ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: oHypercorticism and adrenal axis suppression [see Warnings and Precautions (5.1) oSymptoms of steroid withdrawal in those patients transferred from other systemic corticosteroids [see Warnings and Precautions (5.2) oIncreased risk of infection [see Warnings and Precautions (5.3) oOther corticosteroid effects [see Warnings and Precautions (5.4) . oHypercorticism and adrenal axis suppression [see Warnings and Precautions (5.1) . oSymptoms of steroid withdrawal in those patients transferred from other systemic corticosteroids [see Warnings and Precautions (5.2) . oIncreased risk of infection [see Warnings and Precautions (5.3) . oOther 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 at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 delayed-release capsules in 520 patients with Crohns disease, including 520 exposed to mg per day (total daily dose) for weeks and 145 exposed to 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 delayed-release capsules was evaluated in 651 adult patients in five clinical trials of 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 TrialsAdverse ReactionBudesonide Delayed-Release Capsules9 mgn 520Number (%)Placebon 107Number (%)PrednisolonePrednisolone tapering scheme: either 40 mg in week to 2, thereafter tapering with mg per week; or 40 mg in week to 2, 30 mg in week to 4, thereafter tapering with mg per week.40 mgn 145Number (%)ComparatorThis drug is not approved for the treatment of Crohns disease in the United States.n 88Number (%)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 of the 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/SymptomBudesonide Delayed-Release Capsules9 mgn 427Number (%)Placebo = 107Number (%)PrednisolonePrednisolone tapering scheme: either 40 mg in week 1-2, thereafter tapering with mg/week; or 40 mg in week to 2, 30 mg in week to 4, thereafter tapering with mg/week. 40 mgn 145Number (%)Total145 (34%)29 (27%)69 (48%)Acne63 (15)14 (13)33 (23)Statistically significantly different from budesonide delayed-release capsules 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 Crohns Disease. The safety of budesonide delayed-release 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 Crohns disease. total of 145 patients were treated with budesonide delayed-release capsules mg once daily. The adverse reaction profile of budesonide delayed-release capsules mg once daily in maintenance of Crohns disease was similar to that of short-term treatment with budesonide delayed-release capsules 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 TrialsSigns/SymptomBudesonideDelayed-Release Capsules3 mgn 88Number (%)Budesonide Delayed-ReleaseCapsules6 mgn 145Number (%)Placebon 143Number (%)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/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 delayed-release capsules mg (total daily dose) in short-term treatment clinical studies and/or budesonide delayed-release capsules mg (total daily dose) in long-term maintenance clinical trials, with an incidence are listed below by system organ class:Cardiac Disorders: palpitation, tachycardiaEye Disorders: eye abnormality, vision abnormalGeneral Disorders and Administration Site Conditions: asthenia, chest pain, dependent edema, face edema, flu-like disorder, malaise, feverGastrointestinal 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, amnesiaPsychiatric Disorders: agitation, confusion, insomnia, nervousness, sleep disorder Renal and Urinary Disorders: dysuria, micturition frequency, nocturiaReproductive System and Breast Disorders: intermenstrual bleeding, menstrual disorderRespiratory, 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. randomized, open, parallel-group multicenter safety clinical trial specifically compared the effect of budesonide delayed-release capsules (less than mg per day) and prednisolone (less than 40 mg per day) on bone mineral density over years when used at doses adjusted to disease severity. Bone mineral density decreased significantly less with budesonide delayed-release capsules than with prednisolone in steroid-naive 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 delayed-release 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.. Pediatrics -- Treatment of Mild to Moderate Active Crohns Disease Adverse reactions reported in pediatric patients to 17 years of age, who weigh more than 25 kg, were similar to those reactions described above in adult patients. 6.2Postmarketing Experience The following adverse reactions have been reported during post-approval use of budesonide delayed-release capsules. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Immune System Disorders: Anaphylactic reactions Nervous System Disorders: Benign intracranial hypertension Psychiatric Disorders: Mood swings.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Budesonide is an anti-inflammatory corticosteroid and has high glucocorticoid effect and 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 delayed-release capsules are associated with suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. There was 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 delayed-release capsules and prednisolone in 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 delayed-release capsules mg per day.. Pediatrics. The effect of budesonide on endogenous cortisol concentrations was compared between pediatrics (n 8, aged to 14 years) and adults (n 6) with active Crohns disease following administration of budesonide delayed-release capsules mg once daily for days. Compared to baseline values before treatment, the mean decrease in the AUC0-24 of cortisol was 64% (+- 18%) in pediatrics and 50% (+- 27%) in adults after budesonide delayed-release capsules treatment [see Warnings and Precautions (5.1), Adverse Reactions (6.1) and Use in Specific Populations (8.4) ].The responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) was studied in pediatric patients aged to 17 years, with mild to moderate active Crohns disease in randomized, double-blind, active control study [see Clinical Studies (14.1)]. After weeks of treatment with mg once daily budesonide delayed-release capsules or with prednisolone, administered at tapering doses starting from mg/kg, the proportion of patients with normal response to the ACTH challenge was 6% in the budesonide group compared to none in the prednisolone group; the proportion of patients with morning p-cortisol of greater than mcg/dL was 50% in the budesonide group compared to 22% in the prednisolone group. The mean morning p-cortisol was 6.3 mcg/dL in the budesonide group and 2.6 mcg/dL in the prednisolone group (Table 4).Table 4: Proportion of Pediatric Patients to 17 years old with Peak Endogenous Cortisol Levels (above 18 mcg/dL) after ACTH Stimulation and Normal ResponseThe normal response to ACTH challenge included criteria, as defined in the cosyntropin label: 1) morning cortisol level above mcg/dL; 2) increase in cortisol level by at least mcg/dL above the morning (pre-challenge) level following ACTH challenge; and cortisol level of above 18 mcg/dL following ACTH challenge. Cortisol concentration was measured at 30 min after intravenous or intramuscular injection of 0.25 mg cosyntropin at baseline and at week after treatment. to ACTH Challenge Following Administration of Budesonide Delayed-Release Capsules or Prednisolone for weeksBudesonidePrednisolonePeak plasma cortisol above 18 mcg/dLAt baseline91% (20/22)91% (21/23)At week 825% (4/16)0% (0/18)Normal response to ACTH challengeAt baseline73% (16/22)78% (18/23)At week 86% (1/16)0% (0/18). 