Uceris budesonide 9 mg Tablet, Extended Release, 30-count — NDC 68012-309-30 (Billing 68012-0309-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Budesonide has a high topical glucocorticosteroid (GCS) activity and substantial first-pass elimination. The formulation contains budesonide in an extended-release tablet core. The tablet core is enteric coated to protect dissolution in gastric juice which delays budesonide release until exposure to a pH ≥7 in the small intestine.

Upon disintegration of the coating, the core matrix provides extended release of budesonide in a time dependent manner.

12.2Pharmacodynamics Budesonide has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to GCS receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone. Treatment with systemically active GCS, including UCERIS, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. Markers, indirect and direct, of this are cortisol levels in plasma or urine and response to ACTH stimulation.

In a study assessing the response to ACTH stimulation test in patients treated with UCERIS 9 mg once daily, the proportion of patients with abnormal response was 47% at 4 weeks and 79% at 8 weeks.

12.3Pharmacokinetics Absorption Following single oral administration of UCERIS 9 mg in healthy subjects, peak plasma concentration (C max ) was 1.35 ± 0.96 ng/mL, the time to peak concentration (T max ) on average was 13.3 ± 5.9 hours, although it varied across different individual patients, and the area under the plasma concentration time curve (AUC) was approximately 16.43 ± 10.52 ng·hr/mL. The pharmacokinetic parameters of UCERIS 9 mg have a high degree of variability among subjects. There was no accumulation of budesonide with respect to both AUC and C max following 7 days of UCERIS 9 mg once daily dosing.

Food Effect A food-effect study involving administration of UCERIS to healthy volunteers under fasting conditions and with a high-fat meal indicated that the C max was decreased by 27% while there was no significant decrease in AUC. Additionally, a mean delay in absorption lag time of 2.4 hours was observed under fed conditions. Distribution The mean volume of distribution (V SS ) of budesonide varies between 2.2 and

3.9L/kg in healthy subjects and in patients. Plasma protein binding is estimated to be 85 to 90% in the concentration range 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations is about 0.8.

Elimination Metabolism Following absorption, budesonide is subject to high first-pass metabolism (80-90%). In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound.

In vivo investigations with intravenous doses in healthy subjects are in agreement with the in vitro findings and demonstrate that budesonide has a high plasma clearance, 0.9-1.8 L/min. These high plasma clearance values approach the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug. The plasma elimination half-life, t 1/2 , after administration of intravenous doses ranges between 2 and 3.6 hours.

Excretion Budesonide is 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 is found in urine. The major metabolites, including 6β-hydroxy budesonide and 16α-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms.

No unchanged budesonide is detected in urine. Specific Populations Patients with Renal Impairment The pharmacokinetics of budesonide in patients wit… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Budesonide has a high topical glucocorticosteroid (GCS) activity and substantial first-pass elimination. The formulation contains budesonide in an extended-release tablet core. The tablet core is enteric coated to protect dissolution in gastric juice which delays budesonide release until exposure to a pH ≥7 in the small intestine.

Upon disintegration of the coating, the core matrix provides extended release of budesonide in a time dependent manner.

12.3Pharmacokinetics Absorption Following single oral administration of UCERIS 9 mg in healthy subjects, peak plasma concentration (C max ) was 1.35 ± 0.96 ng/mL, the time to peak concentration (T max ) on average was 13.3 ± 5.9 hours, although it varied across different individual patients, and the area under the plasma concentration time curve (AUC) was approximately 16.43 ± 10.52 ng·hr/mL. The pharmacokinetic parameters of UCERIS 9 mg have a high degree of variability among subjects. There was no accumulation of budesonide with respect to both AUC and C max following 7 days of UCERIS 9 mg once daily dosing.

Food Effect A food-effect study involving administration of UCERIS to healthy volunteers under fasting conditions and with a high-fat meal indicated that the C max was decreased by 27% while there was no significant decrease in AUC. Additionally, a mean delay in absorption lag time of 2.4 hours was observed under fed conditions. Distribution The mean volume of distribution (V SS ) of budesonide varies between 2.2 and

3.9L/kg in healthy subjects and in patients. Plasma protein binding is estimated to be 85 to 90% in the concentration range 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations is about 0.8.

Elimination Metabolism Following absorption, budesonide is subject to high first-pass metabolism (80-90%). In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound.

