budesonide

1 INDICATIONS AND USAGE Budesonide 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. Budesonide rectal foam is a glucocorticosteroid 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. ( 1 )

2 DOSAGE AND ADMINISTRATION • The recommended dosage is 1 metered dose administered twice daily for 2 weeks followed by 1 metered dose administered once daily for 4 weeks. ( 2.1 ) • For rectal administration only. ( 2.2 ) • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use. ( 2.2 ) 2.1 Recommended 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. 2.2 Administration Instructions Advise patients: • Budesonide rectal foam is only to be applied rectally. It is not for oral use. • Before using budesonide 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. • Budesonide rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet). • Apply budesonide 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 budesonide rectal foam.

3 DOSAGE FORMS AND STRENGTHS Budesonide 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. Budesonide rectal foam contains 2 mg budesonide per metered dose. ( 3 )

4 CONTRAINDICATIONS Budesonide rectal foam is contraindicated in patients with a history of a known hypersensitivity to budesonide or any of the ingredients of budesonide rectal foam. Reactions have included anaphylaxis [see Adverse Reactions ( 6.2 )] . Known hypersensitivity to budesonide or any of the ingredients in budesonide rectal foam. ( 4 )

6 ADVERSE REACTIONS Serious and important adverse reactions include: • Hypercorticism and adrenal axis 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 )] • Increased susceptibility to infection [see Warnings and Precautions ( 5.3 )] • Other glucocorticosteroid effects [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (≥ 2%) are decreased blood cortisol, adrenal insufficiency, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Oceanside Pharmaceuticals at 1-800-321-4576 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 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 budesonide 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. Budesonide 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 budesonide rectal foam 2 mg twice a day for 2 weeks followed by 2 mg once a day for 4 weeks [see Clinical Studies ( 14 )] . The most common adverse reactions (≥ 2% of the budesonide rectal foam or Placebo group and at higher frequency in the budesonide 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 budesonide 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 Experienced by ≥ 2% of the budesonide rectal foam or Placebo group and at higher frequency in the budesonide rectal foam group. (Studies 1 and 2) Adverse Reaction Budesonide Rectal Foam 2 mg/25 mL N=268 n (%) Placebo N=278 n (%) Decreased blood cortisol Decreased blood cortisol was defined as a morning cortisol level of <5 mcg/dL. 46 (17) 6 (2) Adrenal insufficiency Adrenal insufficiency was defined as a cortisol level of <18 mcg/dL at 30 minutes post-challenge with ACTH. 10 (4) 2 (1) Nausea 6 (2) 2 (1) Of the 46 budesonide 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) Adverse Reaction Budesonide Rectal Foam 2 mg/25 mL N=268 n (%) Placebo N=278 n (%) Overall 60 (22) 10 (4) Blood cortisol decreased 46 (17) Decreases in serum cortisol levels associated with budesonide treatment were seen at Weeks 1 and 2 (twice daily treatment) in the budesonide rectal foam group, but gradually returned to baseline levels during the 4 weeks of once daily treatment. 6 (2) Adrenal insufficiency 10 (4) 2 (1) Insomnia 1 (0.4) 1 (0.4) Sleep disorder 1 (0.4) 0 Acne 1 (0.4) 0 Depression 1 (0.4) 1 (0.4) Hyperglycemia 1 (0.4) 0 No clinically significant differences were observed with respect to the overall percentages of patients with any glu …

7 DRUG INTERACTIONS CYP3A4 Inhibitors (e.g., ketoconazole, grapefruit juice): May cause increased systemic corticosteroid effects; avoid concomitant use. ( 7.1 ) 7.1 CYP3A4 Inhibitors The active ingredient of budesonide 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 budesonide rectal foam [see Clinical Pharmacology ( 12.3 )] .

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. ( 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 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, 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 of 2% to 4%, and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal 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 embryo-fetal 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 1.2 times the recommended human intrarectal dose on a body surface area basis). In an embryo-fetal 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 0.12 times the recommended human intrarectal dose of 4 mg/day 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 0.02 times the recommended human intrarectal dose on a body surface area basis) and 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose of 4 mg/day on a body surface area basis). In a pre-and post-natal 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 0.05 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 rectal foam or other rectally administered budesonide products and no information is available on the effects of budesonide on the b …

12.1 Mechanism of Action Budesonide has glucocorticosteroid (GCS) activity.

11 DESCRIPTION Budesonide 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 C 25 H 34 O 6 and its molecular weight is 430.5. Its structural formula is: Budesonide 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. structure

10 OVERDOSAGE Acute overdosage with budesonide rectal foam is unlikely. However, budesonide rectal foam is absorbed systemically and chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions ( 5.1 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING Budesonide 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 45802-627-86). Each canister (NDC 45802-627-01) is labeled with a net weight of 33.4 g 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) [see USP Controlled Room Temperature]. Handling Budesonide 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.