Uceris (Page 2 of 6)

6.2 Post-Marketing Experience

In addition to adverse reactions reported from clinical trials for UCERIS rectal foam, the following adverse reactions have been identified during post-approval use of other oral and rectal formulations of budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: hypertension

Gastrointestinal disorders: pancreatitis

General disorders and administration site conditions: pyrexia, peripheral edema

Immune system disorders: anaphylactic reactions

Nervous system disorders: dizziness, benign intracranial hypertension

Psychiatric disorders: mood swings

Skin and subcutaneous tissue disorders: pruritus, maculopapular rash, allergic dermatitis

7 DRUG INTERACTIONS

7.1 CYP3A4 Inhibitors

The active ingredient of UCERIS rectal foam, budesonide, is metabolized by CYP3A4. Inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine and grapefruit juice) can increase systemic budesonide concentrations. Avoid concomitant use of CYP3A4 inhibitors with UCERIS rectal foam [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well controlled studies with UCERIS rectal foam in pregnant women. Animal reproduction studies have been conducted with budesonide. In these studies, subcutaneous administration of budesonide to rats and rabbits at doses 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, produced skeletal abnormalities, fetal loss and decreased pup weight. UCERIS rectal foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4 percent for major malformations, and 15 to 20 percent for pregnancy loss.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Hypoadrenalism may occur in neonates exposed to glucocorticosteroids in utero. Carefully observe these neonates for signs and symptoms of hypoadrenalism.

Animal Data

Budesonide is teratogenic and embryocidal in rabbits and rats. In subcutaneous embryofetal development studies, fetal loss, decreased pup weights, and skeletal abnormalities were observed at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 0.12 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area) and 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area).

8.3 Nursing Mothers

Use of UCERIS rectal foam is likely to result in budesonide in human milk as budesonide delivered by inhalation from a dry powder inhaler is present in human milk at low concentrations. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for UCERIS rectal foam and any potential adverse effects on the breastfed child from UCERIS rectal foam or from the underlying maternal condition. Exercise caution when administering UCERIS rectal foam to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of UCERIS rectal foam has not been established in pediatric patients.

Children who are treated with corticosteroids by any route may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. The long-term effects of this reduction in growth velocity associated with corticosteroid treatment, including the impact on final adult height, are unknown. Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored (e.g., via stadiometry), and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose.

8.5 Geriatric Use

Clinical studies with UCERIS rectal foam did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. 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

No dosage adjustment is needed for patients with mild (Child-Pugh Class A) hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh Class B or C) should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS rectal foam should be considered in these patients if signs of hypercorticism are observed [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

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)

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