Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of Action Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay. The clinical significance of this is unknown. The activity of RHINOCORT AQUA Nasal Spray is due to the parent drug, budesonide. In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22 S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert. The precise mechanism of corticosteroid actions on inflammation in seasonal and perennial allergic rhinitis is not well known. Inflammation is an important component in the pathogenesis of seasonal and perennial allergic rhinitis. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in seasonal and perennial allergic rhinitis. Pharmacodynamics A 3-week clinical study in seasonal rhinitis, comparing RHINOCORT Nasal Inhaler, orally ingested budesonide, and placebo in 98 patients with allergic rhinitis due to birch pollen, demonstrated that the therapeutic effect of RHINOCORT Nasal Inhaler can be attributed to the topical effects of budesonide. HPA Axis Effects The effects of RHINOCORT AQUA (budesonide) Nasal Spray on adrenal function have been evaluated in several clinical trials. In a four-week clinical trial, 61 adult patients who received 256 mcg daily of RHINOCORT AQUA (budesonide) Nasal Spray demonstrated no significant differences from patients receiving placebo in plasma cortisol levels measured before and 60 minutes after 0.25 mg intramuscular cosyntropin. There were no consistent differences in 24-hour urinary cortisol measurements in patients receiving up to 400 mcg daily. Similar results were seen in a study of 150 children and adolescents aged 6 to 17 with perennial rhinitis who were treated with 256 mcg daily for up to 12 months. After treatment with the recommended maximal daily dose of RHINOCORT AQUA (budesonide) Nasal Spray (256 mcg) for seven days, there was a small, but statistically significant decrease in the area under the plasma cortisol-time curve over 24 hours (AUC0-24h) in healthy adult volunteers. A dose-related suppression of 24-hour urinary cortisol excretion was observed after administration of RHINOCORT AQUA (budesonide) Nasal Spray doses ranging from 100-800 mcg daily for up to four days in 78 healthy adult volunteers. The clinical relevance of these results is unknown. Pharmacokinetics Absorption After intranasal administration of a single dose of RHINOCORT AQUA (budesonide) Nasal Spray (128 mcg), the mean peak plasma concentration of approximately 0.3 nmol/L occurs about 0.5 hours post-dose. Compared to an intravenous dose, approximately 34% of the delivered intranasal dose reaches the systemic circulation, most of which is absorbed through the nasal mucosa. While budesonide is well absorbed from the GI tract, the oral bioavailability of budesonide is low (~10%) primarily due to extensive first pass metabolism in the liver. Distribution The volume of distribution of budesonide was approximately 2-3 L/kg. It was 85-90% bound to plasma proteins. The volume of distribution for the 22R epimer is almost twice that of the 22 S epimer. Protein binding was constant over a concentration range (1-100 nmol/L) achieved with, and exceeding, recommended doses of RHINOCORT AQUA Nasal Spray. Budesonide showed little or no binding to corticosteroid binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8. Metabolism In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4)-catalyzed biotransformation have been isolated and identified as 16α-hydroxyprednisolone and 6p-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative difference between the in vitro and in vivo metabolic patterns have been detected. Negligible metabolic inactivation was observed in human lung and serum preparations. Excretion/Elimination The 22R form of budesonide was preferentially cleared by the liver with systemic clearance of 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal half-life, 2 to 3 hours, was the same for both epimers and was independent of dose. Budesonide was excreted in urine and feces in the form of metabolites. Approximately 2/3 of an intranasal radiolabeled dose was recovered in the urine and the remainder in the feces. No unchanged budesonide was detected in the urine. Specific Populations Geriatric The pharmacokinetics of RHINOCORT AQUA (budesonide) Nasal Spray in geriatric patients have not been specifically studied. Pediatric Following administration of RHINOCORT AQUA (budesonide) Nasal Spray, the time to reach peak drug concentrations and plasma half-life were similar in children and in adults. Children had plasma concentrations approximately twice those observed in adults due primarily to differences in weight between children and adults. Gender No specific pharmacokinetic study has been conducted to evaluate the effect of gender on budesonide pharmacokinetics. However, following administration of 400 mcg of RHINOCORT AQUA (budesonide) Nasal Spray to 7 male and 8 female volunteers in a pharmacokinetic study, no major gender differences in the pharmacokinetic parameters were found. Race No specific study has been undertaken to evaluate the effect of race on budesonide pharmacokinetics. Nursing Mothers The disposition of budesonide when delivered by oral inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum concentration of budesonide for the 400 and 800 mcg doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after dosing. The estimated oral daily dose of budesonide from breast milk to the infant was approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide levels in plasma samples obtained from five infants at about 90 minutes after breastfeeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels ( < 0.02 nmol/L in four infants and < 0.04 nmol/L in one infant) [see Use In Specific Populations, Nursing Mothers]. Renal or Hepatic Impairment The pharmacokinetics of budesonide have not been investigated in patients with renal impairment. Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The relevance of this finding to intranasally administered budesonide has not been established. Drug-Drug Interactions Inhibitors of cytochrome P450 enzymes Ketoconazole: Ketoconazole, a strong inhibitor of cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4), the main metabolic enzyme for corticosteroids, increased plasma levels of orally ingested budesonide [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. Cimetidine: At recommended doses, cimetidine, a nonspecific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide. Animal Toxicology and/or Pharmacology Budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 2 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis) and at a subcutaneous dose of 500 mcg/kg in rats (approximately 16 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation doses up to 250 mcg/kg (approximately 8 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). Clinical Studies The therapeutic efficacy of RHINOCORT AQUA (budesonide) Nasal Spray has been evaluated in placebo-controlled clinical trials of seasonal and perennial allergic rhinitis of 3-6 weeks duration. The number of patients treated with budesonide in these studies was 90 males and 51 females aged 6-12 years and 691 males and 694 females 12 years and above. The patients were predominantly Caucasian. Overall, the results of these clinical trials showed that RHINOCORT AQUA (budesonide) Nasal Spray administered once daily provides statistically significant reduction in the severity of nasal symptoms of seasonal and perennial allergic rhinitis including runny nose, sneezing, and nasal congestion. An improvement in nasal symptoms may be noted in patients within 10 hours of first using RHINOCORT AQUA (budesonide) Nasal Spray. This time to onset is supported by an environmental exposure unit study in seasonal allergic rhinitis patients that demonstrated that RHINOCORT AQUA (budesonide) Nasal Spray led to a statistically significant improvement in nasal symptoms compared to placebo by 10 hours. Further support comes from a clinical study of patients with perennial allergic rhinitis which demonstrated a statistically significant improvement in nasal symptoms for both RHINOCORT AQUA (budesonide) Nasal Spray and for the active comparator (mometasone furoate) compared to placebo by 8 hours. Onset was also assessed in this study with peak nasal inspiratory flow rate and this endpoint failed to show efficacy for either active treatment. Although statistically significant improvements in nasal symptoms compared to placebo were noted within 8-10 hours in these studies, about one half to two thirds of the ultimate clinical improvement with RHINOCORT AQUA (budesonide) Nasal Spray occurs over the first 1-2 days, and maximum benefit may not be achieved until approximately 2 weeks after initiation of treatment. REFERENCES 1 Kallen B, Rydhstroem H, Aberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol 1999; 93:392-395. 2 Ericson A, Kallen B. Use of drugs during pregnancy: unique Swedish registration method that can be improved. Swedish Medical Products Agency 1999; 1:8-11. 3 Norjavaara E, Gerhardsson de Verdier M. Normal pregnancy outcomes in a population-based study including 2968 pregnant women exposed to budesonide. J Allergy Clin Immunol 2003;! 11:736-742.