12.3 Pharmacokinetics Absorption. Mean oral bioavailability of budesonide ranged from 9% to 21% both in patients and in healthy subjects, demonstrating high first-pass elimination of the drug. Budesonide pharmacokinetics were dose-proportional following repeated administration in the dose range of to 15 mg. No accumulation of budesonide was observed following repeated dosing. Following oral administration of single dose of mg budesonide delayed-release capsules in healthy subjects under fasting condition, the mean peak plasma concentration (Cmax) and the area under the plasma concentration time curve (AUC) for budesonide were 1.50 +- 0.79 ng/mL and 14.13 +- 7.33 ngohr/mL, respectively. The time to peak concentration (Tmax) varied between and hours with median value of 3.5 hours. In different study, following oral administration of mg budesonide delayed-release capsules for five days in healthy subjects, the mean Cmax and the steady state AUC for budesonide were 2.28 +- 0.77 ng/mL and 15.93 +- 6.29 ngohr/mL, respectively. Following administration of mg budesonide delayed-release capsules once daily in patients with active Crohns disease, the mean Cmax and AUC were 1.7 +- 0.9 ng/mL and 15.1 +- 8.5 ngohr/mL, respectively. Following administration of budesonide delayed-release capsules, the Tmax ranged in individual patients from 0.5 to 10 hours. Concomitant administration of high-fat meal delayed the Tmax of budesonide by 2.3 hours compared to that under fasted conditions but did not significantly affect the AUC in healthy subjects. The mean Cmax and AUC of budesonide were similar when single dose of budesonide delayed-release capsules (9 mg) was administered after opening the capsules and sprinkling the granules on applesauce versus as intact capsules in the fasted state (N 24) in healthy subjects. The Tmax ranged from to 10 hours with median of hours after administration of sprinkled granules on applesauce. 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 0.43 to 99.02 ng/mL, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations was about 0.8. Elimination. Budesonide had 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 high hepatic clearance drug. The plasma elimination half-life, after administration of intravenous doses ranged between and 3.6 hours, and did not differ between healthy adults and patients with Crohns disease. The mean +- SD plasma elimination half-life after single dose of budesonide delayed-release capsules (9 mg) in fasted state (N 24) in healthy subjects was 6.3 +- 1.6 hours and ranged between and hours. 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 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. Age Pediatric Population (8 Years and Older). The pharmacokinetics of budesonide were investigated in pediatric patients aged to 14 years (n 8) after oral administration of budesonide delayed-release capsules and intravenous administration of budesonide. Following administration of mg budesonide delayed-release capsules once daily for days, the median time to peak plasma concentration of budesonide was hours and the mean peak plasma concentration was 2.58 +- 1.51 ng/mL. The mean AUC was 17.78 +- 5.25 ngohr/mL and 17% higher than that in adult patients with Crohns disease in the same study. The mean absolute oral availability was 9.2% (3 to 17%; = 4) in pediatric patients. After single dose administration of intravenous budesonide (n 4), the mean volume of distribution (Vss) was 2.2 +- 0.4 L/kg and mean clearance was 0.81 +- 0.2 L/min. The mean elimination half-life was 1.9 hours in pediatric patients. The body-weight normalized clearance in pediatric patients was 20.5 mL/min/kg in comparison to 15.9 mL/min/kg in adult patients after intravenous administration [see Warnings and Precautions (5.1), Use in Specific Population (8.4)].. Hepatic Impairment In patients with mild (Child-Pugh Class A, = 4) or moderate (Child-Pugh Class B, = 4) hepatic impairment, budesonide mg was administered orally as single dose. The patients with moderate hepatic impairment had 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, healthy subjects were given budesonide 10 mg as single dose, either alone or concomitantly with the last ketoconazole dose of 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, healthy subjects were given budesonide delayed-release capsules mg, either alone, or concomitantly with 600 mL concentrated grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), on the last of daily administrations. Concomitant administration of grapefruit juice resulted in 2-fold increase of the bioavailability of budesonide compared to budesonide alone [see Drug Interactions (7.1) ]. Oral Contraceptives (CYP3A4 Substrates). In 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, CYP3A4 substrate. The effect of budesonide mg once daily on the plasma concentrations of ethinyl estradiol was not studied. Omeprazole. In study in 11 healthy subjects, performed in double-blind, randomized, placebo controlled manner, the effect of to days treatment with omeprazole 20 mg once daily on the pharmacokinetics of budesonide administered as budesonide delayed-release capsules mg as 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 gram daily (200 mg with meals and 400 mg at night) for separate 3-day periods. Budesonide mg was administered either alone or on the last day of one of the cimetidine treatment periods. Co-administration of cimetidine resulted in 52% and 31% increase in the budesonide peak plasma concentration and the AUC of budesonide, respectively.