PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 3 mg NDC 0378-7155-01 Budesonide Capsules 3 mg Enteric Coated Rx only 100 Capsules Each capsule contains: Budesonide, USP 3 mg Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Keep container tightly closed. Keep this and all medication out of the reach of children. Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.] Usual Dosage: Take 3 capsules every morning. See prescribing information. Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Mylan.com RM7155A2

ADVERSE REACTIONS SECTION.


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, and pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. 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. Adults The data described below reflect exposure to budesonide capsules (enteric coated) in 520 patients with Crohns 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 Crohns 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 Crohns 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 Trials Adverse Reaction Budesonide Capsules (Enteric Coated) 9 mg n = 520 Placebo n = 107 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. 40 mg n = 145 Comparator This drug is not approved for the treatment of Crohns disease in the United States. n = 88 Number (%) Number (%) Number (%) 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 Signs/Symptom Budesonide Capsules (Enteric Coated) 9 mg n = 427 Placebo n = 107 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. 40 mg n = 145 Number (%) Number (%) Number (%) Total 145 (34%) 29 (27%) 69 (48%) Acne 63 (15) 14 (13) 33 (23)2 Bruising Easily 63 (15) 12 (11) 13 (9) Moon Face 46 (11) 4 (4) 53 (37)Statistically significantly different from budesonide capsules (enteric coated) 9 mg. Swollen Ankles 32 (7) 6 (6) 13 (9) HirsutismIncluding 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 Crohns 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 Crohns 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 Crohns disease was similar to that of short-term treatment with budesonide capsules (enteric coated) 9 mg once daily in active Crohns 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 Signs/Symptom Budesonide Capsules (Enteric Coated) 3 mg n = 88 Budesonide Capsules (Enteric Coated) 6 mg n = 145 Placebo n = 143 Number (%) Number (%) 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, 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-nave 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. Pediatric use information is approved for Perrigo Pharma International DACs ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DACs 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 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

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS Budesonide Capsules (enteric coated) are available containing 3 mg of budesonide, USP. The 3 mg capsule is a hard-shell gelatin capsule with a red opaque cap and red opaque body filled with white to off-white enteric-coated pellets with no markings. The capsule is axially printed with MYLAN over 7155 in black ink on both the cap and body. Capsules: 3 mg (3)

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE Budesonide capsules (enteric coated) are a corticosteroid indicated for: Treatment of mild to moderate active Crohns disease involving the ileum and/or the ascending colon. (1.1) Maintenance of clinical remission of mild to moderate Crohns 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 Crohns 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. Pediatric use information is approved for Perrigo Pharma International DACs ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DACs marketing exclusivity rights, this drug product is not labeled with that pediatric information. 1.2 Maintenance of Clinical Remission of Mild to Moderate Crohns Disease Budesonide capsules (enteric coated) are indicated for the maintenance of clinical remission of mild to moderate Crohns disease involving the ileum and/or the ascending colon for up to 3 months in adults.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION 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 Crohns disease (2.2): Adults: 9 mg once daily for up to 8 weeks; repeat 8 week treatment courses for recurring episodes of active disease. Maintenance of Clinical Remission of Mild to Moderate Crohns 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 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 Crohns 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 use information is approved for Perrigo Pharma International DACs ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DACs marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.3 Maintenance of Clinical Remission of Mild to Moderate Crohns Disease The recommended dosage in adults, following an 8 week course(s) of treatment for active disease and once the patients 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 Crohns 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) ].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING Budesonide Capsules (enteric coated) are available containing 3 mg of budesonide, USP. The 3 mg capsule is a hard-shell gelatin capsule with a red opaque cap and red opaque body filled with white to off-white enteric-coated pellets with no markings. The capsule is axially printed with MYLAN over 7155 in black ink on both the cap and body. They are available as follows: NDC 0378-7155-01 bottles of 100 capsules Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Keep container tightly closed.

DESCRIPTION SECTION.


11 DESCRIPTION Budesonide, the active ingredient of budesonide capsules (enteric coated), is a synthetic corticosteroid. Budesonide is designated chemically as (RS)-11,16,17,21-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 molecular formula of budesonide is C25H34O6 and its molecular weight is 430.5. Its structural formula is: Budesonide, USP is a white to almost white crystalline 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 x 103 ionic strength 0.01. Budesonide capsules (enteric coated) are formulated as hard gelatin capsules filled with enteric-coated pellets 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, colloidal silicon dioxide, crospovidone, dimethicone, ethylcellulose, FD&C Red No. 40, gelatin, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sodium hydroxide, sodium lauryl sulfate, talc, titanium dioxide and triethyl citrate. The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.