CLINICAL PHARMACOLOGY Mechanism of Action Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay. The activity of PULMICORT TURBUHALER is due to the parent drug, budesonide. In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert. The precise mechanism of corticosteroid actions on inflammation in asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (eg, histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide range of doses from PULMICORT TURBUHALER (budesonide) . This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85-95%), and the low potency of formed metabolites (see below). Pharmacokinetics Absorption:After oral administration of budesonide, peak plasma concentration was achieved in about 1 to 2 hours and the absolute systemic availability was 6-13%. In contrast, most of budesonide delivered to the lungs is systemically absorbed. In healthy subjects, 34% of the metered dose was deposited in the lungs (as assessed by plasma concentration method) with an absolute systemic availability of 39% of the metered dose. Pharmacokinetics of budesonide do not differ significantly in healthy volunteers and asthmatic patients. Peak plasma concentrations of budesonide occurred within 30 minutes of inhalation from PULMICORT TURBUHALER. In asthmatic patients, budesonide showed a linear increase in AUC and Cmax with increasing dose after both a single dose and repeated dosing from PULMICORT TURBUHALER (budesonide) . Distribution: The volume of distribution of budesonide was approximately 3 L/kg. It was 85-90% bound to plasma proteins. Protein binding was constant over the concentration range (1-100 nmol/L) achieved with, and exceeding, recommended doses of PULMICORT TURBUHALER. Budesonide showed little or no binding to corticosteroid binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8. Metabolism: In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16α-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative differences between the in vitro and in vivo metabolic patterns have been detected. Negligible metabolic inactivation was observed in human lung and serum preparations. Excretion/Elimination: The 22R form of budesonide was preferentially cleared by the liver with systemic clearance of 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal half-life, 2 to 3 hours, was the same for both epimers and was independent of dose. Budesonide was excreted in urine and feces in the form of metabolites. Approximately 60% of an intravenous radiolabelled dose was recovered in the urine. No unchanged budesonide was detected in the urine. Special Populations: No pharmacokinetic differences have been identified due to race, gender or advanced age. Pediatric: Following intravenous dosing in pediatric patients age 10-14 years, plasma half-life was shorter than in adults (1.5 hours vs. 2.0 hours in adults). In the same population following inhalation of budesonide via a pressurized metered-dose inhaler, absolute systemic availability was similar to that in adults. Hepatic Insufficiency: Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The intravenous pharmacokinetics of budesonide were, however, similar in cirrhotic patients and in healthy subjects. Drug-Drug Interactions: Ketoconazole, a potent inhibitor of cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4), the main metabolic enzyme for corticosteroids, increased plasma levels of orally ingested budesonide. At recommended doses, cimetidine had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide. Pharmacodynamics To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled budesonide, a clinical study in patients with asthma was performed comparing 400 mcg budesonide administered via a pressurized metered-dose inhaler with a tube spacer to 1400 mcg of oral budesonide and placebo. The study demonstrated the efficacy of inhaled budesonide but not orally ingested budesonide despite comparable systemic levels. Thus, the therapeutic effect of conventional doses of orally inhaled budesonide are largely explained by its direct action on the respiratory tract. Generally, PULMICORT TURBUHALER (budesonide) has a relatively rapid onset of action for an inhaled corticosteroid. Improvement in asthma control following inhalation of PULMICORT TURBUHALER (budesonide) can occur within 24 hours of beginning treatment although maximum benefit may not be achieved for 1 to 2 weeks, or longer. PULMICORT TURBUHALER (budesonide) has been shown to decrease airway reactivity in various challenge models, including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate in patients with hyperreactive airways. The clinical relevance of these models is not certain. Pretreatment with PULMICORT TURBUHALER (budesonide) 1600 mcg daily (800 mcg twice daily) for 2 weeks reduced the acute (early-phase reaction) and delayed (late-phase reaction) decrease in FEV1 following inhaled allergen challenge. The effects of PULMICORT TURBUHALER (budesonide) on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 905 adults and 404 pediatric patients with asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by cosyntropin (ACTH) stimulation test, remained intact with PULMICORT TURBUHALER (budesonide) treatment at recommended doses. For adult patients treated with 100, 200, 400, or 800 mcg twice daily for 12 weeks, 4%, 2%, 6%, and 13% respectively, had an abnormal stimulated cortisol response (peak cortisol <14.5 mcg/dL assessed by liquid chromatography following short-cosyntropin test) as compared with 8% of patients treated with placebo. Similar results were obtained in pediatric patients. In another study in adults, doses of 400, 800 and 1600 mcg budesonide twice daily via PULMICORT TURBUHALER (budesonide) for 6 weeks were examined; 1600 mcg twice daily (twice the maximum recommended dose) resulted in a 27% reduction in stimulated cortisol (6-hour ACTH infusion) while 10 mg prednisone resulted in a 35% reduction. In this study, no patient on PULMICORT TURBUHALER (budesonide) at doses of 