In vivo investigations with intravenous doses in healthy subjects are in agreement with the in vitro findings and demonstrate that budesonide has a high plasma clearance, 0.9-1.8 L/min. These high plasma clearance values approach the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug. The plasma elimination half-life, t 1/2 , after administration of intravenous doses ranges between 2 and 3.6 hours.

Excretion Budesonide is 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 is found in urine. The major metabolites, including 6β-hydroxy budesonide and 16α-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms.

No unchanged budesonide is detected in urine. Specific Populations Patients with Renal Impairment The pharmacokinetics of budesonide in patients with renal impairment have not been studied. Intact budesonide is not renally excreted, but metabolites are to a large extent, and might therefore reach higher levels in patients with impaired renal function.

However, these metabolites have negligible corticosteroid activity as compared with budesonide (<1/100). Patients with Hepatic Impairment In patients with liver cirrhosis, systemic availability of orally administered budesonide correlates with disease severity and is, on average, 2.5-fold higher compared with healthy controls. Patients with mild liver disease are minimally affected.

Patients with severe liver dysfunction were not studied. Absorption parameters were not altered, and for the intravenous dose, no significant differences in CL or V SS were observed. Drug Interaction Studies Budesonide is metabolized via CYP3A4.

Potent inhibitors of CYP3A4 can increase the plasma levels of budesonide several-fold. Co-administration of ketoconazole results in an eight-fold increase in AUC of budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral budesonide.

Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma levels [see Dosage and Administration (2) and… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Budesonide has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to GCS receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone. Treatment with systemically active GCS, including UCERIS, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. Markers, indirect and direct, of this are cortisol levels in plasma or urine and response to ACTH stimulation.

In a study assessing the response to ACTH stimulation test in patients treated with UCERIS 9 mg once daily, the proportion of patients with abnormal response was 47% at 4 weeks and 79% at 8 weeks.

14 CLINICAL STUDIES Induction of Remission in Active, Mild to Moderate Ulcerative Colitis Two similarly designed, randomized, double-blind, placebo-controlled studies were conducted in a total of 970 adult patients with active, mild to moderate ulcerative colitis (UC) which was defined as an Ulcerative Colitis Disease Activity Index (UCDAI of ≥4 and ≤10). Eight hundred ninety-nine of these patients had histology consistent with active UC; this was considered the primary analysis population. UCDAI is a four-component scale (total score of 0 to 12) that encompasses the clinical assessments of stool frequency, rectal bleeding, mucosal appearance and physician’s rating of disease activity (score of 0 to 3 for each of the components).

The baseline median UCDAI score in both studies was 7. In Study 1, 56% of patients were male, and the median age was 42 years. In Study 2, 57% of patients were male, and the median age was 44 years.

In Study 1, 50% of patients were Caucasian, 7% were African American, and 34% were Asian. In Study 2, more than 99% were Caucasian. Both studies compared UCERIS 9 mg and 6 mg with placebo and included an active reference arm (a mesalamine 2.4 g in Study 1 and a budesonide* 9 mg not approved for the treatment of UC in Study 2).

The primary endpoint was induction of remission after 8 weeks of treatment. Remission was defined as a UCDAI score of ≤1, with subscores of 0 for rectal bleeding, stool frequency, and mucosal appearance and with a ≥1 point reduction in an endoscopy-only score. In both studies, UCERIS 9 mg extended-release tablets demonstrated superiority to placebo in inducing remission (Table 4).

Table 4: Induction of Remission in Studies 1 and 2 Treatment Group Treatment Group Study 1 n/N (%) Study 2 n/N (%) UCERIS 9 mg 22/123 (17.9) 19/109 (17.4) UCERIS 6 mg 16/121 (13.2) 9/109 (8.3) Reference arm* 15/124 (12.1) 13/103 (12.6) Placebo 9/121 (7.4) 4/89 (4.5) Treatment difference between UCERIS 9 mg and placebo (95% CI) † 10.4% (2.2%, 18.7%) 12.9% (4.6%, 21.3%) The primary analysis population included only patients that had histology consistent with active UC. CI=Confidence Interval *The reference arm in Study 1 is a delayed release mesalamine 2.4 g; the reference arm in Study 2 is a budesonide 9 mg not approved for the treatment of UC. † p<0.025 for UCERIS 9 mg vs. placebo in both Studies 1 and 2 based on the Chi-square test (alpha=0.025)

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity 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 glucocorticosteroids (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). Mutagenesis 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 hepatocycte unscheduled DNA synthesis (UDS) test and the mouse micronucleus test.

Impairment of Fertility 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).