Budesonide ER Tablets

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.

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.

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.

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)].

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.

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)]

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 Tablets9 mg Group (Studies 1 and 2)

	Budesonide extended release tablets9 mg (N=255) n (%)	Budesonide extended release tablets6 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 tablets9 mg (N=255) n (%)	Budesonide extended release tablets6 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 tablets6 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)

Postmarketing Experience

In addition to adverse events reported from clinical trials, the following adverse reactions have been identified during post-approval use of oral 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. These events have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to budesonide extended release tablets, or a combination of these factors.

Gastrointestinal Disorders: diarrhea, rectal bleeding

General Disorders and Administrative Site Conditions: peripheral edema

Immune System Disorders: anaphylactic reactions

Musculoskeletal and Connective Tissue Disorders: muscle cramps/spasms

Nervous System Disorders: benign intracranial hypertension, dizziness

Psychiatric Disorders: mood swings

Skin and Subcutaneous Tissue Disorders: rash

Vascular Disorders: increased blood pressure

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 C25H34O6  and its molecular weight is 430.5. Its structural formula is:

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.

Budesonide extended release tablets, 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.

Induction of Remission in Active, Mild to Moderate Ulcerative Colitis

Two similarly designed, randomized, double-blind, placebo-controlled studies were conducted in a total of 970 adult patients with active, mild to moderate ulcerative colitis (UC) which was defined as an Ulcerative Colitis Disease Activity Index (UCDAI of  ≥4 and ≤10).  Eight hundred ninety-nine of these patients had histology consistent with active UC; this was considered the primary analysis population. UCDAI is a four-component scale (total score of 0 to 12) that encompasses the clinical assessments of stool frequency, rectal bleeding, mucosal appearance and physician’s rating of disease activity (score of 0 to 3 for each of the components).

The baseline median UCDAI score in both studies was 7.

In Study 1, 56% of patients were male, and the median age was 42 years. In Study 2, 57% of patients were male, and the median age was 44 years. In Study 1, 50% of patients were Caucasian, 7% were African American, and 34% were Asian. In Study 2, more than 99% were Caucasian.

Both studies compared budesonide extended release tablets 9 mg and 6 mg with placebo and included an active reference arm (a mesalamine 2.4 g in Study 1 and a budesonide* 9 mg not approved for the treatment of UC in Study 2). The primary endpoint was induction of remission after 8 weeks of treatment. Remission was defined as a UCDAI score of ≤1, with subscores of 0 for rectal bleeding, stool frequency, and mucosal appearance and with a ≥1 point reduction in an endoscopy-only score.2 In both studies, budesonide extended release tablets 9 mg demonstrated superiority to placebo in inducing remission (Table 4).

Table 4.          Induction of Remission in Studies 1 and 2

Treatment Group	Study 1 n/N (%)	Study 2 n/N (%)
Budesonide extended release tablets 9 mg	22/123 (17.9)	19/109 (17.4)
Budesonide extended release tablets 6 mg	16/121 (13.2)	9/109 (8.3)
Reference arm*	15/124 (12.1)	13/103 (12.6)
Placebo	9/121 (7.4)	4/89 (4.5)
Treatment difference between budesonide extended release tablets 9 mg and placebo (95% CI)†	10.4% (2.2%, 18.7%)	12.9% (4.6%, 21.3%)

Remission is defined as a UCDAI score of ≤1, with subscores of 0 for rectal bleeding, stool frequency, and mucosal appearance and with a ≥1 point reduction in an endoscopy-only score.2

The primary analysis population included only patients that had histology consistent with active UC.

CI=Confidence Interval

*The reference arm in Study 1 is a delayed release mesalamine 2.4 g; the reference arm in Study 2 is a budesonide 9 mg not approved for the treatment of UC.

†p<0.025 for budesonide extended release tablets 9 mg vs. placebo in both Studies 1 and 2 based on the Chi-square test (alpha=0.025)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Patients being treated with budesonide extended release tablets should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of budesonide extended release tablets. 

Hypercorticism and Adrenal Suppression

Patients should be advised that budesonide extended release tablets may cause systemic glucocorticosteroid effects of hypercorticism and adrenal suppression. Patients should taper slowly from systemic corticosteroids if transferring to budesonide extended release tablets [see Warnings and Precautions (5.1) and (5.2)].

Immunosuppression

Patients who are on immunosuppressant doses of glucocorticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician immediately. If exposure to such a person occurs, and the patient has not had chickenpox or been properly vaccinated, a physician should be consulted immediately. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.3)].

How to Take Budesonide Extended Release Tablets

Budesonide extended release tablets should be swallowed whole with water and NOT CHEWED, CRUSHED, OR BROKEN. Patients should be advised to avoid the consumption of grapefruit juice for the duration of their budesonide extended release tablets therapy [see Dosage and Administration (2)].