OVERDOSAGE SECTION.


10 OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. If corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism and adrenal axis suppression may occur. For chronic overdosage in the case of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. Single oral 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.

SPL PATIENT PACKAGE INSERT SECTION.


Patient Information It is not known if budesonide capsules (enteric coated) are safe and effective in children under 8 years of age. Pediatric use information is approved for Perrigo Pharma International DACs ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DACs marketing exclusivity rights, this drug product is not labeled with that pediatric information. Effects of having too much corticosteroid medicine in your blood (hypercorticism). Adrenal suppression. Worsening of allergies. Increased risk of infection. Budesonide Capsules (enteric coated) (bue des' oh nide) Read this Patient Information before you start taking budesonide capsules (enteric coated) and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What are budesonide capsules (enteric coated)? Budesonide capsules (enteric coated) are a prescription corticosteroid medicine used to treat mild to moderate Crohns disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon): in people with active Crohns disease in adults to help keep symptoms from coming back for up to 3 months Who should not take budesonide capsules (enteric coated)? Do not take budesonide capsules (enteric coated) if: you are allergic to budesonide or any of the ingredients in budesonide capsules (enteric coated). See the end of this leaflet for a complete list of ingredients in budesonide capsules (enteric coated). What should I tell my healthcare provider before taking budesonide capsules (enteric coated)? Before you take budesonide capsules (enteric coated) tell your healthcare provider if you: have liver problems are planning to have surgery have chicken pox or measles or have recently been near anyone with chicken pox or measles have an infection have diabetes or glaucoma or have a family history of diabetes or glaucoma have cataracts have or had tuberculosis have high blood pressure (hypertension) have decreased bone mineral density (osteoporosis) have stomach ulcers have any other medical condition are pregnant or plan to become pregnant. Budesonide capsules (enteric coated) may harm your unborn baby. Talk to your healthcare provider about the possible risk to your unborn baby if you take budesonide capsules (enteric coated) when you are pregnant. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during your treatment with budesonide capsules (enteric coated). are breastfeeding or plan to breastfeed. It is not known if budesonide passes into your breast milk or if it will affect your baby. Talk to your healthcare provider about the best way to feed your baby if you take budesonide capsules (enteric coated). Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide capsules (enteric coated) and other medicines may affect each other causing side effects. How should I take budesonide capsules (enteric coated)? Take budesonide capsules (enteric coated) exactly as your healthcare provider tells you. Your healthcare provider will tell you how many budesonide capsules (enteric coated) to take. Your healthcare provider may change your dose if needed. Take budesonide capsules (enteric coated) 1 time each day in the morning. Take budesonide capsules (enteric coated) whole. Do not chew or crush budesonide capsules (enteric coated) before swallowing. If you take too many budesonide capsules (enteric coated) call your healthcare provider right away or go to the nearest hospital emergency room. What should I avoid while taking budesonide capsules (enteric coated)? Do not drink grapefruit juice during your treatment with budesonide capsules (enteric coated). Drinking grapefruit juice can increase the level of budesonide in your blood. What are the possible side effects of budesonide capsules (enteric coated)? Budesonide capsules (enteric coated) may cause serious side effects, including: Long-time use of budesonide capsules (enteric coated) can cause you to have too much corticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism: oacne obruise easily orounding of your face (moon face) oankle swelling othicker or more hair on your body and face oa fatty pad or hump between your shoulders (buffalo hump) opink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms When budesonide capsules (enteric coated) are taken for a long period of time (chronic use), adrenal suppression can happen. This is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal suppression include: tiredness, weakness, nausea and vomiting and low blood pressure. Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide capsules (enteric coated). If you take certain other corticosteroid medicines to treat allergies, switching to budesonide capsules (enteric coated) may cause your allergies to come back. These allergies may include a skin condition called eczema or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while taking budesonide capsules (enteric coated). Budesonide capsules (enteric coated) weaken your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases, such as chicken pox or measles, while taking budesonide capsules (enteric coated). Tell your healthcare provider right away if you come in contact with anyone who has chicken pox or measles. Tell your healthcare provider about any signs or symptoms of infection during treatment with budesonide capsules (enteric coated), including: ofever opain oaches ochills ofeeling tired onausea and vomiting The most common side effects of budesonide capsules (enteric coated) in adults include: headache infection in your air passages (respiratory infection) nausea back pain indigestion dizziness stomach area (abdominal) pain gas vomiting tiredness pain Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of budesonide capsules (enteric coated). For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX). How should I store budesonide capsules (enteric coated)? Store budesonide capsules (enteric coated) at room temperature between 20 to 25C (68 to 77F). Keep budesonide capsules (enteric coated) in a tightly closed container. Keep budesonide capsules (enteric coated) and all medicines out of the reach of children. General information about the safe and effective use of budesonide capsules (enteric coated). Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use budesonide capsules (enteric coated) for a condition for which it was not prescribed. Do not give budesonide capsules (enteric coated) to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about budesonide capsules (enteric coated) that is written for health professionals. What are the ingredients in budesonide capsules (enteric coated)? Active ingredient: budesonide Inactive ingredients: acetyltributyl citrate, colloidal silicon dioxide, crospovidone, dimethicone, ethylcellulose, FD&C Red No. 40, gelatin, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sodium hydroxide, sodium lauryl sulfate, talc, titanium dioxide and triethyl citrate. The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze. Pediatric use information is approved for Perrigo Pharma International DACs ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DACs marketing exclusivity rights, this drug product is not labeled with that pediatric information. Manufactured by: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX). This Patient Information has been approved by the U.S. Food and Drug Administration. Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Revised: 1/2018 BUDE:R6p

