FDA label cfb79484-a508-4dc7-b2ec-d0e5a0e0b077

5 WARNINGS AND PRECAUTIONS Hypercorticism and Adrenal Axis Suppression: Follow general warnings concerning corticosteroids; pediatrics and patients with hepatic impairment may be at increased risk. (2.4, 5.1, 8.4, 8.6) Symptoms of Steroid Withdrawal in Patients Transferred from Other Systemic Corticosteroids: Taper slowly from corticosteroids with high systemic effects; monitor for withdrawal symptoms and unmasking of allergies (rhinitis, eczema). (5.2) Increased Risk of Infection, including Serious and Fatal Chicken Pox and Measles: Monitor patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex. (5.3) Other Corticosteroid Effects: Monitor patients with concomitant conditions where corticosteroids may have unwanted effects (e.g., hypertension, diabetes mellitus). (5.4) 5.1 Hypercorticism and Adrenal Axis Suppression When corticosteroids are used chronically, systemic effects such as hypercorticism and adrenal axis suppression may occur. Corticosteroids 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 corticosteroid is recommended. Since BUDESONIDE Capsules contains a corticosteroid, general warnings concerning corticosteroids should be followed [see Warnings and Precautions (5.2), (5.3), (5.4) ]. Pediatric patients with Crohn’s disease have a slightly higher systemic exposure of budesonide and increased cortisol suppression than adults with Crohn’s disease [see Use in Specific Populations (8.4), Clinical Pharmacology (12.2) ]. Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure of oral budesonide. Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism and consider reducing the dosage in patients with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration (2.4), Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ]. 5.2 Symptoms of Steroid Withdrawal in Patients Transferred from Other Systemic Corticosteroids Monitor patients who are transferred from corticosteroid treatment with high systemic effects to corticosteroids with lower systemic availability, such as BUDESONIDE Capsules, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal axis suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of corticosteroid treatment with high systemic effects should be reduced cautiously. Replacement of systemic corticosteroids with BUDESONIDE Capsules may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. 5.3 Increased Risk of Infection Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of corticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid 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 chicken pox develops, treatment with antiviral agents may be considered. Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections,or ocular herpes simplex. 5.4 Other Corticosteroid Effects Monitor 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 corticosteroids may have unwanted effects.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Hypercorticism and Adrenal Suppression [ see Warnings and Precautions (5.1) ] Symptoms of steroid withdrawal in those patients transferred from 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, and pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharmaceuticals, Inc at 1-866-562-4597 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.AdultsThe data described below reflect exposure to BUDESONIDE Capsules 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 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 ReactionsOccurring in greater than or equal to 5% of the patients in any treated group. in 8-Week Treatment Clinical TrialsBUDESONIDE Capsules, 9 mgn = 520Placebon = 107PrednisolonePrednisolone tapering scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mg per week; or 40 mg in week 1to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg per week.40 mgn = 145ComparatorThis drug is not approved for the treatment of Crohn’s disease in the United States.n = 88Adverse ReactionNumber (%)Number (%)Number (%)Number (%)Headache107(21)19(18)31(21)11(13)Respiratory Infection55(11)7(7)20(14)5(6)Nausea57(11)10(9)18(12)7(8)Back Pain36(7)10(9)17(12)5(6)Dyspepsia31(6)4(4)17(12)3(3)Dizziness38(7)5(5)18(12)5(6)Abdominal Pain32(6)18(17)6(4)10(11)Flatulence30(6)6(6)12(8)5(6)Vomiting29(6)6(6)6(4)6(7)Fatigue25(5)8(7)11(8)0(0)Pain24(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 TrialsSigns/SymptomBUDESONIDE9 mgn = 427Number (%)Placebon = 107Number (%)PrednisolonePrednisolone 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.40 mgn = 145Number (%)Total145 (34%)29 (27%)69 (48%)Acne63 (15)14 (13)33 (23)Statistically significantly different from BUDESONIDE Capsules 9 mg.Bruising Easily63 (15)12 (11)13 (9)Moon Face46 (11)4 (4)53 (37)Swollen Ankles32 (7)6 (6)13 (9)HirsutismIncluding hair growth increased, local and hair growth increased, general.22 (5)2 (2)5 (3)Buffalo Hump6 (1)2 (2)5 (3)Skin Striae4 (1)2 (2)0 (0)Maintenance of Clinical Remission of Mild to Moderate Crohn’s DiseaseThe safety of BUDESONIDE Capsules 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 6 mg once daily.The adverse reaction profile of BUDESONIDE Capsules 6 mg once daily in maintenance of Crohn’s disease was similar to that of short-term treatment with BUDESONIDE Capsules 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 Studies.BUDESONIDE Capsules 3 mgn = 88BUDESONIDE Capsules 6 mgn = 145Placebon = 143Signs/SymptomNumber (%)Number (%)Number (%)Bruising Easily4(5)15(10)5(4)Acne4(5)14(10)3(2)Moon Face3(3)6(4)0Hirsutism2(2)5(3)1(1)Swollen Ankles2(2)3(2)3(2)Buffalo Hump1(1)1(1)0Skin Striae2(2)00The incidence of signs/symptom of hypercorticism as described above in long-term clinical trials was similar to that seen in the short-term 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 9 mg (total daily dose) in short-term treatment clinical studies and/or BUDESONIDE Capsules 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, parasthesia, tremor, vertigo, 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 (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 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 , 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. Pediatric use information is approved for Perrigo Pharma International DAC’s Entocort EC (budesonide) capsules. However, due to Perrigo Pharma International DAC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of Budesonide Capsule. 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