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1Treatment of Mild to Moderate Active Crohns Disease Adults. The efficacy of budesonide delayed-release capsules was evaluated in 994 patients with mild to moderate active Crohns disease of the ileum and/or ascending colon in randomized and double-blind studies of 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 studies1. The CDAI is 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 CDAI score of less than or equal to 150 assessed after weeks of treatment, was the primary efficacy variable in these comparative efficacy studies of budesonide delayed-release capsules. Safety assessments in these studies included monitoring of adverse reactions. checklist of potential symptoms of hypercorticism was used. One study (Study 1) compared the efficacy of budesonide delayed-release capsules mg daily in the morning to comparator. At baseline, the median CDAI was 272. Budesonide delayed-release capsules mg daily resulted in significantly higher clinical improvement rate at Week than the comparator. See Table 5.Table 5: Clinical Improvement Rates (CDAI less than or equal to 150) After Weeks of TreatmentClinicalStudyBudesonide Delayed-Release Capsules9 mg DailyBudesonide Delayed-Release Capsules4.5 Twice mg DailyComparatorThis drug is not approved for the treatment of Crohns disease in the United States. PlaceboPrednisolone162/91 (69%)p 0.0004 compared to comparator. 37/83 (45%)231/61 (51%)p 0.001 compared to placebo. 13/64 (20%)338/79 (48%)41/78 (53%)13/40 (33%)435/58 (60%)25/60 (42%)35/58 (60%)545/86 (52%)56/85 (65%)Two placebo-controlled clinical trials (Studies and 3) were conducted. Study involved 258 patients and tested the effects of graded doses of budesonide delayed-release capsules (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 delayed-release capsules dose was increased to 15 mg per day (data not shown). Study was 3-armed parallel group study. The groups were treated with budesonide delayed-release capsules mg once daily, budesonide delayed-release capsules 4.5 mg twice daily and placebo for weeks, followed by 2-week double-blind taper phase. The median CDAI at baseline was 263. Neither mg daily nor 4.5 mg twice daily budesonide delayed-release capsules dose levels were statistically different from placebo (Table 5). The recommended dosage of budesonide delayed-release capsules for the treatment of mild to moderate active Crohns disease involving the ileum and/or the ascending colon in adults is mg once daily in the morning for up to weeks [see Dosage and Administration (2.1) ].Two clinical trials (Studies and 5) compared budesonide delayed-release capsules with oral prednisolone (initial dose 40 mg per day). Study was 3-armed parallel group study. The groups were treated with budesonide delayed-release capsules mg once daily, budesonide delayed-release capsules 4.5 mg twice daily and prednisolone 40 mg (tapered dose) for weeks, followed by 4-week double blind taper phase. At baseline, the median CDAI was 277. Equal clinical improvement rates (60%) were seen in the budesonide delayed-release capsules mg daily and the prednisolone groups in Study 4. In Study 5, 13% fewer patients in the budesonide delayed-release capsules 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 64.58 ng/mL) was significantly higher in the budesonide delayed-release capsule groups in both trials (60% to 66%) than in the prednisolone groups (26% to 28%) at Week 8. Pediatrics (8 to 17 Years of Age). The effectiveness of budesonide delayed-release capsules, in pediatric patients aged to 17 years, who weigh more than 25 kg with mild to moderate active Crohns disease (defined as Crohns Disease Activity Index (CDAI) >= 200) involving the ileum and/or the ascending colon, was assessed in one randomized, double-blind, active control study. This study compared budesonide delayed-release capsules mg once daily, with prednisolone, administered at tapering doses starting from mg/kg. Twenty-two (22) patients were treated with budesonide delayed-release capsules and 24 patients were treated with prednisolone. After weeks of treatment, 55% (95% CI: 32%, 77%) of patients treated with budesonide delayed-release capsules reached the endpoint (CDAI <=150), as compared to 68% (95% CI: 47%, 89%) of patients treated with prednisolone. The average number of liquid or very soft stools per day (assessed over days) decreased from 1.49 at baseline to 0.96 after treatment with budesonide delayed-release capsules and 2.00 at baseline to 0.52 after treatment with prednisolone. The average daily abdominal pain rating (where = none, = mild, = moderate, and = severe) decreased from 1.49 at baseline to 0.54 after treatment with budesonide delayed-release capsules and 1.64 at baseline to 0.38 after weeks of treatment with prednisolone. Use of budesonide delayed-release capsules in this age group is supported by evidence from adequate and well-controlled studies of budesonide delayed-release capsules in adults, and by safety and pharmacokinetic studies performed in pediatric patients.. 14.2Maintenance of Clinical Remission of Mild to Moderate Crohns Disease Adults. The efficacy of budesonide delayed-release capsules 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 mg or mg budesonide delayed-release capsules 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 delayed-release capsules mg per day prolonged the time to relapse, defined as an increase in CDAI of at least 60 units to total score greater than 150 or withdrawal due to disease deterioration. The median time to relapse in the pooled population of the studies was 154 days for patients taking placebo, and 268 days for patients taking budesonide delayed-release capsules mg per day. Budesonide delayed-release capsules mg per day reduced the proportion of patients with loss of symptom control relative to placebo in the pooled population for the studies at months (28% versus 45% for placebo).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION Administration Instructions (2.1):oTake once daily in the morning.oSwallow whole. Do not chew or crush.oFor patients unable to swallow an intact capsule, open the capsules and empty the pellets onto one tablespoonful of applesauce. Mix and consume the entire contents within 30 minutes. Do not chew or crush. Follow with ounces of water. oAvoid consumption of grapefruit juice for the duration of therapy.Recommended Dosage:Mild to moderate active Crohns disease (2.2):oAdults: mg once daily for up to weeks; repeat week treatment courses for recurring episodes of active disease.oPediatrics to 17 years who weigh more than 25 kg: mg once daily for up to weeks, followed by mg once daily in the morning for weeks.Maintenance of Clinical Remission of Mild to Moderate Crohns Disease (2.3):oAdults: mg once daily for up to months; taper to complete cessation after months. Continued treatment for more than months has not been shown to provide substantial clinical benefit.oWhen switching from oral prednisolone, begin tapering prednisolone concomitantly with initiating budesonide delayed-release capsules.Hepatic Impairment:oConsider reducing the dosage to mg once daily in adult patients with moderate hepatic impairment (Child-Pugh Class B). (2.4, 5.1, 8.6). oTake once daily in the morning.. oSwallow whole. Do not chew or crush.. oFor patients unable to swallow an intact capsule, open the capsules and empty the pellets onto one tablespoonful of applesauce. Mix and consume the entire contents within 30 minutes. Do not chew or crush. Follow with ounces of water. oAvoid consumption of grapefruit juice for the duration of therapy.. oAdults: mg once daily for up to weeks; repeat week treatment courses for recurring episodes of active disease.. oPediatrics to 17 years who weigh more than 25 kg: mg once daily for up to weeks, followed by mg once daily in the morning for weeks.. oAdults: mg once daily for up to months; taper to complete cessation after months. Continued treatment for more than months has not been shown to provide substantial clinical benefit.. oWhen switching from oral prednisolone, begin tapering prednisolone concomitantly with initiating budesonide delayed-release capsules.. oConsider reducing the dosage to mg once daily in adult patients with moderate hepatic impairment (Child-Pugh Class B). (2.4, 5.1, 8.6). 