BUDESONIDE (ENTERIC COATED)

Budesonide, the active ingredient in budesonide extended-release capsules (enteric coated), is a synthetic corticosteroid. 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 C 25 H 34 O 6 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 and heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 5 is 1.6 × 10 3 ionic strength 0.01. Budesonide capsules (enteric coated) is formulated as hard gelatin capsules filled with enteric-coated granules that dissolve at pH greater than 5.5. Each capsule for oral administration contains 3 mg of micronized budesonide with the following inactive ingredients: acetyltributyl citrate, ethylcellulose, hypromellose, methacrylic acid copolymer (type C powder), polyethylene glycol, polysorbate 80, sodium lauryl sulfate, sugar spheres (sucrose and corn starch), talc, and triethyl citrate. The capsule shells have the following inactive ingredients gelatin, D&C red #28, D&C red #33, and titanium dioxide. In addition, the black ink S-1-8114/S-1-8115 contains, black iron oxide, D&C yellow #10 aluminum lake, FD&C blue#1 brilliant blue FCF aluminum lake, FD&C blue #2 indigo carmine aluminum lake, FD&C red #40 allura red AC aluminum lake, propylene glycol, and shellac. Chemical Structure

Budesonide capsules (enteric coated) are a corticosteroid indicated for: Treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon, in patients 8 years and older. ( 1.1 ) Maintenance of clinical remission of mild to moderate Crohn's disease involving the ileum and/or the ascending colon for up to 3 months in adults. ( 1.2 ) 1.1 Treatment of Mild to Moderate Active Crohn's Disease Budesonide capsules (enteric coated) are indicated for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon in patients 8 years of age and older. 1.2 Maintenance of Clinical Remission of Mild to Moderate Crohn's Disease Budesonide capsules (enteric coated) are indicated for the maintenance of clinical remission of mild to moderate Crohn's disease involving the ileum and/or the ascending colon for up to 3 months in adults.

Administration Instructions ( 2.1 ): Take once daily in the morning. Swallow whole. Do not chew or crush. Avoid consumption of grapefruit juice for the duration of therapy. Recommended Dosage: Mild to moderate active Crohn's disease ( 2.2 ): Adults: 9 mg once daily for up to 8 weeks; repeat 8 week treatment courses for recurring episodes of active disease. Pediatrics: 8 to 17 years who weigh more than 25 kg: 9 mg once daily for up to 8 weeks, followed by 6 mg once daily in the morning for 2 weeks. Maintenance of clinical remission of mild to moderate Crohn's disease ( 2.3 ): Adults: 6 mg once daily for up to 3 months; taper to complete cessation after 3 months. Continued treatment for more than 3 months has not been shown to provide substantial clinical benefit. When switching from oral prednisolone, begin tapering prednisolone concomitantly with initiating budesonide capsules (enteric coated). Hepatic Impairment: Consider reducing the dosage to 3 mg once daily in adult patients with moderate hepatic impairment (Child-Pugh Class B). ( 2.4 , 5.1 , 8.6 ) 2.1 Administration Instructions Take budesonide capsules (enteric coated) once daily in the morning. Swallow budesonide extended-release capsules (enteric coated) whole. Do not chew or crush. Avoid consumption of grapefruit juice for the duration of budesonide capsules (enteric coated) therapy [see Drug Interactions (7.1) ]. 2.2 Treatment of Mild to Moderate Active Crohn's Disease The recommended dosage of budesonide capsules (enteric coated) is: Adults: 9 mg orally once daily for up to 8 weeks. Repeated 8 week courses of budesonide capsules (enteric coated) can be given for recurring episodes of active disease. Pediatric patients 8 to 17 years who weigh more than 25 kg : 9 mg orally once daily for up to 8 weeks, followed by 6 mg once daily for 2 weeks. 2.3 Maintenance of Clinical Remission of Mild to Moderate Crohn's Disease The recommended dosage in adults, following an 8 week course(s) of treatment for active disease and once the patient's symptoms are controlled (CDAI less than 150), is budesonide capsules (enteric coated) 6 mg orally once daily for maintenance of clinical remission up to 3 months. If symptom control is still maintained at 3 months an attempt to taper to complete cessation is recommended. Continued treatment with budesonide capsules (enteric coated) 6 mg for more than 3 months has not been shown to provide substantial clinical benefit. Patients with mild to moderate active Crohn's disease involving the ileum and/or ascending colon have been switched from oral prednisolone to budesonide capsules (enteric coated) with no reported episodes of adrenal insufficiency. Since prednisolone should not be stopped abruptly, tapering should begin concomitantly with initiating budesonide capsules (enteric coated) treatment. 2.4 Dosage Adjustment in Adult Patients with Hepatic Impairment Consider reducing the dosage of budesonide capsules (enteric coated) to 3 mg once daily for adult patients with moderate hepatic impairment (Child-Pugh Class B). Avoid use in patients with severe hepatic impairment (Child-Pugh Class C) [see Warnings and Precautions (5.1) , Use in Specific Populations (8.6) ].

