C max and AUC were 1.7 ± 0.9 ng/mL and 15.1 ± 8.5 ng•hr/mL, respectively. Following administration of budesonide delayed-release capsules, the T max ranged in individual patients from 0.5 to 10 hours. Concomitant administration of a high-fat meal delayed the T max of budesonide by 2.3 hours compared to that under fasted conditions but did not significantly affect the AUC in healthy subjects.

The mean C max and AUC of budesonide were similar when single dose of budesonide delayed-release capsules (9 mg) was administered after opening the capsules and sprinkling the granules on applesauce versus as intact capsules in the fasted state (N=24) in healthy subjects. The T max ranged from 3 to 10 hours with a median of 4 hours after administration of sprinkled granules on appleasauce. Distribution The mean volume of distribution (V ss ) of budesonide varied between 2.2 and

3.9L/kg in healthy subjects and in patients. Plasma protein binding was estimated to be 85% to 90% in the concentration range 0.43 to 99.02 ng/mL, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations was about 0.8. Elimination Budesonide had a plasma clearance, 0.9 to

1.8L/min in healthy adults. Mean plasma clearance after intravenous administration of budesonide in patients with Crohn's disease was

1.0L/min. These plasma clearance values approached the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug. The plasma elimination half-life after administration of intravenous doses ranged between 2 and 3.6 hours, and did not differ between healthy adults and patients with Crohn's disease.

The mean ± SD plasma elimination half-life after a single dose of budesonide delayed-release capsules (9 mg) in the fasted state (N=24) in healthy subjects was 6.3 ± 1.6 hours and ranged between 2 and 8 hours. Metabolism Following absorption, budesonide is subject to high first pass metabolism (80% to 90%). In vitro experiments in human liver microsomes demonstrated that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone.

The corticosteroid activity of these metabolites was negligible (less than 1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects were in agreement with the in vitro findings. Excretion Budesonide was excreted in urine and feces in the form of metabolites.

After oral as well as intravenous administration of micronized [ 3 H]-budesonide, approximately 60% of the recovered radioactivity was found in urine. The major metabolites, including 6β-hydroxy budesonide and 16α-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms.… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Treatment with glucocorticoids, including budesonide delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 Delayed-Release Capsules or Prednisolone for 8 weeks *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. Budesonide Prednisolone 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)

14 CLINICAL STUDIES

14.1Treatment of Mild to Moderate Active Crohn’s Disease Adults The efficacy of budesonide delayed-release capsules were evaluated in 994 patients with mild to moderate active Crohn's disease of the ileum and/or ascending colon in 5 randomized and double-blind studies of 8 weeks duration. The study patients ranged in age from 17 to 85 (mean 35), 40% were male and 97% were white. The Crohn's Disease Activity Index (CDAI) was the main clinical assessment used for determining efficacy in these 5 studies.

1 The CDAI is a validated index based on subjective aspects rated by the patient (frequency of liquid or very soft stools, abdominal pain rating and general well-being) and objective observations (number of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal mass, body weight and hematocrit). Clinical improvement, defined as a CDAI score of less than or equal to 150 assessed after 8 weeks of treatment, was the primary efficacy variable in these 5 comparative efficacy studies of budesonide delayed-release capsules.

Safety assessments in these studies included monitoring of adverse reactions. A checklist of potential symptoms of hypercorticism was used. One study (Study 1) compared the efficacy of budesonide delayed-release capsules 9 mg daily in the morning to a comparator.

At baseline, the median CDAI was 272. budesonide delayed-release capsules 9 mg daily resulted in a significantly higher clinical improvement rate at Week 8 than the comparator. See Table 5. Table 5 Clinical Improvement Rates (CDAI less than or equal to 150) After 8 weeks of Treatment 1. p=0.0004 compared to comparator.

2. p=0.001 compared to placebo. 3. This drug is not approved for the treatment of Crohn's disease in the United States.

Clinical Study Budesonide Delayed-Release Capsules 9 mg Daily Budesonide Delayed-Release Capsules 4.5 mg Twice Daily Comparator 3 Placebo Prednisolone 1 62/91 (69%) 1 37/83 (45%) 2 31/61 (51%) 2 13/64 (20%) 3 38/79 (48%) 41/78 (53%) 13/40 (33%) 4 35/58 (60%) 25/60 (42%) 35/58 (60%) 5 45/86 (52%) 56/85 (65%) Two placebo-controlled clinical trials (Studies 2 and 3) were conducted. Study 2 involved 258 patients and tested the effects of graded doses of budesonide delayed-release capsules (1.5 mg twice daily, 4.5 mg twice daily, or 7.5 mg twice daily) versus placebo.

At baseline, the median CDAI was 290. The 1.5 mg twice daily arm (data not shown) could not be differentiated from placebo. The 4.5 mg twice daily arm was statistically different from placebo (Table 5), while no additional benefit was seen when the daily budesonide delayed-release capsules dose was increased to 15 mg per day (data not shown).

Study 3 was a 3-armed parallel group study. The groups were treated with budesonide delayed-release capsules 9 mg once daily, budesonide delayed-release capsules 4.5 mg twice daily and placebo for 8 weeks, followed by a 2-week double-blind taper phase. The median CDAI at baseline was 263.

Neither 9 mg daily nor 4.5 mg twice daily budesonide delayed-release capsules dose levels were statistically different from placebo (Table 5). The recommended dosage of budesonide delayed-release capsules for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon in adults is 9 mg once daily in the morning for up to 8 weeks [see Dosage and Administration ( 2.1 )] . Two clinical trials (Studies 4 and 5) compared budesonide delayed-release capsules with oral prednisolone (initial dose 40 mg per day).

Study 4 was a 3-armed parallel group study. The groups were treated with budesonide delayed-release capsules 9 mg once daily, budesonide delayed-release capsules 4.5 mg twice daily and prednisolone 40 mg (tapered dose) for 8 weeks, followed by a 4-week double blind taper phase. At baseline, the median CDAI was 277.

Equal clinical improvement rates (60%) were seen in the budesonide delayed-release capsules 9 mg daily and the prednisolone groups in Study 4. In… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above.

No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis).

The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK +/- ) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test and the mouse micronucleus test.

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).