WARNINGS AND PRECAUTIONS SECTION.


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 (enteric coated) contain a corticosteroid, general warnings concerning corticosteroids should be followed [see Warnings and Precautions (5.2), (5.3), (5.4)]. Pediatric patients with Crohns disease have a slightly higher systemic exposure of budesonide and increased cortisol suppression than adults with Crohns 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 (enteric coated), 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 (enteric coated) 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.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS 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 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) ].

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test and the mouse micronucleus test. In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1) Pediatric use information is approved for Perrigo Pharma International DACs ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DACs marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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, administration of subcutaneous budesonide during organogenesis at doses approximately 0.5 times or 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. 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 Embryo/Fetal Risk Some published epidemiological studies show an association of adverse pregnancy outcomes in women with Crohns disease, including preterm birth and low birth weight infants, during periods of increased disease activity (including increased stool frequency and abdominal pain). Pregnant women with Crohns disease should be counseled regarding the importance of controlling disease. 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 0.5 times the maximum recommended human 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, 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 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 0.02 times the MRHD (on a mg/m2 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 oral budesonide, including budesonide capsules (enteric coated), and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. One published study reports that budesonide is present in human milk following maternal inhalation of budesonide [see Data ]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for budesonide capsules (enteric coated) and any potential adverse effects on the breastfed infant from budesonide capsules (enteric coated), or from the underlying maternal condition. Data One published study reports that budesonide is present in human milk following maternal inhalation of budesonide which resulted in infant doses approximately 0.3% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.4 and 0.5. Budesonide plasma concentrations were not detected and no adverse events were noted in the breastfed infants following maternal use of inhaled budesonide. The recommended daily dose of budesonide capsules (enteric coated) is higher (up to 9 mg daily) compared with inhaled budesonide (up to 800 mcg daily) given to mothers in the above described study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5 to 10 nmol/L which is up to 10 times higher than the 1 to 2 nmol/L for a 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of budesonide capsules (enteric coated), budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. 8.4 Pediatric Use Systemic corticosteroids, including budesonide capsules (enteric coated), may cause a reduction of growth velocity in pediatric patients. Pediatric patients with Crohns disease have a 17% higher mean systemic exposure and cortisol suppression than adults with Crohns disease [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ]. The safety and effectiveness of budesonide capsules (enteric coated) have not been established in pediatric patients less than 8 years of age. Pediatric use information is approved for Perrigo Pharma International DACs ENTOCORT EC (budesonide) capsules. Additional information describing a clinical study in which efficacy was not demonstrated in patients ages 5 to 17 years for another indication is approved for Perrigo Pharma International DACs ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DACs marketing exclusivity rights, this drug product is not labeled with that pediatric information. 8.5 Geriatric Use Clinical studies of budesonide capsules (enteric coated) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 651 patients treated with budesonide capsules (enteric coated) in clinical studies, 17 (3%) were greater than or equal to 65 years of age and none were greater than 74 years of age. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment 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 to budesonide [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism and consider dosage reduction in patients with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration (2.4) ]. No dosage adjustment is needed in patients with mild hepatic impairment (Child-Pugh Class A).