400 and 800 mcg twice daily met the criterion for an abnormal stimulated cortisol response (peak cortisol <14.5 mcg/dL assessed by liquid chromatography) following ACTH infusion. An open-label, long-term follow-up of 1133 patients for up to 52 weeks confirmed the minimal effect on the HPA axis (both basal and stimulated plasma cortisol) of PULMICORT TURBUHALER (budesonide) when administered at recommended doses. In patients who had previously been oral steroid-dependent, use of PULMICORT TURBUHALER (budesonide) in recommended doses was associated with higher stimulated cortisol response compared with baseline following 1 year of therapy. The administration of budesonide via PULMICORT TURBUHALER (budesonide) in doses up to 800 mcg/day (mean daily dose 445 mcg/day) or via a pressurized metered-dose inhaler in doses up to 1200 mcg/day (mean daily dose 620 mcg/day) to 216 pediatric patients (age 3 to 11 years) for 2 to 6 years had no significant effect on statural growth compared with non-corticosteroid therapy in 62 matched control patients. However, the long-term effect of PULMICORT TURBUHALER (budesonide) on growth is not fully known. Clinical Trails The therapeutic efficacy of PULMICORT TURBUHALER (budesonide) has been evaluated in controlled clinical trials involving more than 1300 patients (6 years and older) with asthma of varying disease duration (<1 year to >20 years) and severity. Double-blind, parallel, placebo-controlled clinical trials of 12 weeks duration and longer have shown that, compared with placebo, PULMICORT TURBUHALER (budesonide) significantly improved lung function (measured by PEF and FEV1), significantly decreased morning and evening symptoms of asthma, and significantly reduced the need for as-needed inhaled β2-agonist use at doses of 400 mcg to 1600 mcg per day (200 mcg to 800 mcg twice daily) in adults and 400 mcg to 800 mcg per day (200 mcg to 400 mcg twice daily) in pediatric patients 6 years of age and older. Improved lung function (morning PEF) was observed within 24 hours of initiating treatment in both adult and pediatric patients 6 years of age and older, although maximum benefit was not achieved for 1 to 2 weeks, or longer, after starting treatment. Improved lung function was maintained throughout the 12 weeks of the double-blind portion of the trials. Patients Not Receiving Corticosteroid Therapy In a 12-week clinical trial in 273 patients with mild to moderate asthma (mean baseline FEV1 2.27 L) who were not well controlled by bronchodilators alone, PULMICORT TURBUHALER (budesonide) was evaluated at doses of 200 mcg twice daily and 400 mcg twice daily versus placebo. The FEV1 results from this trial are shown in the figure below. Pulmonary function improved significantly on both doses of PULMICORT TURBUHALER (budesonide) compared with placebo. A 12-Week Trial in Patients Not on Corticosteroid Therapy Prior to Study Entry In a 12-month controlled trial in 75 patients not previously receiving corticosteroids, PULMICORT TURBUHALER (budesonide) at 200 mcg twice daily resulted in improved lung function (measured by PEF) and reduced bronchial hyperreactivity compared with placebo. Patients Previously Maintained on Inhaled Corticosteroids The safety and efficacy of PULMICORT TURBUHALER (budesonide) was also evaluated in adult and pediatric patients (age 6 to 18 years) previously maintained on inhaled corticosteroids (adults: N=473, mean baseline FEV1 2.04 L, baseline doses of beclomethasone dipropionate 126-1008 mcg/day; pediatrics: N=404, mean baseline FEV1 2.09 L, baseline doses of beclomethasone dipropionate 126-672 mcg/day or triamcinolone acetonide 300-1800 mcg/day). The FEV1 results of these two trials, both 12 weeks in duration, are presented in the following figures. Pulmonary function improved significantly with all doses of PULMICORT TURBUHALER (budesonide) compared with placebo in both trials. Adult Patients Previously Maintained on Inhaled Corticosteroids Pediatric Patients Age 6 to 18 Years Previously Maintained on Inhaled Corticosteroids Patients Receiving PULMICORT TURBUHALER (budesonide) Once Daily The efficacy and safety of once-daily administration of PULMICORT TURBUHALER (budesonide) 200 mcg and 400 mcg and placebo were also evaluated in 309 adult asthmatic patients (mean baseline FEV1 2.7 L) in an 18-week study. Compared with placebo, patients receiving Pulmicort 200 or 400 mcg once daily showed significantly better asthma stability as assessed by PEF and FEV1 over an initial 6-week treatment period, which was maintained with a 200 mcg daily dose over the subsequent 12 weeks. Although the study population included both patients previously treated with inhaled corticosteroids, as well as patients not previously receiving corticosteroid therapy, the results showed that once-daily dosing was most clearly effective for those patients previously maintained on orally inhaled corticosteroids (see DOSAGE AND ADMINISTRATION). Patients Previously Maintained on Oral Corticosteroids In a clinical trial in 159 severe asthmatic patients requiring chronic oral prednisone therapy (mean baseline prednisone dose 19.3 mg/day) PULMICORT TURBUHALER (budesonide) at doses of 400 mcg twice daily and 800 mcg twice daily was compared with placebo over a 20-week period. Approximately two-thirds (68% on 400 mcg twice daily and 64% on 800 mcg twice daily) of PULMICORT TURBUHALER (budesonide) -treated patients were able to achieve sustained (at least 2 weeks) oral corticosteroid cessation (compared with 8% of placebo-treated patients) and improved asthma control. The average oral corticosteroid dose was reduced by 83% on 400 mcg twice daily and 79% on 800 mcg twice daily for PULMICORT TURBUHALER (budesonide) -treated patients vs. 27% for placebo. Additionally, 58 out of 64 patients (91%) who completely eliminated oral corticosteroids during the double-blind phase of the trial remained off oral corticosteroids for an additional 12 months while receiving PULMICORT TURBUHALER (budesonide) .

