BUDESONIDE (ENTERIC COATED)

1 INDICATIONS AND USAGE 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.

6 ADVERSE REACTIONS 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