2.1Administration Instructions oTake budesonide delayed-release capsules once daily in the morning.oSwallow budesonide delayed-release capsules whole. Do not chew or crush.oFor patients unable to swallow an intact capsule, budesonide delayed-release capsules can be opened and administered as follows:1.Place one tablespoonful of applesauce into clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing.2.Open the capsule(s).3.Carefully empty all the pellets inside the capsule(s) on the applesauce.4.Mix the pellets with the applesauce.5.Consume the entire contents within 30 minutes of mixing. Do not chew or crush the pellets. Do not save the applesauce and pellets for future use. 6.Follow the applesauce and pellets immediately with glass (8 ounces) of cool water to ensure complete swallowing of the pellets.oAvoid consumption of grapefruit juice for the duration of budesonide delayed-release capsules therapy [see Drug Interactions (7.1) ].. oTake budesonide delayed-release capsules once daily in the morning.. oSwallow budesonide delayed-release capsules whole. Do not chew or crush.. oFor patients unable to swallow an intact capsule, budesonide delayed-release capsules can be opened and administered as follows:1.Place one tablespoonful of applesauce into clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing.2.Open the capsule(s).3.Carefully empty all the pellets inside the capsule(s) on the applesauce.4.Mix the pellets with the applesauce.5.Consume the entire contents within 30 minutes of mixing. Do not chew or crush the pellets. Do not save the applesauce and pellets for future use. 6.Follow the applesauce and pellets immediately with glass (8 ounces) of cool water to ensure complete swallowing of the pellets.. 1.Place one tablespoonful of applesauce into clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing.. 2.Open the capsule(s).. 3.Carefully empty all the pellets inside the capsule(s) on the applesauce.. 4.Mix the pellets with the applesauce.. 5.Consume the entire contents within 30 minutes of mixing. Do not chew or crush the pellets. Do not save the applesauce and pellets for future use. 6.Follow the applesauce and pellets immediately with glass (8 ounces) of cool water to ensure complete swallowing of the pellets.. oAvoid consumption of grapefruit juice for the duration of budesonide delayed-release capsules therapy [see Drug Interactions (7.1) ].. 2.2Treatment of Mild to Moderate Active Crohns Disease The recommended dosage of budesonide delayed-release capsules is:. Adults. mg orally once daily for up to weeks. Repeated week courses of budesonide delayed-release capsules can be given for recurring episodes of active disease. Pediatric Patients to 17 Years Who Weigh More Than 25 kg. mg orally once daily for up to weeks, followed by mg once daily for weeks. 2.3Maintenance of Clinical Remission of Mild to Moderate Crohns Disease The recommended dosage in adults, following an week course(s) of treatment for active disease and once the patients symptoms are controlled (CDAI less than 150), is budesonide delayed-release capsules mg orally once daily for maintenance of clinical remission up to months. If symptom control is still maintained at months an attempt to taper to complete cessation is recommended. Continued treatment with budesonide delayed-release capsules mg for more than 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 delayed-release capsules with no reported episodes of adrenal insufficiency. Since prednisolone should not be stopped abruptly, tapering should begin concomitantly with initiating budesonide delayed-release capsules treatment.. 2.4Dosage Adjustment in Adult Patients with Hepatic Impairment Consider reducing the dosage of budesonide delayed-release capsules to 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) ].

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 delayed-release capsules may cause hypercorticism and adrenal axis suppression and to follow taper schedule, as instructed by their healthcare provider if transferring to budesonide delayed-release capsules from systemic corticosteroids [see Warnings and Precautions (5.1, 5.2) ]. Advise patients that replacement of systemic corticosteroids with budesonide delayed-release capsules 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 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 delayed-release capsules may cause fetal harm and to inform their healthcare provider with known or suspected pregnancy [see Use in Specific Populations (8.1) ].AdministrationoTake budesonide delayed-release capsules once daily in the morning. oSwallow budesonide delayed-release capsules whole. Do not chew or crush. oFor patients unable to swallow an intact capsule, budesonide delayed-release capsules can be opened and administered as follows:1.Place one tablespoonful of applesauce into clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing. 2.Open the capsule(s).3.Carefully empty all the pellets inside the capsule(s) on the applesauce.4.Mix the pellets with the applesauce.5.Consume the entire contents within 30 minutes of mixing. Do not chew or crush the pellets. Do not save the applesauce and pellets for future use. 6.Follow the applesauce and pellets immediately with glass (8 ounces) of cool water to ensure complete swallowing of the pellets.oAvoid consumption of grapefruit juice for the duration of their budesonide delayed-release capsules therapy [see Drug Interactions (7.1) ]. oTake budesonide delayed-release capsules once daily in the morning. oSwallow budesonide delayed-release capsules whole. Do not chew or crush. oFor patients unable to swallow an intact capsule, budesonide delayed-release capsules can be opened and administered as follows:1.Place one tablespoonful of applesauce into clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing. 2.Open the capsule(s).3.Carefully empty all the pellets inside the capsule(s) on the applesauce.4.Mix the pellets with the applesauce.5.Consume the entire contents within 30 minutes of mixing. Do not chew or crush the pellets. Do not save the applesauce and pellets for future use. 6.Follow the applesauce and pellets immediately with glass (8 ounces) of cool water to ensure complete swallowing of the pellets.. 