Uceris (Page 3 of 7)

10 OVERDOSAGE

Acute overdosage with UCERIS rectal foam is unlikely. However, UCERIS rectal foam is absorbed systemically and chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.1)].

11 DESCRIPTION

UCERIS rectal foam contains budesonide, a non-halogenated synthetic glucocorticoid, as the active ingredient. It is a mixture of the 2 epimers (22R and 22S) differing in the position of an acetal chain. Both epimers are active glucocorticoids applied in a mixture of approximately 1:1.

Budesonide is designated chemically as (RS)-11β, 16α, 17,21 tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. The empirical formula of budesonide is C25 H34 O6 and its molecular weight is 430.5. Its structural formula is:

image11
(click image for full-size original)

UCERIS rectal foam contains 2 mg budesonide per metered dose.

Inactive ingredients: cetyl alcohol, citric acid monohydrate, edetate disodium, emulsifying wax, polyoxyl (10) stearyl ether, propylene glycol, and purified water.

Propellant: n-butane, isobutane, and propane.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Budesonide has glucocorticosteroid (GCS) activity.

12.2 Pharmacodynamics

Treatment with glucocorticosteroids, including UCERIS rectal foam, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamic-pituitary-adrenal (HPA) axis function. These effects were measured by determination of plasma cortisol concentrations and responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) in 2 placebo-controlled, 6-week trials in patients with active disease [see Clinical Studies (14)]. These trials enrolled subjects with post-ACTH stimulation cortisol levels of >18 mcg/dL at baseline. Subjects received UCERIS rectal foam 2 mg or a placebo twice daily for 2 weeks followed by once daily for 4 weeks. Normal morning serum cortisol levels >5 mcg/dL were maintained in 85% and 84% of UCERIS rectal foam treated subjects during Weeks 1 and 2 (twice daily treatment) and 93% and 94% during Weeks 4 and 6 (once daily treatment), respectively (see Table 3).

At baseline (predose), 84% of subjects in the UCERIS rectal foam group had a normal response to the ACTH challenge and at Week 6, 63% of subjects had a normal response to the ACTH challenge; in the placebo group, these values were 86% and 76%, respectively (see Table 3). ACTH stimulation test was not performed routinely during the twice daily treatment period (Weeks 1 and 2).

Table 3: Proportion of Subjects with Normal Endogenous Cortisol Levels (>5 mcg/dL) During the Study and Proportion of Subjects with Normal Response to ACTH Challenge
*
The normal response to ACTH challenge included 3 criteria, as defined in the cosyntropin label: 1) morning cortisol level > 5 mcg/dL; 2) increase in cortisol level by ≥ 7 mcg/dL above the morning (pre-challenge) level following ACTH challenge; and cortisol level of > 18 mcg/dL following ACTH challenge.
Denominator includes 20 subjects in the UCERIS rectal foam arm and 2 subjects in the placebo arm who discontinued prior to week 6 due to adverse events related to low cortisol or abnormal response to ACTH challenge.

Cortisol Parameter

UCERIS Rectal Foam

2 mg/25 mL N=268 n (%)

Placebo

N=278

n (%)

Total cortisol ˃5 mcg/dL

(lower limit of normal range)

Baseline

259/268

(96.6)

275/278

(98.9)

Week 1

224/263

(85.2)

264/269

(98.1)

Week 2

216/257

(84.0)

263/266

(98.9)

Week 4

218/235

(92.8)

243/249

(97.6)

Week 6

211/224

(94.2)

234/241

(97.1)

Normal response to ACTH challenge *

Baseline

222/266

(83.5)

238/278

(85.6)

Week 6

148/236

(62.7)

180/237

(75.9)

12.3 Pharmacokinetics

Absorption

Distal Ulcerative Colitis Patients

Based on population pharmacokinetic analysis from sparse PK samples from phase 3 studies, the estimated AUC0-12

following administration of UCERIS rectal foam 2 mg twice a day was 4.31 ng*hr/mL with a CV of 64% in the target

patient population.

Distribution

The volume of distribution (VSS) of budesonide varies between 2.2 and 3.9 L/kg in healthy subjects and in patients.

Plasma protein binding is estimated to be 85 to 90% in the concentration range of 1 to 230 nmol/L, independent of gender.

The erythrocyte/plasma partition ratio at clinically relevant concentrations is approximately 0.8.

Elimination

Metabolism

Following absorption, budesonide is subject to first-pass metabolism. 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 demonstrate that budesonide has a plasma clearance of

0.9-1.8 L/min. These plasma clearance values approach the estimated liver blood flow, suggesting that budesonide is a

high hepatic clearance drug.

Excretion

Budesonide is excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of

micronized [3H]-budesonide, approximately 60% of the recovered radioactivity is found in urine. The major metabolites,

including 6β-hydroxybudesonide and 16α-hydroxyprednisolone, 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 has 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.

Patients with Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of UCERIS rectal foam has not been studied. In a study in

patients with mild to moderate hepatic impairment (Child-Pugh Class A and Child-Pugh Class B) dosed with budesonide

4 mg oral capsules, systemic exposure was similar between patients with mild hepatic impairment (Child-Pugh Class A;

n=4) and healthy subjects (n=8), and 3.5-fold higher in patients with moderate hepatic impairment (Child-Pugh Class B;

n=4) than in healthy subjects. For the intravenous dose, no significant differences in CL or VSS are observed. Patients with

severe liver dysfunction (Child-Pugh Class C) were not studied [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of

budesonide. Co-administration of ketoconazole (inhibitor of CYP3A4) results in an 8-fold increase in AUC of oral

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 concentrations. The effect of CYP3A4 inhibitors and inducers on the pharmacokinetics of UCERIS rectal foam

have not been studied [see Dosage and Administration (2) and Drug Interactions (7)].

Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do not affect the

pharmacokinetics of oral budesonide. Budesonide does not affect the plasma concentrations of oral contraceptives (i.e.,

ethinyl estradiol).

In vitro interaction studies performed with budesonide showed that budesonide did not inhibit human cytochrome P450

isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2D6, or CYP2E1 at concentrations ranging from 0.11 to 1130 ng/mL.

Isoenzyme CYP3A4 was inhibited at the highest concentration tested but the IC50 was >1130 ng/mL. UCERIS rectal foam

is not expected to inhibit these enzymes in clinical use. No significant induction of CYP1A2, CYP2B6, CYP2C9 or

CYP3A4/5 expression was observed in human hepatocytes in vitro at budesonide concentrations up to 9000 nM (3.88

mcg/mL).

In an in vitro study, budesonide was not a substrate of human transporters OATP1B3 and may be a weak substrate of

OATP1B1. Budesonide at concentrations up to 300 nM (129 ng/mL) did not inhibit OATP1B1 or OATP1B3.

Budesonide was not a substrate of BCRP and was a weak substrate of P-glycoprotein. Budesonide was a weak inhibitor of

P-glycoprotein (IC50 9.78 μM or 4.21 mcg/mL) and BCRP (IC50 43.1 μM or 18.6 mcg/mL). UCERIS rectal foam is not

expected to inhibit these transporters in clinical use.

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