CLINICAL PHARMACOLOGY 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. Pharmacodynamics Treatment with glucocorticoids, including ENTOCORT EC 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 ENTOCORT EC capsules 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 (AUC 0-24) was greater (78%) with prednisolone 20 mg per day compared to 45% with ENTOCORT EC 9 mg per day. Pediatrics The effect of budesonide on endogenous cortisol concentrations was compared between pediatrics (n=8, aged 9 to 14 years) and adults (n=6) with active Crohn’s disease following administration of ENTOCORT EC 9 mg once daily for 7 days. Compared to baseline values before treatment, the mean decrease in the AUC 0-24 of cortisol was 64% (±18%) in pediatrics and 50% (±27%) in adults after ENTOCORT EC treatment [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS and Use In Specific Populations]. The responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) was studied in pediatric patients aged 8 to 17 years, with mild to moderate active Crohn’s disease in randomized, double-blind, active control study [see Clinical Studies]. After 8 weeks of treatment with 9 mg once daily ENTOCORT EC or with prednisolone, administered at tapering doses starting from 1 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 5 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 8 to 17 years old with Peak Endogenous Cortisol Levels (above 18 mcg/dL) after ACTH Stimulation and Normal Response* to ACTH Challenge Following Administration of ENTOCORT EC or Prednisolone for 8 weeks Budesonide Prednisolone Peak plasma cortisol above 18 mcg/dL At baseline 91% (20/22) 91% (21/23) At week 8 25% (4/16) 0% (0/18) Normal response* to ACTH challenge At baseline 73% (16/22) 78% (18/23) At week 8 6% (1/16) 0% (0/18) *The normal response to ACTH challenge included 3 criteria, as defined in the cosyntropin label: 1) morning cortisol level above 5 mcg/dL; 2) increase in cortisol level by at least 7 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 8 after treatment. Pharmacokinetics Absorption Following administration of ENTOCORT EC, 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 ENTOCORT EC 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 nmol•hr/L, respectively. Following administration of 9 mg ENTOCORT EC once daily in patients with active Crohn’s disease, the mean peak plasma concentration and AUC were 4.0 ±2.1 nmol/L and 35.0 ±19.8 nmol•h/L, respectively. Concomitant administration of a high-fat meal delayed the time to peak concentration of budesonide from ENTOCORT EC 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 Crohn’s 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 Crohn’s 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, 6β-hydroxy budesonide and 16α-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 6β-hydroxy budesonide and 16α-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 9 to 14 years (n=8) after oral administration of ENTOCORT EC and intravenous administration of budesonide. Following administration of 9 mg ENTOCORT EC once daily for 7 days, the median time to peak plasma concentration of budesonide was 5 hours and the mean peak plasma concentration was 6.0 ± 3.5 nmol/L. The mean AUC was 41.3 ±12.2 nmol•h/L and 17% higher than that in adult patients with Crohn’s disease in the same study. The mean absolute oral availability was 9.2% (3 to 17%; n=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, Use In Specific Populations]. 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, WARNINGS AND PRECAUTIONS]. 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]. Grapefruit Juice In an open, randomized, cross-over study, 8 healthy subjects were given ENTOCORT EC capsules 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]. 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 μg 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 ENTOCORT EC 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. Clinical Studies Treatment Of Mild To Moderate Active Crohn’s Disease Adults The efficacy of ENTOCORT EC were evaluated in 994 patients with mild to moderate active Crohn’s 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 Crohn’s Disease Activity Index (CDAI) was the main clinical assessment used for determining efficacy in these 5 studies. 1The 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 ENTOCORT EC capsules. 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 ENTOCORT EC 9 mg daily in the morning to a comparator. At baseline, the median CDAI was 272. ENTOCORT EC 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 Study ENTOCORT EC 9 mg Daily ENTOCORT EC 4.5 Twice mg Daily Comparator3 Placebo Prednisolone 1 62/91 (69%)1 37/83 (45%) 2 31/61 (51%)2 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%) 1. p=0.0004 compared to comparator. 2. p=0.001 compared to placebo. 3. This drug is not approved for the treatment of Crohn’s disease in the United States. Two placebo-controlled clinical trials (Studies 2 and 3) were conducted. Study 2 involved 258 patients and tested the effects of graded doses of ENTOCORT EC (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 ENTOCORT EC 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 ENTOCORT EC 9 mg once daily, ENTOCORT EC 4.5 mg twice daily and placebo for 8 weeks, followed by a 2week double-blind taper phase. The median CDAI at baseline was 263. Neither 9 mg daily nor 4.5 mg twice daily ENTOCORT EC dose levels were statistically different from placebo (Table 5). The recommended dosage of ENTOCORT EC for the treatment of mild to moderate active Crohn’s 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]. Two clinical trials (Studies 4 and 5) compared ENTOCORT EC capsules with oral prednisolone (initial dose 40 mg per day). Study 4 was a 3-armed parallel group study. The groups were treated with ENTOCORT EC 9 mg once daily, ENTOCORT EC 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 ENTOCORT EC 9 mg daily and the prednisolone groups in Study 4. In Study 5, 13% fewer patients in the ENTOCORT EC 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 ENTOCORT EC 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 ENTOCORT EC, in pediatric patients aged 8 to 17 years, who weigh more than 25 kg with mild to moderate active Crohn’s disease (defined as Crohn's 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 ENTOCORT EC 9 mg once daily, with prednisolone, administered at tapering doses starting from 1 mg/kg. Twenty-two (22) patients were treated with ENTOCORT EC capsules and 24 patients were treated with prednisolone. After 8 weeks of treatment, 55% (95% CI: 32%, 77%) of patients treated with ENTOCORT EC 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 7 days) decreased from 1.49 at baseline to 0.96 after treatment with ENTOCORT EC and 2.00 at baseline to 0.52 after treatment with prednisolone. The average daily abdominal pain rating (where 0=none, 1=mild, 2=moderate, and 3=severe) decreased from 1.49 at baseline to 0.54 after treatment with ENTOCORT EC and 1.64 at baseline to 0.38 after 8 weeks of treatment with prednisolone. Use of ENTOCORT EC in this age group is supported by evidence from adequate and well-controlled studies of ENTOCORT EC in adults, and by safety and pharmacokinetic studies performed in pediatric patients. Maintenance Of Clinical Remission Of Mild To Moderate Crohn’s Disease Adults The efficacy of ENTOCORT EC 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 ENTOCORT EC 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. ENTOCORT EC 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 ENTOCORT EC 6 mg per day. ENTOCORT EC 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). REFERENCES 1. Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohn’s Disease Activity Index, National Cooperative Crohn’s Disease Study. Gastroenterology 1976; 70(3): 439-444.