Budesonide capsules (enteric coated) are contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of budesonide capsules (enteric coated). Serious hypersensitivity reactions, including anaphylaxis have occurred [see Adverse Reactions (6.2) ] . Hypersensitivity to any of the ingredients in budesonide capsules (enteric coated). ( 4 )

The following clinically significant adverse reactions are described elsewhere in labeling: Hypercorticism and adrenal axis suppression [see Warnings and Precautions (5.1) ] Symptoms of steroid withdrawal in those patients transferred from other systemic corticosteroids [see Warnings and Precautions (5.2) ] Increased risk of infection [see Warnings and Precautions (5.3) ] Other corticosteroid effects [see Warnings and Precautions (5.4) ] Most common adverse reactions (≥5%) in adults are: headache, respiratory infection, nausea, back pain, dyspepsia, dizziness, abdominal pain, flatulence, vomiting, fatigue, pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 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. Adults The data described below reflect exposure to budesonide capsules (enteric coated) in 520 patients with Crohn's disease, including 520 exposed to 9 mg per day (total daily dose) for 8 weeks and 145 exposed to 6 mg per day for one year in placebo controlled clinical trials. Of the 520 patients, 38% were males and the age range was 17 to 74 years. Treatment of Mild to Moderate Active Crohn's Disease The safety of budesonide capsules (enteric coated) was evaluated in 651 adult patients in five clinical trials of 8 weeks duration in patients with active mild to moderate Crohn's disease. The most common adverse reactions, occurring in greater than or equal to 5% of the patients, are listed in Table 1. Table 1: Common Adverse Reactions Occurring in greater than or equal to 5% of the patients in any treated group. in 8-Week Treatment Clinical Trials Budesonide capsules (enteric coated) Prednisolone Prednisolone tapering scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mg per week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg per week. Adverse Reaction 9 mg n=520 Number (%) Placebo n=107 Number (%) 40 mg n=145 Number (%) Comparator This drug is not approved for the treatment of Crohn's disease in the United States. n=88 Number (%) Headache 107 (21) 19 (18) 31 (21) 11 (13) Respiratory Infection 55 (11) 7 (7) 20 (14) 5 (6) Nausea 57 (11) 10 (9) 18 (12) 7 (8) Back Pain 36 (7) 10 (9) 17 (12) 5 (6) Dyspepsia 31 (6) 4 (4) 17 (12) 3 (3) Dizziness 38 (7) 5 (5) 18 (12) 5 (6) Abdominal Pain 32 (6) 18 (17) 6 (4) 10 (11) Flatulence 30 (6) 6 (6) 12 (8) 5 (6) Vomiting 29 (6) 6 (6) 6 (4) 6 (7) Fatigue 25 (5) 8 (7) 11 (8) 0 (0) Pain 24 (5) 8 (7) 17 (12) 2 (2) The incidence of signs and symptoms of hypercorticism reported by active questioning of patients in 4 of the 5 short-term clinical trials are displayed in Table 2. Table 2: Summary and Incidence of Signs/Symptoms of Hypercorticism in 8-Week Treatment Clinical Trials Budesonide capsules (enteric coated) Prednisolone Prednisolone tapering scheme: either 40 mg in week 1-2, thereafter tapering with 5 mg/week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg/week. Signs/Symptom 9 mg n=427 Number (%) Placebo n=107 Number (%) 40 mg n=145 Number (%) Total 145 (34%) 29 (27%) 69 (48%) Acne 63 (15) 14 (13) 33 (23) Statistically significantly different from budesonide capsules (enteric coated) 9 mg. Bruising Easily 63 (15) 12 (11) 13 (9) Moon Face 46 (11) 4 (4) 53 (37) Swollen Ankles 32 (7) 6 (6) 13 (9) Hirsutism including hair growth increased, local and hair growth increased, general. 22 (5) 2 (2) 5 (3) Buffalo Hump 6 (1) 2 (2) 5 (3) Skin Striae 4 (1) 2 (2) 0 (0) Maintenance of Clinical Remission of Mild to Moderate Crohn's Disease The safety of budesonide capsules (enteric coated) was evaluated in 233 adult patients in four long-term clinical trials (52 weeks) of maintenance of clinical remission in patients with mild to moderate Crohn's disease. A total of 145 patients were treated with budesonide capsules (enteric coated) 6 mg once daily. The adverse reaction profile of budesonide capsules (enteric coated) 6 mg once daily in maintenance of Crohn's disease was similar to that of short-term treatment with budesonide capsules (enteric coated) 9 mg once daily in active Crohn's disease. In the long-term clinical trials, the following adverse reactions occurred in greater than or equal to 5% and are not listed in Table 1: diarrhea (10%); sinusitis (8%); infection viral (6%); and arthralgia (5%). Signs/symptoms of hypercorticism reported by active questioning of patients in the long-term maintenance clinical trials are displayed in Table 3. Table 3: Summary and Incidence of Signs/Symptoms