REFERENCES SECTION.


15 REFERENCES 1.Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohns Disease Activity Index, National Cooperative Crohns Disease Study. Gastroenterology 1976; 70(3): 439-444.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise Patients to read the FDA-Approved patient labeling (Patient Information). Hypercorticism and Adrenal Axis Suppression: Advise patients that budesonide capsules (enteric coated) may cause hypercorticism and adrenal axis suppression and to follow a taper schedule, as instructed by their healthcare provider if transferring to budesonide capsules (enteric coated) from systemic corticosteroids [see Warnings and Precautions (5.1), (5.2)]. Advise patients that replacement of systemic corticosteroids with budesonide capsules (enteric coated) may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. Increased Risk of Infection: Advise patients to avoid exposure to people with chicken pox or measles and, if exposed, to consult their healthcare provider immediately. Inform patients that they are at increased risk of developing a variety of infections; including worsening of existing tuberculosis, fungal, bacterial, viral or parasitic infections or ocular herpes simplex and to contact their healthcare provider if they develop any symptoms of infection [see Warnings and Precautions (5.3) ]. Pregnancy: Advise female patients that budesonide capsules (enteric coated) may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1) ]. Administration: Advise patients to: Take budesonide capsules (enteric coated) once daily in the morning. Swallow budesonide capsules (enteric coated) whole. Do not chew or crush. Avoid consumption of grapefruit juice for the duration of their budesonide capsules (enteric coated) therapy [see Drug Interactions (7.1) ].

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES 14.1 Treatment of Mild to Moderate Active Crohns Disease Adults The efficacy of budesonide capsules (enteric coated) were evaluated in 994 patients with mild to moderate active Crohns disease of the ileum and/or ascending colon in 5 randomized and double-blind studies of 8 weeks duration. The study patients ranged in age from 17 to 85 (mean 35), 40% were male and 97% were white. The Crohns Disease Activity Index (CDAI) was the main clinical assessment used for determining efficacy in these 5 studies1. The CDAI is a validated index based on subjective aspects rated by the patient (frequency of liquid or very soft stools, abdominal pain rating and general well-being) and objective observations (number of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal mass, body weight and hematocrit). Clinical improvement, defined as a CDAI score of less than or equal to 150 assessed after 8 weeks of treatment, was the primary efficacy variable in these 5 comparative efficacy studies of budesonide capsules (enteric coated). Safety assessments in these studies included monitoring of adverse reactions. A checklist of potential symptoms of hypercorticism was used. One study (Study 1) compared the efficacy of budesonide capsules (enteric coated) 9 mg daily in the morning to a comparator. At baseline, the median CDAI was 272. Budesonide capsules (enteric coated) 9 mg daily resulted in a significantly higher clinical improvement rate at Week 8 than the comparator. See Table 5. Table 5: Clinical Improvement Rates (CDAI less than or equal to 150) After 8 Weeks of Treatment Clinical Budesonide Capsules (Enteric Coated) Comparator This drug is not approved for the treatment of Crohns disease in the United States. Placebo Prednisolone Study 9 mg Daily 4.5 mg Twice Daily 1 62/91 (69%)p = 0.0004 compared to comparator. 37/83 (45%) 2 31/61 (51%) p = 0.001 compared to placebo. 