Manufactured for:
Oceanside Pharmaceuticals, a division of
Valeant Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA

By:
Cosmo S.p.A.
Milan, 20020 Italy

By license of Cosmo Technologies Ltd., Dublin, Ireland

U.S. Patent Numbers: 7,410,651; 7,431,943; 8,293,273; 8,784,888; 8,895,064;
9,132,093; 9,192,581; 9,320,716; 9,532,954; 9,592,203 and RE43799

© Valeant Pharmaceuticals North America LLC

9628700
70013430

Budesonide (bew DEH so nide)
extended release tablets

What are budesonide extended release tablets?

Budesonide extended release tablets are a prescription corticosteroid medicine used to help get mild to moderate ulcerative colitis (UC) under control (induce remission).

It is not known if budesonide extended release tablets are safe and effective in children.

Who should not take budesonide extended release tablets?

Do not take budesonide extended release tablets if:

• you are allergic to budesonide or any of the ingredients in budesonide extended release tablets. See the end of this leaflet for a complete list of ingredients in budesonide extended release tablets.

What should I tell my healthcare provider before taking budesonide extended release tablets?

Before you take budesonide extended release tablets tell your healthcare provider if you:

• have liver problems • are planning to have surgery • have chickenpox or measles or have recently been near anyone with chickenpox or measles • have an infection • have or had a family history of diabetes, cataracts or glaucoma • have or had tuberculosis • have high blood pressure (hypertension) • have decreased bone mineral density (osteoporosis) • have stomach ulcers • have any other medical condition • are pregnant or plan to become pregnant. It is not known if budesonide extended release tablets will harm your unborn baby. • are breastfeeding or plan to breastfeed. budesonide extended release tablets can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will take budesonide extended release tablets or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter vitamins, and herbal supplements. budesonide extended release tablets and other medicines may affect each other causing side effects.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take budesonide extended release tablets?

• Take budesonide extended release tablets exactly as your healthcare provider tells you to take them. • Your healthcare provider will tell you how many budesonide extended release tablets to take. • Take budesonide extended release tablets in the morning. • Take budesonide extended release tablets whole with water. Do not chew, crush, or break budesonide extended release tablets before swallowing. • If you take too much of budesonide extended release tablets, call your healthcare provider right away or go to the nearest hospital emergency room.

What should I avoid while taking budesonide extended release tablets?

• Do not eat grapefruit or drink grapefruit juice while taking budesonide extended release tablets. Eating grapefruit or drinking grapefruit juice can increase the level of budesonide extended release tablets in your blood.

What are the possible side effects of budesonide extended release tablets?

Budesonide extended release tablets can cause some serious side effects, including:

Effects of having too much corticosteroid medicine in your blood (hypercorticism). Long-time use of budesonide extended release tablets can cause you to have too much glucocorticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism:

• acne • bruise easily • rounding of your face (moon face) • ankle swelling • thicker or more hair on your body and face • a fatty pad or hump between your shoulders (buffalo hump) • pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms

Adrenal suppression. When budesonide extended release tablets are taken for a long period of time (chronic use), the adrenal glands do not make enough steroid hormones (adrenal suppression). Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide extended release tablets including:

• tiredness • weakness • nausea • vomiting • low blood pressure

Immune system effects and a higher chance of infections.

Budesonide extended release tablets weaken your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases such as chickenpox or measles, while taking budesonide extended release tablets.

Tell your health care provider about any signs or symptoms of infection during treatment with budesonide extended release tablets, including:

• fever • pain • aches • chills • feeling tired • nausea and vomiting

Worsening of allergies. If you take certain other corticosteroid medicines to treat allergies, switching to budesonide extended release tablets may cause your allergies to come back. These allergies may include eczema (a skin disease) or rhinitis (inflammation inside your nose). Tell your healthcare provider if any of your allergies become worse while taking budesonide extended release tablets.

The most common side effects of budesonide extended release tablets include:

• headache • nausea • decreased blood cortisol levels • stomach-area pain • tiredness • stomach or intestinal gas • bloating • acne • urinary tract infection • joint pain • constipation

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of budesonide extended release tablets. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store budesonide extended release tablets?

• Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. • Keep the bottle tightly closed to protect budesonide extended release tablets from light and moisture.

Keep out of reach of children

General Information about budesonide extended release tablets

Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use budesonide extended release tablets for a condition for which it was not prescribed. Do not give budesonide extended release tablets to other people, even if they have the same symptoms you have. It may harm them.

If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about budesonide that is written for health professionals.

For more information call 1-800-321-4576.

What are the ingredients in budesonideextended release tablets?

Active Ingredients: budesonide

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.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured for:
Oceanside Pharmaceuticals, a division of
Valeant Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA

By:
Cosmo S.p.A.
Milan, 20020 Italy

By license of Cosmo Technologies Ltd., Dublin, Ireland

U.S. Patent Numbers: 7,410,651; 7,431,943; 8,293,273; 8,784,888; 8,895,064;
9,132,093; 9,192,581; 9,320,716; 9,532,954; 9,592,203 and RE43799

© Valeant Pharmaceuticals North America LLC

9628700 70013430 Rev. 03/2018