of Hypercorticism in Long-Term Clinical Trials Budesonide capsules (enteric coated) Budesonide capsules (enteric coated) Signs/Symptom 3 mg n=88 Number (%) 6 mg n=145 Number (%) Placebo n=143 Number (%) Bruising Easily 4 (5) 15 (10) 5 (4) Acne 4 (5) 14 (10) 3 (2) Moon Face 3 (3) 6 (4) 0 Hirsutism 2 (2) 5 (3) 1 (1) Swollen Ankles 2 (2) 3 (2) 3 (2) Buffalo Hump 1 (1) 1 (1) 0 Skin Striae 2 (2) 0 0 The incidence of signs/symptoms of hypercorticism as described above in long-term maintenance clinical trials was similar to that seen in the short-term treatment clinical trials. Less Common Adverse Reactions in Treatment and Maintenance Clinical Trials Less common adverse reactions (less than 5%), occurring in adult patients treated with budesonide capsules (enteric coated) 9 mg (total daily dose) in short-term treatment clinical studies and/or budesonide capsules (enteric coated) 6 mg (total daily dose) in long-term maintenance clinical trials, with an incidence are listed below by system organ class: Cardiac disorders: palpitation, tachycardia Eye disorders: eye abnormality, vision abnormal General disorders and administration site conditions: asthenia, chest pain, dependent edema, face edema, flu-like disorder, malaise, fever Gastrointestinal disorders: anus disorder, enteritis, epigastric pain, gastrointestinal fistula, glossitis, hemorrhoids, intestinal obstruction, tongue edema, tooth disorder Infections and infestations: Ear infection-not otherwise specified, bronchitis, abscess, rhinitis, urinary tract infection, thrush Investigations: weight increased Metabolism and nutrition disorders: appetite increased Musculoskeletal and connective tissue disorders: arthritis, cramps, myalgia Nervous system disorders: hyperkinesia, paresthesia, tremor, vertigo, dizziness, somnolence, amnesia Psychiatric disorders: agitation, confusion, insomnia, nervousness, sleep disorder Renal and urinary disorders: dysuria, micturition frequency, nocturia Reproductive system and breast disorders: intermenstrual bleeding, menstrual disorder Respiratory, thoracic and mediastinal disorders: dyspnea, pharynx disorder Skin and subcutaneous tissue disorders: alopecia, dermatitis, eczema, skin disorder, sweating increased, purpura Vascular disorders: flushing, hypertension Bone Mineral Density A randomized, open, parallel-group multicenter safety clinical trial specifically compared the effect of budesonide capsules (enteric coated) (less than 9 mg per day) and prednisolone (less than 40 mg per day) on bone mineral density over 2 years when used at doses adjusted to disease severity. Bone mineral density decreased significantly less with budesonide capsules (enteric coated) than with prednisolone in steroid-naïve patients, whereas no difference could be detected between treatment groups for steroid-dependent patients and previous steroid users. The incidence of symptoms associated with hypercorticism was significantly higher with prednisolone treatment. Clinical Laboratory Test Findings The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to budesonide capsules (enteric coated), were reported in greater than or equal to 1% of patients: hypokalemia, leukocytosis, anemia, hematuria, pyuria, erythrocyte sedimentation rate increased, alkaline phosphatase increased, atypical neutrophils, c-reactive protein increased and adrenal insufficiency. Pediatrics – Treatment of Mild to Moderate Active Crohn's Disease Adverse reactions reported in pediatric patients 8 to 17 years of age, who weigh more than 25 kg, were similar to those reactions described above in adult patients. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of budesonide capsules (enteric coated). 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. Immune System Disorders: Anaphylactic reactions Nervous System Disorders: Benign intracranial hypertension Psychiatric Disorders: Mood swings

CYP3A4 Inhibitors (e.g., ketoconazole, grapefruit juice) : Can increase systemic budesonide concentrations: avoid use. ( 2.1 , 7.1 ) 7.1 CYP3A4 Inhibitors Budesonide is a substrate for CYP3A4. Avoid use with CYP3A4 inhibitors. Concomitant oral administration of a strong CYP3A4 inhibitor (ketoconazole) caused an eight-fold increase of the systemic exposure to oral budesonide. Inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, and cyclosporine) can increase systemic budesonide concentrations [see Clinical Pharmacology (12.3) ] . Grapefruit Juice Avoid ingestion of grapefruit or grapefruit juice with budesonide. Intake of grapefruit juice which inhibits CYP3A4 activity with budesonide can increase the systemic exposure for budesonide [see Clinical Pharmacology (12.3) ].

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Keep container tightly closed.