Uceris (Oral)

Dosage Forms And Strengths

UCERIS rectal foam is formulated as an emulsion which is filled into an aluminum canister with an aerosol propellant. It is available in 1 strength: 2 mg budesonide per metered dose.

Storage And Handling

UCERIS rectal foam is supplied as a kit containing 2 aerosol canisters with 28 PVC applicators coated with paraffin lubricant for administration of the foam (NDC 65649-651-03). Each canister (NDC 65649-651-02) is labeled with a net weight of 33.4g and contains 14 metered doses.

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Handling

UCERIS rectal foam contains a flammable propellant. Do not have the canister burned after use and do not spray contents directly towards flames.

• Do not expose to heat or store at temperatures above 120°F (49°C).
• Flammable. Avoid fire, flame, or smoking during and immediately following administration.
• Contents under pressure. Do not puncture or incinerate.

DO NOT REFRIGERATE.

Distributed by: Salix Pharmaceuticals, a division of Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USA. Revised: Nov 2015

UCERIS rectal foam is indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge.

Dosage

The recommended dosage regimen is 1 metered dose administered rectally twice daily for 2 weeks followed by 1 metered dose administered rectally once daily for 4 weeks.

Administration Instructions

Advise patients:

• UCERIS rectal foam is only to be applied rectally. It is not for oral use.
• Before using UCERIS rectal foam, use the bathroom to empty your bowels.
• Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
• Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
• UCERIS rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
• Apply UCERIS rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
• Avoid concomitant use of CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) during treatment with UCERIS rectal foam.

UCERIS rectal foam is contraindicated in patients with a history of a known hypersensitivity to budesonide or any of the ingredients of UCERIS rectal foam. Reactions have included anaphylaxis.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypercorticism And Adrenal Axis Suppression

When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since UCERIS rectal foam contains a glucocorticosteroid, general warnings concerning glucocorticoids should be followed.

Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis.

Impaired Adrenal Suppression In Patients Transferred From Other Glucocorticoids

Monitor patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as UCERIS rectal foam, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.

Replacement of systemic glucocorticosteroids with UCERIS rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.

How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (See prescribing information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered.

Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.

Other Glucocorticosteroid Effects

Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

Flammable Contents

The contents of UCERIS rectal foam include n-butane, isobutane and propane as propellants which are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following administration. Patients should temporarily discontinue use of UCERIS rectal foam before initiation of bowel preparation for colonoscopy and consult their health care provider before resuming therapy.

Patient And Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)

Administration

Advise patients:

• UCERIS rectal foam is only to be applied rectally. It is not for oral use.
• Before using UCERIS rectal foam, use the bathroom to empty your bowels.
• Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
• Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
• UCERIS rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
• Apply UCERIS rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
• Avoid consumption of grapefruit or grapefruit juice during treatment with UCERIS rectal foam.
• Avoid fire, flame, and smoking during and immediately following administration since UCERIS rectal foam is flammable.

Hypercorticism And Adrenal Suppression

Advise patients that UCERIS rectal foam may cause hypercorticism and adrenal suppression and that they should taper slowly from systemic corticosteroids if transferring to UCERIS rectal foam. Advise patients that replacement of systemic glucocorticosteroids with UCERIS rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Advise patients to avoid exposure to people with chicken pox or measles and if exposed, consult a physician. Also, inform patients that they are at increased risk of developing a variety of infections, including worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex and to contact their physician if they develop any symptoms of infection.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity

Carcinogenicity studies with budesonide were conducted in rats and mice. In a 2-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 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.06 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

In an additional 2-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). 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 0.24 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

Mutagenesis

Budesonide showed no evidence of mutagenic potential 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 or the mouse micronucleus test.

Impairment Of Fertility

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg(approximately 0.20 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). 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 0.05 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No such effects were noted at 5 mcg/kg.

Use In Specific Populations

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).

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.

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.

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.

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.

SIDE EFFECTS

Serious and important adverse reactions include:

• Hypercorticism and adrenal axis suppression
• Symptoms of steroid withdrawal in those patients transferring from systemic glucocorticosteroid therapy
• Increased susceptibility to infection
• Other glucocorticosteroid effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to UCERIS rectal foam in 332 patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The median duration of exposure was 42 days. This included 14 patients exposed for at least 6 months.

UCERIS rectal foam was studied primarily in 2 placebo-controlled, 6-week trials in patients with active disease (Study 1 and Study 2). In these trials, 268 patients received UCERIS rectal foam 2 mg twice a day for 2 weeks followed by 2 mg once a day for 4 weeks.

The most common adverse reactions ( ≥ 2% of the UCERIS rectal foam or Placebo group and at higher frequency in the UCERIS rectal foam group) were decreased blood cortisol, adrenal insufficiency, and nausea (Table 1). Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/dL. Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with adrenocorticotropic hormone (ACTH).

A total of 10% of UCERIS rectal foam-treated patients discontinued treatment due to an adverse reaction compared with 4% of placebo-treated patients.

Table 1: Summary of Adverse Reactions in 2 Placebo Controlled Trials* (Studies 1and 2)

Of the 46 UCERIS rectal foam treated patients with decreased blood cortisol (defined as a morning cortisol level of < 5 mcg/dL) reported as an adverse event, none had adrenal insufficiency (defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH) (see Table 2). All cases of adrenal insufficiency resolved.

Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebo-controlled trials (Studies 1 and 2).

Table 2: Summary of Glucocorticoid Related Effects in Two Placebo- Controlled Trials (Studies 1 and 2)

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between UCERIS rectal foam and placebo after 6 weeks of therapy.

For additional details on morning cortisol levels and the response to the ACTH stimulation test, see CLINICAL PHARMACOLOGY.

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, maculo-papular rash, allergic dermatitis

DRUG INTERACTIONS

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.

Serious and important adverse reactions include:

• Hypercorticism and adrenal axis suppression
• Symptoms of steroid withdrawal in those patients transferring from systemic glucocorticosteroid therapy
• Increased susceptibility to infection
• Other glucocorticosteroid effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to UCERIS rectal foam in 332 patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The median duration of exposure was 42 days. This included 14 patients exposed for at least 6 months.

UCERIS rectal foam was studied primarily in 2 placebo-controlled, 6-week trials in patients with active disease (Study 1 and Study 2). In these trials, 268 patients received UCERIS rectal foam 2 mg twice a day for 2 weeks followed by 2 mg once a day for 4 weeks.

The most common adverse reactions ( ≥ 2% of the UCERIS rectal foam or Placebo group and at higher frequency in the UCERIS rectal foam group) were decreased blood cortisol, adrenal insufficiency, and nausea (Table 1). Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/dL. Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with adrenocorticotropic hormone (ACTH).

A total of 10% of UCERIS rectal foam-treated patients discontinued treatment due to an adverse reaction compared with 4% of placebo-treated patients.

Table 1: Summary of Adverse Reactions in 2 Placebo Controlled Trials* (Studies 1and 2)

Of the 46 UCERIS rectal foam treated patients with decreased blood cortisol (defined as a morning cortisol level of < 5 mcg/dL) reported as an adverse event, none had adrenal insufficiency (defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH) (see Table 2). All cases of adrenal insufficiency resolved.

Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebo-controlled trials (Studies 1 and 2).

Table 2: Summary of Glucocorticoid Related Effects in Two Placebo- Controlled Trials (Studies 1 and 2)

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between UCERIS rectal foam and placebo after 6 weeks of therapy.

For additional details on morning cortisol levels and the response to the ACTH stimulation test, see CLINICAL PHARMACOLOGY.

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, maculo-papular rash, allergic dermatitis

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.