Budesonide

Warnings and Precautions, Immunosuppression and Increased Risk of Infection ( 5.3 ) 06/2024 Kaposi’s Sarcoma ( 5.4 ) 06/2024

1 INDICATIONS AND USAGE Budesonide extended-release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. Budesonide extended-release tablets are a glucocorticosteroid indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis ( 1 ).

2 DOSAGE AND ADMINISTRATION The recommended dosage for the induction of remission in adult patients with active, mild to moderate ulcerative colitis is one 9 mg tablet to be taken once daily in the morning with or without food for up to 8 weeks. ( 2.1 ) 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 Budesonide Extended-Release Tablets are available containing 9 mg of budesonide, USP. • The 9 mg tablets are white, film-coated, round, unscored tablets with M over BE9 imprinted in black ink on one side of the tablet and blank on the other side. Extended-release tablets: 9 mg ( 3 )

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) ] . • Known hypersensitivity to budesonide or any of the ingredients in budesonide extended-release tablets ( 4 )

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 and Increased Risk of Infection [see Warnings and Precautions (5.3) ] • Kaposi’s Sarcoma [see Warnings and Precautions (5.4) ] • Increased Systemic Glucocorticoid Susceptibility [see Warnings and Precautions (5.5) ] • Other Glucocorticosteroid Effects [see Warnings and Precautions (5.6) ] Most common adverse reactions (incidence ≥ 2%) are headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 has 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 afte …

7 DRUG INTERACTIONS • Avoid cytochrome P450 3A4 inhibitors (e.g., ketoconazole, grapefruit juice). May cause increased systemic corticosteroid effects. ( 2.2 , 7 , 12.3 ) 7.1 Interaction with CYP3A4 Inhibitors Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eight-fold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of budesonide extended-release tablets should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be avoided in connection with budesonide extended-release tablets administration [see Dosage and Administration (2) and Clinical Pharmacology (12.3) ] . 7.2 Inhibitors of Gastric Acid Secretion Since the dissolution of the coating of budesonide extended-release tablets is pH dependent, the release properties and uptake of the compound may be altered when budesonide extended-release tablets are used after treatment with gastric acid reducing agents (e.g., proton pump inhibitors (PPIs), H 2 blockers and antacids).

8 USE IN SPECIFIC POPULATIONS • Pregnancy : Based on animal data, may cause fetal harm. ( 8.1 ) • Hepatic Impairment : Monitor patients for signs and/or symptoms of hypercorticism. ( 5.5 , 8.6 ) 8.1 Pregnancy Risk Summary Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations (see Clinical Considerations ). In animal reproduction studies with pregnant rats and rabbits, subcutaneous administration of budesonide during organogenesis at doses 0.5 times and 0.05 times, respectively, the maximum recommended human dose, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels ( see Data ). Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4%, and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Fetal/Neonatal Adverse Reactions Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions (5.1) ] . Data Animal Data Budesonide was teratogenic and embryolethal in rabbits and rats. In an embryofetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6-15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In an embryofetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.01 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In a peri- and postnatal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced, and surviving offspring had decreased mean body weights at birth and during lactation at exposures 0.02 times the MRHD (on a mg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity. 8.2 Lactation Risk Summary Lactation studies have not been conducted with budesonide extended-release tablets or other oral budesonide products and no information is available on the effects of budesonide on the breastfed infant or the effects of the drug on …

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 greater than or equal to 7 in the small intestine. Upon disintegration of the coating, the core matrix provides extended-release of budesonide in a time dependent manner.

11 DESCRIPTION Budesonide extended-release tablets, for oral administration, contain budesonide USP, a synthetic corticosteroid, as the active ingredient. Budesonide, USP is designated chemically as (RS)-11β, 16α, 17, 21 tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide, USP is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide, USP is C 25 H 34 O 6 and its molecular weight is 430.54. Its structural formula is: Budesonide, USP is a white to almost white, tasteless, odorless powder that is practically insoluble in water, sparingly soluble in alcohol, and freely soluble in chloroform. Budesonide extended-release, 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: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose 2910, iron oxide black, lactose monohydrate, magnesium stearate, methacrylic acid copolymer types A and B, microcrystalline cellulose, polyethylene glycol 400, polysorbate 80, propylene glycol, sodium starch glycolate Type A, soy lecithin powder, talc, titanium dioxide, and triethyl citrate. The structural formula for Budesonide

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Budesonide Extended-Release Tablets are available containing 9 mg of budesonide, USP. The 9 mg tablets are white, film-coated, round, unscored tablets with M over BE9 imprinted in black ink on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-4500-93 bottles of 30 tablets Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Keep container tightly closed. Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.