1.Place one tablespoonful of applesauce into clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing. 2.Open the capsule(s).. 3.Carefully empty all the pellets inside the capsule(s) on the applesauce.. 4.Mix the pellets with the applesauce.. 5.Consume the entire contents within 30 minutes of mixing. Do not chew or crush the pellets. Do not save the applesauce and pellets for future use. 6.Follow the applesauce and pellets immediately with glass (8 ounces) of cool water to ensure complete swallowing of the pellets.. oAvoid consumption of grapefruit juice for the duration of their budesonide delayed-release capsules therapy [see Drug Interactions (7.1) ].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Treatment with glucocorticoids, including budesonide delayed-release capsules are associated with suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. There was 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 delayed-release capsules and prednisolone in 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 delayed-release capsules mg per day.. Pediatrics. The effect of budesonide on endogenous cortisol concentrations was compared between pediatrics (n 8, aged to 14 years) and adults (n 6) with active Crohns disease following administration of budesonide delayed-release capsules mg once daily for days. Compared to baseline values before treatment, the mean decrease in the AUC0-24 of cortisol was 64% (+- 18%) in pediatrics and 50% (+- 27%) in adults after budesonide delayed-release capsules treatment [see Warnings and Precautions (5.1), Adverse Reactions (6.1) and Use in Specific Populations (8.4) ].The responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) was studied in pediatric patients aged to 17 years, with mild to moderate active Crohns disease in randomized, double-blind, active control study [see Clinical Studies (14.1)]. After weeks of treatment with mg once daily budesonide delayed-release capsules or with prednisolone, administered at tapering doses starting from mg/kg, the proportion of patients with normal response to the ACTH challenge was 6% in the budesonide group compared to none in the prednisolone group; the proportion of patients with morning p-cortisol of greater than mcg/dL was 50% in the budesonide group compared to 22% in the prednisolone group. The mean morning p-cortisol was 6.3 mcg/dL in the budesonide group and 2.6 mcg/dL in the prednisolone group (Table 4).Table 4: Proportion of Pediatric Patients to 17 years old with Peak Endogenous Cortisol Levels (above 18 mcg/dL) after ACTH Stimulation and Normal ResponseThe normal response to ACTH challenge included criteria, as defined in the cosyntropin label: 1) morning cortisol level above mcg/dL; 2) increase in cortisol level by at least mcg/dL above the morning (pre-challenge) level following ACTH challenge; and cortisol level of above 18 mcg/dL following ACTH challenge. Cortisol concentration was measured at 30 min after intravenous or intramuscular injection of 0.25 mg cosyntropin at baseline and at week after treatment. to ACTH Challenge Following Administration of Budesonide Delayed-Release Capsules or Prednisolone for weeksBudesonidePrednisolonePeak plasma cortisol above 18 mcg/dLAt baseline91% (20/22)91% (21/23)At week 825% (4/16)0% (0/18)Normal response to ACTH challengeAt baseline73% (16/22)78% (18/23)At week 86% (1/16)0% (0/18).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Absorption. Mean oral bioavailability of budesonide ranged from 9% to 21% both in patients and in healthy subjects, demonstrating high first-pass elimination of the drug. Budesonide pharmacokinetics were dose-proportional following repeated administration in the dose range of to 15 mg. No accumulation of budesonide was observed following repeated dosing. Following oral administration of single dose of mg budesonide delayed-release capsules in healthy subjects under fasting condition, the mean peak plasma concentration (Cmax) and the area under the plasma concentration time curve (AUC) for budesonide were 1.50 +- 0.79 ng/mL and 14.13 +- 7.33 ngohr/mL, respectively. The time to peak concentration (Tmax) varied between and hours with median value of 3.5 hours. In different study, following oral administration of mg budesonide delayed-release capsules for five days in healthy subjects, the mean Cmax and the steady state AUC for budesonide were 2.28 +- 0.77 ng/mL and 15.93 +- 6.29 ngohr/mL, respectively. Following administration of mg budesonide delayed-release capsules once daily in patients with active Crohns disease, the mean Cmax and AUC were 1.7 +- 0.9 ng/mL and 15.1 +- 8.5 ngohr/mL, respectively. Following administration of budesonide delayed-release capsules, the Tmax ranged in individual patients from 0.5 to 10 hours. Concomitant administration of high-fat meal delayed the Tmax of budesonide by 2.3 hours compared to that under fasted conditions but did not significantly affect the AUC in healthy subjects. The mean Cmax and AUC of budesonide were similar when single dose of budesonide delayed-release capsules (9 mg) was administered after opening the capsules and sprinkling the granules on applesauce versus as intact capsules in the fasted state (N 24) in healthy subjects. The Tmax ranged from to 10 hours with median of hours after administration of sprinkled granules on applesauce. 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 0.43 to 99.02 ng/mL, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations was about 0.8. Elimination. Budesonide had 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 high hepatic clearance drug. The plasma elimination half-life, after administration of intravenous doses ranged between and 3.6 hours, and did not differ between healthy adults and patients with Crohns disease. The mean +- SD plasma elimination half-life after single dose of budesonide delayed-release capsules (9 mg) in fasted state (N 24) in healthy subjects was 6.3 +- 1.6 hours and ranged between and hours. 