Find Lowest Prices on RHINOCORT AQUA 32 mcg (budesonide) Nasal Spray DESCRIPTION Budesonide, the active ingredient of RHINOCORT AQUA (budesonide) Nasal Spray, is an anti-inflammatory synthetic corticosteroid. It is designated chemically as (RS)-11-beta, 16-alpha, 17, 21-tetrahydroxypregna-l,4-diene-3,20-dione cyclic 16, 17-acetal with butyraldehyde. Budesonide is provided as the mixture of two epimers (22R and 22S). The empirical formula of budesonide is C25H34O6 and its molecular weight is 430.5. Its structural formula is: Budesonide is a white to off-white, odorless powder that is practically insoluble in water and in heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 5 is 1.6 x103. RHINOCORT AQUA (budesonide) Nasal Spray is an unscented, metered-dose, manual-pump spray formulation containing a micronized suspension of budesonide in an aqueous medium. Microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose anhydrous, polysorbate 80, disodium edetate, potassium sorbate, and purified water are contained in this medium; hydrochloric acid is added to adjust the pH to a target of 4.5. RHINOCORT AQUA Nasal Spray delivers 32 mcg of budesonide per spray. Each bottle of RHINOCORT AQUA (budesonide) Nasal Spray 32 mcg contains 120 metered sprays after initial priming. Prior to initial use, the container must be shaken gently and the pump must be primed by actuating eight times. If used daily, the pump does not need to be reprimed. If not used for two consecutive days, reprime with one spray or until a fine spray appears. If not used for more than 14 days, rinse the applicator and reprime with two sprays or until a fine spray appears.

PULMICORT TURBUHALER® (budesonide) Inhalation Powder 200 mcg For Oral Inhalation Only. DESCRIPTION Budesonide, the active component of PULMICORT TURBUHALER (budesonide) 200 mcg, is a corticosteroid designated chemically as (RS)-11β, 16α, 17,21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C25H34O6 and its molecular weight is 430.5. Its structural formula is: Budesonide is a white to off-white, tasteless, odorless powder that is practically insoluble in water and in heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 7.4 is 1.6 x 103. PULMICORT TURBUHALER (budesonide) is an inhalation-driven multi-dose dry powder inhaler that contains only micronized budesonide. Each actuation of PULMICORT TURBUHALER provides 200 mcg budesonide per metered dose, which delivers approximately 160 mcg budesonide from the mouthpiece (based on in vitro testing at 60 L/min for 2 sec). In vitro testing has shown that the dose delivery for PULMICORT TURBUHALER (budesonide) is substantially dependent on airflow through the device. Patient factors such as inspiratory flow rates will also affect the dose delivered to the lungs of patients in actual use (see Patient's Instructions for Use). In adult patients with asthma (mean FEV1 2.9 L [0.8 - 5.1 L]) mean peak inspiratory flow (PIF) through PULMICORT TURBUHALER (budesonide) was 78 (40-111) L/min. Similar results (mean PIF 82 [43-125] L/min) were obtained in asthmatic children (6 to 15 years, mean FEV1 2.1 L [0.9 - 5.4 L]). Patients should be carefully instructed on the use of this drug product to assure optimal dose delivery.

ENTOCORT® EC (budesonide) Capsules, for Oral Use DESCRIPTION Budesonide, the active ingredient of ENTOCORT EC capsules, is a synthetic corticosteroid. Budesonide is designated chemically as (RS)-11β, 16α, 17,21-tetrahydroxypregna-1,4-diene3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C25H34O6 and its molecular weight is 430.5. Its structural formula is: Budesonide is a white to off-white, tasteless, odorless powder that is practically insoluble in water and heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 5 is 1.6 x 103 ionic strength 0.01. Entocort EC is formulated as hard gelatin capsules filled with enteric-coated granules that dissolve at pH greater than 5.5. Each capsule for oral administration contains 3 mg of micronized budesonide with the following inactive ingredients: ethylcellulose, acetyltributyl citrate, methacrylic acid copolymer type C, triethyl citrate, antifoam M, polysorbate 80, talc, and sugar spheres. The capsule shells have the following inactive ingredients: gelatin, iron oxide, and titanium dioxide.

