Budesonide

BUDESONIDE- budesonide tablet, extended release
Bryant Ranch Prepack

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1 INDICATIONS AND USAGE

Budesonide extended-release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis.

2 DOSAGE AND ADMINISTRATION

2.1 Mild to Moderate Ulcerative Colitis

The recommended dosage for the induction of remission in adult patients with active, mild to moderate ulcerative colitis is 9 mg taken orally once daily in the morning with or without food for up to 8 weeks. Budesonide extended-release tablets should be swallowed whole and not chewed, crushed or broken.

2.2 CYP3A4 Inhibitors

If concomitant administration with ketoconazole, or any other CYP3A4 inhibitor, is indicated, patients should be closely monitored for increased signs and/or symptoms of hypercorticism. Avoid grapefruit juice, which is known to inhibit CYP3A4, when taking budesonide extended-release tablets. In these cases, discontinuation of budesonide extended- release tablets or the CYP3A4 inhibitor should be considered [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

White, round, biconvex extended-release tablets debossed with “MX9”. Each extended-release tablet contains 9 mg budesonide.

4 CONTRAINDICATIONS

Budesonide extended-release tablets are contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of budesonide extended-release tablets. Anaphylactic reactions have occurred with other budesonide formulations [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 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 budesonide extended-release tablets are a glucocorticosteroid, general warnings concerning glucocorticoids should be followed.

5.2 Transferring Patients from Systemic Glucocorticosteroid Therapy

Care is needed in patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as budesonide extended-release tablets, 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.

5.3 Immunosuppression

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chickenpox 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 chickenpox 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.

Replacement of systemic glucocorticosteroids with budesonide extended-release tablets may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

5.4 Increased Systemic Glucocorticoid Susceptibility

Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis [see Use in Specific Populations (8.6).

5.5 Other Glucocorticosteroid Effects

Caution should be taken in 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.

6 ADVERSE REACTIONS

Systemic glucocorticosteroid use may result in the following:

•

Hypercorticism and Adrenal Suppression [see Warnings and Precautions (5.1)]

•

Symptoms of steroid withdrawal in those patients transferring from Systemic Glucocorticosteroid Therapy [see Warnings and Precautions (5.2)]

•

Immunosuppression [see Warnings and Precautions (5.3)]

•

Increased Systemic Glucocorticoid Susceptibility [see Warnings and Precautions (5.4)]

•

Other Glucocorticosteroid Effects [see Warnings and Precautions (5.5)]

6.1 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of budesonide extended-release tablets have been evaluated in controlled and open-label clinical trials which enrolled a combined total of 1,105 patients with ulcerative colitis.

In two 8-week, placebo-controlled studies in patients with active disease (Study 1 and Study 2), a total of 255 patients received budesonide extended-release tablets 9 mg, 254 patients received budesonide extended-release tablets 6 mg, and 258 patients received placebo. They ranged in age from 18-77 years (mean=43), 56% were male, and 75% were Caucasian. The most common adverse reactions were headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. The adverse reactions occurring in 2% or more of patients on therapy with budesonide extended-release tablets 9 mg are summarized in Table 1.

Table 1. Summary of Adverse Reactions in Two Placebo-Controlled Trials Experienced by at Least 2% of the Budesonide Extended-Release Tablets 9 mg Group (Studies 1 and 2)

	Budesonide extended- release tablets 9 mg (N=255) n (%)	Budesonide extended- release tablets 6 mg (N=254) n (%)	Placebo (N=258) n (%)
Headache	29 (11.4)	37 (14.6)	27 (10.5)
Nausea	13 (5.1)	12 (4.7)	11 (4.3)
Decreased blood cortisol	11 (4.3)	6 (2.4)	1 (0.4)
Upper abdominal pain	10 (3.9)	8 (3.1)	5 (1.9)
Fatigue	8 (3.1)	5 (2.0)	5 (1.9)
Flatulence	6 (2.4)	8 (3.1)	5 (1.9)
Abdominal distension	6 (2.4)	4 (1.6)	2 (0.8)
Acne	6 (2.4)	2 (0.8)	5 (1.9)
Urinary tract infection	5 (2.0)	1 (0.4)	1 (0.4)
Arthralgia	5 (2.0)	5 (2.0)	4 (1.6)
Constipation	5 (2.0)	1 (0.4)	2 (0.8)

Of budesonide extended-release tablets 9 mg patients, a total of 15% discontinued treatment due to any adverse event (including adverse reactions) compared with 17% in the placebo group.

Table 2 summarizes the percentages of patients reporting glucocorticoid-related effects in the 2 placebo-controlled studies.

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

	Budesonide extended- release tablets 9 mg (N=255) n (%)	Budesonide extended- release tablets 6 mg (N=254) n (%)	Placebo (N=258) n (%)
Overall	26 (10.2)	19 (7.5)	27 (10.5)
Mood changes	9 (3.5)	10 (3.9)	11 (4.3)
Sleep changes	7 (2.7)	10 (3.9)	12 (4.7)
Insomnia	6 (2.4)	6 (2.4)	8 (3.1)
Acne	6 (2.4)	2 (0.8)	5 (1.9)
Moon face	3 (1.2)	3 (1.2)	4 (1.6)
Fluid retention	2 (0.8)	3 (1.2)	3 (1.2)
Hirsutism	1 (0.4)	0	0
Striae rubrae	0	0	2 (0.8)
Flushing	0	1 (0.4)	3 (1.2)

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid-related effects between budesonide extended-release tablets and placebo after 8 weeks of induction therapy.

Study 3 was an open-label study evaluating budesonide extended-release tablets 9 mg once daily for 8 weeks in 60 patients who had previously completed an 8-week induction study (Study 1) but had not achieved remission. Among patients who took budesonide extended-release tablets 9 mg up to 16 weeks cumulatively across Study 1 and Study 3 combined, similar rates of adverse reactions and glucocorticoid-related effects were seen compared to those who took budesonide extended-release tablets 9 mg for 8 weeks in Study 1.

In Study 4, the safety of long-term treatment with budesonide extended-release tablets 6 mg was evaluated in a placebo-controlled 12-month maintenance study of 123 patients. Patients who had previously completed 8 weeks of therapy in any induction study (Study 1, 2, or 3) and were in remission were randomized to budesonide extended-release tablets 6 mg or placebo once daily for 12 months. In patients who took budesonide extended-release tablets 6 mg for up to 12 months, similar rates of adverse reactions were seen between placebo and budesonide extended-release tablets 6 mg. After up to 12 months of study treatment, 77% (27/35) of the patients in the budesonide extended-release tablets 6 mg and 74% (29/39) of the patients in the placebo treatment groups had normal bone density scans.

In Study 4, the glucocorticoid-related effects were similar in patients with up to 12 months of therapy with budesonide extended-release tablets 6 mg and placebo (Table 3).

Table 3. Summary of Glucocorticoid-Related Effects Over 12-Month Treatment (Study 4)

	Budesonide extended- release tablets 6 mg (N=62) n (%)	Placebo (N=61) n (%)
Overall	9 (14.5)	7 (11.5)
Insomnia	4 (6.5)	4 (6.6)
Mood changes	4 (6.5)	2 (3.3)
Moon face	3 (4.8)	3 (4.9)
Sleep changes	3 (4.8)	3 (4.9)
Acne	3 (4.8)	0
Hirsutism	3 (4.8)	0
Flushing	1 (1.6)	1 (1.6)
Fluid retention	1 (1.6)	1 (1.6)