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 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. Age Pediatric Population (8 Years and Older). The pharmacokinetics of budesonide were investigated in pediatric patients aged to 14 years (n 8) after oral administration of budesonide delayed-release capsules and intravenous administration of budesonide. Following administration of mg budesonide delayed-release capsules once daily for days, the median time to peak plasma concentration of budesonide was hours and the mean peak plasma concentration was 2.58 +- 1.51 ng/mL. The mean AUC was 17.78 +- 5.25 ngohr/mL and 17% higher than that in adult patients with Crohns disease in the same study. The mean absolute oral availability was 9.2% (3 to 17%; = 4) in pediatric patients. After single dose administration of intravenous budesonide (n 4), the mean volume of distribution (Vss) was 2.2 +- 0.4 L/kg and mean clearance was 0.81 +- 0.2 L/min. The mean elimination half-life was 1.9 hours in pediatric patients. The body-weight normalized clearance in pediatric patients was 20.5 mL/min/kg in comparison to 15.9 mL/min/kg in adult patients after intravenous administration [see Warnings and Precautions (5.1), Use in Specific Population (8.4)].. Hepatic Impairment In patients with mild (Child-Pugh Class A, = 4) or moderate (Child-Pugh Class B, = 4) hepatic impairment, budesonide mg was administered orally as single dose. The patients with moderate hepatic impairment had 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, healthy subjects were given budesonide 10 mg as single dose, either alone or concomitantly with the last ketoconazole dose of 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, healthy subjects were given budesonide delayed-release capsules mg, either alone, or concomitantly with 600 mL concentrated grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), on the last of daily administrations. Concomitant administration of grapefruit juice resulted in 2-fold increase of the bioavailability of budesonide compared to budesonide alone [see Drug Interactions (7.1) ]. Oral Contraceptives (CYP3A4 Substrates). In 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, CYP3A4 substrate. The effect of budesonide mg once daily on the plasma concentrations of ethinyl estradiol was not studied. Omeprazole. In study in 11 healthy subjects, performed in double-blind, randomized, placebo controlled manner, the effect of to days treatment with omeprazole 20 mg once daily on the pharmacokinetics of budesonide administered as budesonide delayed-release capsules mg as 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 gram daily (200 mg with meals and 400 mg at night) for separate 3-day periods. Budesonide mg was administered either alone or on the last day of one of the cimetidine treatment periods. Co-administration of cimetidine resulted in 52% and 31% increase in the budesonide peak plasma concentration and the AUC of budesonide, respectively.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary. Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform 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 fetus. The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 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 body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of mcg/kg in rabbits (approximately 0.01 times the maximum recommended human dose on body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on body surface area basis). In 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 mg/m2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information Budesonide Delayed-Release Capsules(bue des oh nide)Read this Patient Information before you start taking budesonide delayed-release capsules and each time you get 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 delayed-release capsules Budesonide delayed-release capsules are 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):oin people years of age and older with active Crohns diseaseoin adults to help keep symptoms from coming back for up to months It is not known if budesonide delayed-release capsules are safe and effective in children under years of age, or in children to 17 years of age who weigh 55 pounds (25 kg) or less, for the treatment of mild to moderate active Crohns disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon).It is not known if budesonide delayed-release capsules are safe and effective in children to help keep symptoms of mild to moderate Crohns disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon) from coming back.Who should not take budesonide delayed-release capsules Do not take budesonide delayed-release capsules if: oyou are allergic to budesonide or any of the ingredients in budesonide delayed-release capsules. See the end of this leaflet for complete list of ingredients in budesonide delayed-release capsules.Before you take budesonide delayed-release capsules tell your healthcare provider if you have any other medical conditions including if you:ohave liver problems. oare planning to have surgery. ohave chicken pox or measles or have recently been near anyone with chicken pox or measles.ohave an infection. ohave diabetes or glaucoma or have family history of diabetes or glaucoma.ohave cataracts. ohave or had tuberculosis.ohave high blood pressure (hypertension). ohave decreased bone mineral density (osteoporosis). ohave stomach ulcers. oare pregnant or plan to become pregnant. Budesonide delayed-release capsules may harm your unborn baby. Talk to your healthcare provider about the possible risk to your unborn baby if you take budesonide delayed-release capsules 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 delayed-release capsules. oare 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 delayed-release capsules. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide delayed-release capsules and other medicines may affect each other causing side effects.How should take budesonide delayed-release capsules oTake budesonide delayed-release capsules exactly as your healthcare provider tells you. oYour healthcare provider will tell you how many budesonide delayed-release capsules to take. Your healthcare provider may change your dose if needed. oTake budesonide delayed-release capsules time each day in the morning. oTake budesonide delayed-release capsules whole. Do not chew or crush budesonide delayed-release capsules before swallowing.oFor patients, unable to swallow whole capsule, budesonide delayed-release capsules can be opened and administered as follows: 1.Place tablespoonful of applesauce into clean container, such as an empty bowl. The applesauce used should not be hot and should be soft enough to be swallowed without chewing.2.Open the capsule. You may need to use more than budesonide delayed-release capsule for the dose prescribed by your healthcare provider.3.Carefully empty all of the pellets inside the capsule on the applesauce.4.Stir the pellets with the applesauce. 