INDICATIONS Treatment of Seasonal or Perennial Allergic Rhinitis RHINOCORT AQUA (budesonide) Nasal Spray is indicated for the treatment of nasal symptoms of seasonal or perennial allergic rhinitis in adults and children six years of age and older. DOSAGE AND ADMINISTRATION The recommended starting dosage for adults and children 6 years of age and older is 64 mcg per day administered as one spray per nostril of RHINOCORT AQUA (budesonide) Nasal Spray 32 mcg once daily. Some patients who do not achieve symptom control at the recommended starting dosage may benefit from an increased dosage. The maximum recommended dosage for adults (12 years of age and older) is 256 mcg per day administered as four sprays per nostril once daily of RHINOCORT AQUA (budesonide) Nasal Spray 32 mcg and the maximum recommended dose for pediatric patients (6 to < 12 years of age) is 128 mcg per day administered as two sprays per nostril once daily of RHINOCORT AQUA (budesonide) Nasal Spray 32 mcg. It is always desirable to titrate an individual patient to the minimum effective dosage to reduce the possibility of side effects. An improvement in nasal symptoms may be noted in patients within 10 hours of first using RHINOCORT AQUA (budesonide) Nasal Spray, however, clinical improvement usually takes 1 -2 days with maximum benefit in approximately 2 weeks. When the maximum benefit has been achieved and symptoms have been controlled, reducing the dosage may be effective in maintaining control of the allergic rhinitis symptoms in patients who were initially controlled on higher dosages. Prior to initial use, the container must be shaken gently and the pump must be primed by actuating eight times. If used daily, the pump does not need to be reprimed. If not used for two consecutive days, reprime with one spray or until a fine spray appears. If not used for more than 14 days, rinse the applicator and reprime with two sprays or until a fine spray appears. Shake the container gently before each use. Illustrated Patient's Instructions for Use accompany each package of RHINOCORT AQUA (budesonide) Nasal Spray 32 mcg. HOW SUPPLIED Dosage Forms and Strengths RHINOCORT AQUA (budesonide) Nasal Spray is a nasal spray suspension. Each spray delivers 32 mcg of budesonide. Each bottle of RHINOCORT AQUA (budesonide) Nasal Spray 32 mcg contains 120 metered sprays after initial priming. RHINOCORT AQUA (budesonide) Nasal Spray 32 mcg is available in an amber glass bottle with a metered-dose pump spray and a green protection cap. RHINOCORT AQUA (budesonide) Nasal Spray 32 mcg (NDC 0186-1070-08) provides 120 metered sprays after initial priming; net fill weight 8.6 g. The RHINOCORT AQUA (budesonide) Nasal Spray 32 mcg bottle has been filled with an excess to accommodate the priming activity. The bottle should be discarded after 120 sprays following initial priming, since the amount of budesonide delivered per spray thereafter may be substantially less than the labeled dose. Each spray delivers 32 mcg of budesonide to the patient. RHINOCORT AQUA (budesonide) Nasal Spray should be stored at controlled room temperature, 20 to 25°C (68 to 77°F) with the valve up. Do not freeze. Protect from light. Shake gently before use. Do not spray in eyes. Distributed by: AstraZeneca LP, Wilmington, DE 19850. Revised: 12/2010

INDICATIONS PULMICORT TURBUHALER (budesonide) is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients six years of age or older. It is also indicated for patients requiring oral corticosteroid therapy for asthma. Many of those patients may be able to reduce or eliminate their requirement for oral corticosteroids over time. PULMICORT TURBUHALER (budesonide) is NOT indicated for the relief of acute bronchospasm. DOSAGE AND ADMINISTRATION PULMICORT TURBUHALER (budesonide) should be administered by the orally inhaled route in asthmatic patients age 6 years and older. Individual patients will experience a variable onset and degree of symptom relief. Generally, PULMICORT TURBUHALER (budesonide) has a relatively rapid onset of action for an inhaled corticosteroid. Improvement in asthma control following inhaled administration of PULMICORT TURBUHALER (budesonide) can occur within 24 hours of initiation of treatment, although maximum benefit may not be achieved for 1 to 2 weeks, or longer. The safety and efficacy of PULMICORT TURBUHALER (budesonide) when administered in excess of recommended doses have not been established. The recommended starting dose and the highest recommended dose of PULMICORT TURBUHALER (budesonide) , based on prior asthma therapy, are listed in the following table. Previous Therapy Recommended Starting Dose Highest Recommended Dose Adults: Bronchodilators alone 200 to 400 mcg twice daily 400 mcg twice daily Inhaled Corticosteroids* 200 to 400 mcg twice daily 800 mcg twice daily Oral Corticosteroids 400 to 800 mcg twice daily 800 mcg twice daily Children: Bronchodilators alone 200 mcg twice daily 400 mcg twice daily Inhaled Corticosteroids* 200 mcg twice daily 400 mcg twice daily Oral Corticosteroids The highest recommended dose in children is 400 mcg twice daily *In patients with mild to moderate asthma who are well controlled on inhaled corticosteroids, dosing with PULMICORT TURBUHALER (budesonide) 200 mcg or 400 mcg once daily may be considered. PULMICORT TURBUHALER (budesonide) can be administered once daily either in the morning or in the evening. If the once-daily treatment with PULMICORT TURBUHALER (budesonide) does not provide adequate control of asthma symptoms, the total daily dose should be increased and/or administered as a divided dose. Patients Maintained on Chronic Oral Corticosteroids Initially, PULMICORT TURBUHALER (budesonide) should be used concurrently with the patient's usual maintenance dose of systemic corticosteroid. After approximately one week, gradual withdrawal of the systemic corticosteroid is started by reducing the daily or alternate daily dose. The next reduction is made after an interval of one or two weeks, depending on the response of the patient. Generally, these decrements should not exceed 2.5 mg of prednisone or its equivalent. A slow rate of withdrawal is strongly recommended. During reduction of oral corticosteroids, patients should be carefully monitored for asthma instability, including objective measures of airway