13/64 (20%) 3 38/79 (48%) 41/78 (53%) 13/40 (33%) 4 35/58 (60%) 25/60 (42%) 35/58 (60%) 5 45/86 (52%) 56/85 (65%) Two placebo-controlled clinical trials (Studies 2 and 3) were conducted. Study 2 involved 258 patients and tested the effects of graded doses of budesonide capsules (enteric coated) (1.5 mg twice daily, 4.5 mg twice daily, or 7.5 mg twice daily) versus placebo. At baseline, the median CDAI was 290. The 1.5 mg twice daily arm (data not shown) could not be differentiated from placebo. The 4.5 mg twice daily arm was statistically different from placebo (Table 5), while no additional benefit was seen when the daily budesonide capsules (enteric coated) dose was increased to 15 mg per day (data not shown). Study 3 was a 3-armed parallel group study. The groups were treated with budesonide capsules (enteric coated) 9 mg once daily, budesonide capsules (enteric coated) 4.5 mg twice daily and placebo for 8 weeks, followed by a 2-week double-blind taper phase. The median CDAI at baseline was 263. Neither 9 mg daily nor 4.5 mg twice daily budesonide capsules (enteric coated) dose levels were statistically different from placebo (Table 5). The recommended dosage of budesonide capsules (enteric coated) for the treatment of mild to moderate active Crohns disease involving the ileum and/or the ascending colon in adults is 9 mg once daily in the morning for up to 8 weeks [see Dosage and Administration (2.1) ]. Two clinical trials (Studies 4 and 5) compared budesonide capsules (enteric coated) with oral prednisolone (initial dose 40 mg per day). Study 4 was a 3-armed parallel group study. The groups were treated with budesonide capsules (enteric coated) 9 mg once daily, budesonide capsules (enteric coated) 4.5 mg twice daily and prednisolone 40 mg (tapered dose) for 8 weeks, followed by a 4-week double blind taper phase. At baseline, the median CDAI was 277. Equal clinical improvement rates (60%) were seen in the budesonide capsules (enteric coated) 9 mg daily and the prednisolone groups in Study 4. In Study 5, 13% fewer patients in the budesonide capsules (enteric coated) group experienced clinical improvement than in the prednisolone group (no statistical difference) (Table 5). The proportion of patients with normal plasma cortisol values (greater than 150 nmol/L) was significantly higher in the budesonide capsule (enteric coated) groups in both trials (60% to 66%) than in the prednisolone groups (26% to 28%) at Week 8. Pediatric use information is approved for Perrigo Pharma International DACs ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DACs marketing exclusivity rights, this drug product is not labeled with that pediatric information. 14.2 Maintenance of Clinical Remission of Mild to Moderate Crohns Disease Adults The efficacy of budesonide capsules (enteric coated) for maintenance of clinical remission were evaluated in four double-blind, placebo-controlled, 12-month trials in which 380 patients were randomized and treated once daily with 3 mg or 6 mg budesonide capsules (enteric coated) or placebo. Patients ranged in age from 18 to 73 (mean 37) years. Sixty percent of the patients were female and 99% were Caucasian. The mean CDAI at entry was 96. Among the four clinical trials, approximately 75% of the patients enrolled had exclusively ileal disease. Colonoscopy was not performed following treatment. Budesonide capsules (enteric coated) 6 mg per day prolonged the time to relapse, defined as an increase in CDAI of at least 60 units to a total score greater than 150 or withdrawal due to disease deterioration. The median time to relapse in the pooled population of the 4 studies was 154 days for patients taking placebo, and 268 days for patients taking budesonide capsules (enteric coated) 6 mg per day. Budesonide capsules (enteric coated) 6 mg per day reduced the proportion of patients with loss of symptom control relative to placebo in the pooled population for the 4 studies at 3 months (28% versus 45% for placebo).