5.Swallow the applesauce and pellets mixture within 30 minutes after preparing it. Follow the applesauce and pellets immediately with glass (8 ounces) of cool water to help with complete swallowing of the pellets.6.Do not chew or crush the pellets.7.Do not save the applesauce and pellets for later use. oIf you take too many budesonide delayed-release capsules call your healthcare provider right away or go to the nearest hospital emergency room.What should avoid while taking budesonide delayed-release capsules oDo not drink grapefruit juice during your treatment with budesonide delayed-release capsules. Drinking grapefruit juice can increase the level of budesonide in your blood. What are the possible side effects of budesonide delayed-release capsulesBudesonide delayed-release capsules may cause serious side effects, including:oEffects of having too much corticosteroid medicine in your blood (hypercorticism). Long-time use of budesonide delayed-release capsules 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: oacneobruise easily orounding of your face (moon face)oankle swellingothicker 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 armsoAdrenal suppression. When budesonide delayed-release capsules are taken for long period of time (chronic use), adrenal suppression can happen. This is 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 delayed-release capsules. oWorsening of allergies. If you take certain other corticosteroid medicines to treat allergies, switching to budesonide delayed-release capsules may cause your allergies to come back. These allergies may include skin condition called eczema or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while taking budesonide delayed-release capsules.oIncreased risk of infection. Budesonide delayed-release capsules 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 delayed-release capsules. 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 delayed-release capsules, including: ofeveropainoachesochillsofeeling tiredonausea and vomitingThe most common side effects of budesonide delayed-release capsules in adults include: oheadacheostomach area (abdominal) painoinfection in your air passages (respiratory infection)ogasonauseaovomitingoback painotirednessoindigestionopainodizzinessThe most common side effects of budesonide delayed-release capsules in children to 17 years of age, who weigh more than 55 pounds (25 kg), are similar to the most common side effects in adults. oTell 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 delayed-release capsules. 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.How should store budesonide delayed-release capsules oStore budesonide delayed-release capsules at room temperature between 20o to 25oC (68o to 77oF). oKeep budesonide delayed-release capsules in tightly closed container. Keep budesonide delayed-release capsules and all medicines out of the reach of children.General information about the safe and effective use of budesonide delayed-release capsules. Medicines are sometimes prescribed for purposes other than those listed in Medication Guide or Patient Information leaflet. Do not use budesonide delayed-release capsules for condition for which they were not prescribed. Do not give budesonide delayed-release capsules to other people, even if they have the same symptoms that you have. They may harm them. You can ask your pharmacist or healthcare provider for information about budesonide delayed-release capsules that is written for health professionals.What are the ingredients in budesonide delayed-release capsules 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. In addition, the imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. Aluminum Lake, FD&C Blue No. Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze. Manufactured by: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. For more information, call Mylan 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: 11/2020BUDE:R7p/PL:BUDE:R6p. oin people years of age and older with active Crohns disease. oin adults to help keep symptoms from coming back for up to months oyou are allergic to budesonide or any of the ingredients in budesonide delayed-release capsules. See the end of this leaflet for complete list of ingredients in budesonide delayed-release capsules.. ohave liver problems. oare planning to have surgery. ohave chicken pox or measles or have recently been near anyone with chicken pox or measles.. ohave an infection. ohave diabetes or glaucoma or have family history of diabetes or glaucoma.. ohave cataracts. ohave or had tuberculosis.. ohave high blood pressure (hypertension). ohave decreased bone mineral density (osteoporosis). ohave stomach ulcers. oare pregnant or plan to become pregnant. Budesonide delayed-release capsules may harm your unborn baby. Talk to your healthcare provider about the possible risk to your unborn baby if you take budesonide delayed-release capsules 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 delayed-release capsules. oare 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 delayed-release capsules. oTake budesonide delayed-release capsules exactly as your healthcare provider tells you. oYour healthcare provider will tell you how many budesonide delayed-release capsules to take. Your healthcare provider may change your dose if needed. oTake budesonide delayed-release capsules time each day in the morning. oTake budesonide delayed-release capsules whole. Do not chew or crush budesonide delayed-release capsules before swallowing.. oFor patients, unable to swallow whole capsule, budesonide delayed-release capsules can be opened and administered as follows: 1.Place tablespoonful of applesauce into clean container, such as an empty bowl. The applesauce used should not be hot and should be soft enough to be swallowed without chewing.2.Open the capsule. You may need to use more than budesonide delayed-release capsule for the dose prescribed by your healthcare provider.3.Carefully empty all of the pellets inside the capsule on the applesauce.4.Stir the pellets with the applesauce. 5.Swallow the applesauce and pellets mixture within 30 minutes after preparing it. Follow the applesauce and pellets immediately with glass (8 ounces) of cool water to help with complete swallowing of the pellets.6.Do not chew or crush the pellets.7.Do not save the applesauce and pellets for later use. 1.Place tablespoonful of applesauce into clean container, such as an empty bowl. The applesauce used should not be hot and should be soft enough to be swallowed without chewing.. 2.Open the capsule. You may need to use more than budesonide delayed-release capsule for the dose prescribed by your healthcare provider.. 3.Carefully empty all of the pellets inside the capsule on the applesauce.. 4.Stir the pellets with the applesauce. 5.Swallow the applesauce and pellets mixture within 30 minutes after preparing it. Follow the applesauce and pellets immediately with glass (8 ounces) of cool water to help with complete swallowing of the pellets.. 6.Do not chew or crush the pellets.. 