function, and for adrenal insufficiency (see WARNINGS). During withdrawal, some patients may experience symptoms of systemic corticosteroid withdrawal, eg, joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement in pulmonary function. Such patients should be encouraged to continue with PULMICORT TURBUHALER (budesonide) but should be monitored for objective signs of adrenal insufficiency. If evidence of adrenal insufficiency occurs, the systemic corticosteroid doses should be increased temporarily and thereafter withdrawal should continue more slowly. During periods of stress or a severe asthma attack, transfer patients may require supplementary treatment with systemic corticosteroids. NOTE: In all patients it is desirable to titrate to the lowest effective dose once asthma stability is achieved. Directions for Use Illustrated Patient's Instructions for Use accompany each package of PULMICORT TURBUHALER (budesonide) . Patients should be instructed to prime PULMICORT TURBUHALER (budesonide) prior to its initial use, and instructed to inhale deeply and forcefully each time the unit is used. Rinsing the mouth after inhalation is also recommended. HOW SUPPLIED PULMICORT TURBUHALER (budesonide) consists of a number of assembled plastic details, the main parts being the dosing mechanism, the storage unit for drug substance and the mouthpiece. The inhaler is protected by a white outer tubular cover screwed onto the inhaler. The body of the inhaler is white and the turning grip is brown. The following wording is printed on the grip in raised lettering, “Pulmicort™ 200 mcg”. The TURBUHALER inhaler cannot be refilled and should be discarded when empty. PULMICORT TURBUHALER (budesonide) is available as 200 mcg/dose, 200 doses (NDC 0186-0915-42) and has a target fill weight of 104 mg. When there are 20 doses remaining in PULMICORT TURBUHALER (budesonide) , a red mark will appear in the indicator window. If the unit is used beyond the point at which the red mark appears at the bottom of the window, the correct amount of medication may not be obtained. The unit should be discarded. Store with the cover tightened in a dry place at controlled room temperature 20-25°C (68-77°F) [see USP]. Keep out of the reach of children. All trademarks are the property of the AstraZeneca group of companies. ©AstraZeneca 2001, 2006. Manufactured for: AstraZeneca LP, Wilmington, DE 19850 By: AstraZeneca AB, Sodertalje, Sweden 33020-00. Rev. 10/06. FDA Rev date: 8/20/2007

INDICATIONS Treatment Of Mild To Moderate Active Crohn’s Disease ENTOCORT EC is indicated for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon in patients 8 years of age and older. Maintenance Of Clinical Remission Of Mild To Moderate Crohn’s Disease ENTOCORT EC is indicated for the maintenance of clinical remission of mild to moderate Crohn’s disease involving the ileum and/or the ascending colon for up to 3 months in adults. DOSAGE AND ADMINISTRATION Administration Instructions Take ENTOCORT EC capsules once daily in the morning. Swallow ENTOCORT EC capsules whole. Do not chew or crush. Avoid consumption of grapefruit juice for the duration of ENTOCORT EC therapy [see DRUG INTERACTIONS]. Treatment Of Mild To Moderate Active Crohn’s Disease The recommended dosage of ENTOCORT EC is: Adults 9 mg orally once daily for up to 8 weeks. Repeated 8 week courses of ENTOCORT EC can be given for recurring episodes of active disease. Pediatric Patients 8 To 17 Years Who Weigh More Than 25 kg 9 mg orally once daily for up to 8 weeks, followed by 6 mg once daily for 2 weeks. Maintenance Of Clinical Remission Of Mild To Moderate Crohn’s Disease The recommended dosage in adults, following an 8 week course(s) of treatment for active disease and once the patient’s symptoms are controlled (CDAI less than 150), is ENTOCORT EC 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 ENTOCORT EC 6 mg for more than 3 months has not been shown to provide substantial clinical benefit. Patients with mild to moderate active Crohn’s disease involving the ileum and/or ascending colon have been switched from oral prednisolone to ENTOCORT EC with no reported episodes of adrenal insufficiency. Since prednisolone should not be stopped abruptly, tapering should begin concomitantly with initiating ENTOCORT EC treatment. Dosage Adjustment In Adult Patients With Hepatic Impairment Consider reducing the dosage of ENTOCORT EC 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, Use In Specific Populations]. HOW SUPPLIED Dosage Forms And Strengths Capsules: 3 mg hard gelatin capsules with an opaque light grey body and an opaque pink cap, coded with ENTOCORT EC 3 mg. Storage And Handling ENTOCORT EC 3 mg capsules are hard gelatin capsules with an opaque light grey body and an opaque pink cap, coded with ENTOCORT EC 3 mg on the capsule and are supplied as follows: NDC 0574-9850-10 Bottles of 100 Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]. Keep container tightly closed. Manufactured for and Distributed by: Perrigo, Allegan, MI 49010. Revised: Oct 2017

PATIENT INFORMATION RHINOCORT AQUA (budesonide) ® (RINE-o-cort AH-kwa) (budesonide) Nasal Spray For use in your nose only Read the Patient Information that comes with RHINOCORT AQUA (budesonide) Nasal Spray before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. If you have questions about RHINOCORT AQUA (budesonide) Nasal Spray, ask your healthcare provider or pharmacist. What is RHINOCORT AQUA (budesonide) Nasal Spray? RHINOCORT AQUA (budesonide) Nasal Spray is a prescription medicine used to treat seasonal and year-round allergy symptoms in adults and children 6 years of age and older. RHINOCORT AQUA Nasal Spray contains budesonide, which is a man-made (synthetic) corticosteroid. Intranasal corticosteroids are natural hormones found in the body that reduce swelling of the lining of your nose. When you spray RHINOCORT AQUA (budesonide) Nasal Spray into your nose, it helps reduce the nasal symptoms of allergic rhinitis (inflammation of the lining of the nose), such as stuffy nose, runny nose, itching and sneezing. The safety and effectiveness of RHINOCORT AQUA (budesonide) Nasal Spray has not been shown in children under 6 years of age. Who should not use RHINOCORT AQUA (budesonide) Nasal Spray? Do not use RHINOCORT AQUA (budesonide) Nasal Spray: if you are allergic