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Budesonide is an anti-inflammatory corticosteroid and has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to glucocorticoid receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone. 12.2 Pharmacodynamics Treatment with glucocorticoids, including budesonide capsules (enteric coated) is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. There was a positive correlation between the percent (%) reduction of AUC0-24 of plasma cortisol and systemic exposure to budesonide both in pediatric and adult patients. Adults Plasma cortisol suppression was compared following five days administration of budesonide capsules (enteric coated) and prednisolone in a crossover study in healthy volunteers. The mean decrease in the area under the plasma cortisol concentration-time curve over 24 hour (AUC0-24) was greater (78%) with prednisolone 20 mg per day compared to 45% with budesonide capsules (enteric coated) 9 mg per day. Pediatric use information is approved for Perrigo Pharma International DACs ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DACs marketing exclusivity rights, this drug product is not labeled with that pediatric information. 12.3 Pharmacokinetics Absorption Following administration of budesonide capsules (enteric coated), the time to peak concentration varied in individual patients between 30 and 600 minutes. Mean oral bioavailability of budesonide ranged from 9% to 21% both in patients and in healthy subjects, demonstrating a high first-pass elimination of the drug. Budesonide pharmacokinetics were dose-proportional following repeated administration in the dose range of 3 to 15 mg. No accumulation of budesonide was observed following repeated dosing. Following oral administration of 9 mg budesonide capsules (enteric coated) for five days in healthy subjects, the mean peak plasma concentration and the steady state area under the plasma concentration time curve for budesonide were 5.3 1.8 nmol/L and 37.0 14.6 nmolhr/L, respectively. Following administration of 9 mg budesonide capsules (enteric coated) once daily in patients with active Crohns disease, the mean peak plasma concentration and AUC were 4.0 2.1 nmol/L and 35.0 19.8 nmolh/L, respectively. Concomitant administration of a high-fat meal delayed the time to peak concentration of budesonide from budesonide capsules (enteric coated) by 2.3 hours but did not significantly affect the AUC in healthy subjects. Distribution The mean volume of distribution (Vss) of budesonide varied between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding was estimated to be 85% to 90% in the concentration range 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations was about 0.8. Elimination Budesonide had a plasma clearance, 0.9 to 1.8 L/min in healthy adults. Mean plasma clearance after intravenous administration of budesonide in patients with Crohns disease was 1.0 L/min. These plasma clearance values approached the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug. The plasma elimination half-life, after administration of intravenous doses ranged between 2 and 3.6 hours, and did not differ between healthy adults and patients with Crohns disease. Metabolism Following absorption, budesonide is subject to high first pass metabolism (80% to 90%). In vitro experiments in human liver microsomes demonstrated that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6-hydroxy budesonide and 16-hydroxy prednisolone. The corticosteroid activity of these metabolites was negligible (less than 1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects were in agreement with the in vitro findings. Excretion Budesonide was excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [3H]-budesonide, approximately 60% of the recovered radioactivity was found in urine. The major metabolites, including 6-hydroxy budesonide and 16-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide was detected in urine. Specific Populations Pediatric use information is approved for Perrigo Pharma International DACs ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DACs marketing exclusivity rights, this drug product is not labeled with that pediatric information. Hepatic Impairment In patients with mild (Child-Pugh Class A, n = 4) or moderate (Child-Pugh Class B, n = 4) hepatic impairment, budesonide 4 mg was administered orally as a single dose. The patients with moderate hepatic impairment had a 3.5-fold higher AUC compared to the healthy subjects with normal hepatic function while the patients with mild hepatic impairment had an approximately 1.4-fold higher AUC. The Cmax values demonstrated similar increases [see Dosage and Administration (2.4), Warnings and Precautions (5.1) ]. The increased systemic exposure in patients with mild hepatic impairment was not considered to be clinically relevant. Patients with severe liver impairment (Child-Pugh Class C) were not studied. Drug Interaction Studies Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of budesonide several-fold. Conversely, induction of CYP3A4 potentially could result in the lowering of budesonide plasma concentrations. Effects of Other Drugs on Budesonide Ketoconazole: In an open, non-randomized, cross-over study, 6 healthy subjects were given budesonide 10 mg as a single dose, either alone or concomitantly with the last ketoconazole dose of 3 days treatment with ketoconazole 100 mg twice daily. Co-administration of ketoconazole resulted in an eight-fold increase in AUC of budesonide, compared to budesonide alone [see Drug Interactions (7.1) ]. Grapefruit Juice: In an open, randomized, cross-over study, 8 healthy subjects were given budesonide capsules (enteric coated) 3 mg, either alone, or concomitantly with 600 mL concentrated grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), on the last of 4 daily administrations. Concomitant administration of grapefruit juice resulted in a 2-fold increase of the bioavailability of budesonide compared to budesonide alone [see Drug Interactions (7.1) ]. Oral Contraceptives (CYP3A4 Substrates): In a parallel study, the pharmacokinetics of budesonide were not significantly different between healthy female subjects who received oral contraceptives containing desogestrel 0.15 mg and ethinyl estradiol 30 mcg and healthy female subjects who did not receive oral contraceptives. Budesonide 4.5 mg once daily (one-half the recommended dose) for one week did not affect the plasma concentrations of ethinyl estradiol, a CYP3A4 substrate. The effect of budesonide 9 mg once daily on the plasma concentrations of ethinyl estradiol was not studied. Omeprazole: In a study in 11 healthy subjects, performed in a double-blind, randomized, placebo controlled manner, the effect of 5 to 6 days treatment with omeprazole 20 mg once daily on the pharmacokinetics of budesonide administered as budesonide capsules (enteric coated) 9 mg as a single dose was investigated. Omeprazole 20 mg once daily did not affect the absorption or pharmacokinetics of budesonide. Cimetidine: In an open, non-randomized, cross-over study, the potential effect of cimetidine on the pharmacokinetics of budesonide was studied. Six healthy subjects received cimetidine 1 gram daily (200 mg with meals and 400 mg at night) for 2 separate 3-day periods. Budesonide 4 mg was administered either alone or on the last day of one of the cimetidine treatment periods. Co-administration of cimetidine resulted in a 52% and 31% increase in the budesonide peak plasma concentration and the AUC of budesonide, respectively.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS 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 budesonide or any of the ingredients in budesonide capsules (enteric coated). (4)