7.Do not save the applesauce and pellets for later use. oIf you take too many budesonide delayed-release capsules call your healthcare provider right away or go to the nearest hospital emergency room.. oDo not drink grapefruit juice during your treatment with budesonide delayed-release capsules. Drinking grapefruit juice can increase the level of budesonide in your blood. oEffects of having too much corticosteroid medicine in your blood (hypercorticism). Long-time use of budesonide delayed-release capsules 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. oAdrenal suppression. When budesonide delayed-release capsules are taken for long period of time (chronic use), adrenal suppression can happen. This is 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 delayed-release capsules. oWorsening of allergies. If you take certain other corticosteroid medicines to treat allergies, switching to budesonide delayed-release capsules may cause your allergies to come back. These allergies may include skin condition called eczema or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while taking budesonide delayed-release capsules.. oIncreased risk of infection. Budesonide delayed-release capsules 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 delayed-release capsules. 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 delayed-release capsules, including: ofever. opain. oaches. ochills. ofeeling tired. onausea and vomiting. oheadache. ostomach area (abdominal) pain. oinfection in your air passages (respiratory infection). ogas. onausea. ovomiting. oback pain. otiredness. oindigestion. opain. odizziness. oTell your healthcare provider if you have any side effect that bothers you or that does not go away.. oStore budesonide delayed-release capsules at room temperature between 20o to 25oC (68o to 77oF). oKeep budesonide delayed-release capsules in tightly closed container.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1). 8.1 Pregnancy Risk Summary. Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform 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 fetus. The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 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 body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of mcg/kg in rabbits (approximately 0.01 times the maximum recommended human dose on body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on body surface area basis). In 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 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 delayed-release capsules, 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 delayed-release capsules and any potential adverse effects on the breastfed infant from budesonide delayed-release capsules, 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 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 delayed-release capsules is higher (up to 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 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 2.15 to 4.31 ng/mL which is up to 10 times higher than the 0.43 to 0.86 ng/mL for 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 delayed-release capsules, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. 8.4 Pediatric Use The safety and effectiveness of budesonide delayed-release capsules have been established in pediatric patients to 17 years of age who weigh more than 25 kg for the treatment of mild to moderate active Crohns disease involving the ileum and/or the ascending colon. Use of budesonide delayed-release capsules in this age group is supported by evidence from adequate and well controlled studies of budesonide delayed-release capsules in adults, with additional data from clinical studies in 149 pediatric patients treated up to weeks and one pharmacokinetic study in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. The observed safety profile of budesonide delayed-release capsules in pediatric patients is consistent with its known safety profile in adults and no new safety concerns were identified [see Adverse Reactions (6.1)].The safety and effectiveness of budesonide delayed-release capsules have not been established in pediatric patients less than years of age for the treatment of mild to moderate active Crohns disease involving the ileum and/or the ascending colon.The safety and effectiveness of budesonide delayed-release capsules have not been established in pediatric patients for the maintenance of clinical remission of mild to moderate Crohns disease. An open-label study to evaluate the safety and tolerability of budesonide delayed-release capsules as maintenance treatment in pediatric patients aged to 17 years was conducted, and did not establish the safety and efficacy of maintenance of clinical remission.Systemic corticosteroids, including budesonide delayed-release capsules, may cause reduction of growth velocity in pediatric patients. Pediatric patients with Crohns disease have 17% higher mean systemic exposure and cortisol suppression than adults with Crohns disease [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ]. 8.5 Geriatric Use Clinical studies of budesonide delayed-release capsules 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 delayed-release capsules 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. 8.6Hepatic Impairment Patients with moderate to severe hepatic impairment (Child-Pugh Class 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).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHypercorticism 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)oSymptoms 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)oIncreased 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)oOther Corticosteroid Effects: Monitor patients with concomitant conditions where corticosteroids may have unwanted effects (e.g., hypertension, diabetes mellitus). (5.4). oHypercorticism 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). oSymptoms 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). oIncreased 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). oOther Corticosteroid Effects: Monitor patients with concomitant conditions where corticosteroids may have unwanted effects (e.g., hypertension, diabetes mellitus). (5.4). 5.1Hypercorticism 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 systemic corticosteroid is recommended. Since budesonide delayed-release capsules contain corticosteroid, general warnings concerning corticosteroids should be followed [see Warnings and Precautions (5.2), (5.3), (5.4) ].Pediatric patients with Crohns disease have 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 and 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) ].. 5.2Symptoms 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 delayed-release 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 delayed-release capsules may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.. 5.3Increased 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 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 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. 5.4Other Corticosteroid Effects Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with family history of diabetes or glaucoma, or with any other condition where corticosteroids may have unwanted effects.