Uceris (Page 3 of 5)

10 OVERDOSAGE

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

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

Single oral budesonide 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

UCERIS® (budesonide) extended-release tablets, for oral administration, contain budesonide, a synthetic corticosteroid, as the active ingredient. 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 C25 H34 O6 and its molecular weight is 430.5. Its structural formula is:

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(click image for full-size original)

Budesonide is a white to off-white, tasteless, odorless powder that is practically insoluble in water, sparingly soluble in alcohol, and freely soluble in chloroform.

UCERIS, a delayed and extended-release tablet, is coated with a polymer film, which breaks down at or above pH 7. The tablet core contains budesonide with polymers that provide for extended-release of budesonide.

Each tablet contains the following inactive ingredients: stearic acid, lecithin, microcrystalline cellulose, hydroxypropyl cellulose, lactose, silicon dioxide, magnesium stearate, methacrylic acid copolymer types A and B, talc, triethyl citrate, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism 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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

Absorption

Following single oral administration of UCERIS 9 mg in healthy subjects, peak plasma concentration (Cmax) was 1.35 ±

0.96 ng/mL, the time to peak concentration (Tmax) 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 Cmax 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 Cmax 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 (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 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, t1/2, 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 [3H]-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 VSS 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 Drug Interactions (7)].

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

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

estradiol).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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).

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