to budesonide or any of the ingredients in RHINOCORT AQUA Nasal Spray. See the end of this leaflet for a complete list of the ingredients in RHINOCORT AQUA (budesonide) Nasal Spray. What should I tell my healthcare provider before using RHINOCORT AQUA (budesonide) Nasal Spray? Before you use RHINOCORT AQUA (budesonide) Nasal Spray, tell your healthcare provider or pharmacist if you: have recently been around anyone with chicken pox or measles have liver problems have any untreated infections have ever had an infection called tuberculosis have an eye infection have recently had surgery or an injury to your nose have any other medical conditions are pregnant or plan to become pregnant. It is not known if RHINOCORT AQUA (budesonide) Nasal Spray will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant. are breastfeeding or plan to breastfeed. RHINOCORT AQUA (budesonide) Nasal Spray can pass into your breast milk. Talk to your doctor about the best way to feed your baby if you take RHINOCORT AQUA (budesonide) Nasal Spray. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. RHINOCORT AQUA (budesonide) Nasal Spray may affect the way other medicines work, and other medicines may affect how RHINOCORT AQUA (budesonide) Nasal Spray works. Know the medicines you take. Keep a list of your medicines with you to show your healthcare provider and pharmacist when you get a new medicine. How should I use RHINOCORT AQUA (budesonide) Nasal Spray? RHINOCORT AQUA (budesonide) Nasal Spray is for use in your nose only. Do not spray it in your eyes or mouth. Use RHINOCORT AQUA (budesonide) Nasal Spray exactly as your healthcare provider tells you to use it. It is very important that you use RHINOCORT AQUA (budesonide) Nasal Spray regularly. Do not stop using RHINOCORT AQUA (budesonide) Nasal Spray or change your dose without talking to your healthcare provider, even if you are feeling better. Talk to your healthcare provider if your symptoms do not improve after taking RHINOCORT AQUA (budesonide) Nasal Spray for 2 weeks or if your symptoms get worse. An adult should help a young child use this medicine. See the Patient Instructions for Use at the end of this leaflet for complete information on how to use RHINOCORT AQUA (budesonide) Nasal Spray. What are the possible side effects of RHINOCORT AQUA (budesonide) Nasal Spray? RHINOCORT AQUA (budesonide) Nasal Spray may cause serious side effects including: hole in the cartilage inside the nose (nasal septal perforation). Tell your healthcare provider if you have a whistling sound from your nose when you breathe. slow wound healing. You should not use RHINOCORT AQUA (budesonide) Nasal Spray until your nose has healed if you have a sore in your nose, if you have had surgery on your nose, or if your nose has been injured. fungal infection in your nose. allergic reactions. Tell your healthcare provider or get medical help right away if you have: skin rash, redness or swelling severe itching swelling of the face, mouth and tongue immune system problems that may increase your risk of infections. You are more likely to get infections if you take medicines that weaken your body's ability to fight infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while using RHINOCORT AQUA (budesonide) Nasal Spray. Symptoms of infection may include fever, pain, aches, chills, feeling tired, nausea and vomiting. adrenal insufficiency, Adrenal insufficiency is a condition in which the adrenal glands do not make enough steroid hormones. Symptom of adrenal insufficiency may include tiredness, weakness, nausea, vomiting and low blood pressure. slowed or delayed growth in children. A child's growth should be checked regularly while using RHINOCORT AQUA (budesonide) Nasal Spray. eye problems, such as glaucoma and cataracts. Tell your healthcare provider if you have a change in vision or have a history of increased intraocular pressure, glaucoma, and/or cataracts. Call your healthcare provider or get medical help right away if you have symptoms of any of the serious side effects listed above. The most common side effects of RHINOCORT AQUA (budesonide) Nasal Spray include: nose bleeds sore throat breathing difficulties such as wheezing, or chest tightening cough irritation of your nose Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all of the possible side effects of RHINOCORT AQUA (budesonide) Nasal Spray. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may report side effects to AstraZeneca at 1-800-236-9933. What should I know about allergic rhinitis? "Rhinitis" means inflammation of the lining of the nose. It is sometimes called "hay fever." Allergic rhinitis can be caused by allergies to pollen, animal dander, house dust mite, and mold spores. If you have allergic rhinitis, your nose becomes stuffy, runny, and itchy. You may also sneeze a lot. You may have red, itchy, watery eyes; itchy throat; or blocked, itchy ears. RHINOCORT AQUA (budesonide) Nasal Spray helps to relieve your nasal symptoms. If you also have itchy, watery eyes, you should tell your healthcare provider. He or she can prescribe additional medication to treat these symptoms. How should I store RHINOCORT AQUA (budesonide) Nasal Spray? Store RHINOCORT AQUA (budesonide) Nasal Spray at 68°F to 77°F (20°C to 25°C). Do not freeze RHINOCORT AQUA (budesonide) Nasal Spray. Protect RHINOCORT AQUA (budesonide) Nasal Spray from light. Do not use RHINOCORT AQUA (budesonide) Nasal Spray after the labeled number of sprays have been used (does not include priming) or after the expiration date shown on the carton or bottle label. Keep the green protective cap on RHINOCORT AQUA (budesonide) Nasal Spray when not in use. (Please see Prior to Use on reverse side). Keep RHINOCORT AQUA (budesonide) Nasal Spray and all medications out of the reach of children. General Information about the safe and effective use of RHINOCORT AQUA (budesonide) Nasal Spray: Do not use RHINOCORT AQUA (budesonide) Nasal Spray for a condition for which it was not prescribed. Do not give RHINOCORT AQUA (budesonide) Nasal Spray to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about RHINOCORT AQUA (budesonide) Nasal Spray. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about RHINOCORT AQUA (budesonide) Nasal Spray that is written for health professionals. For more information, go to www.astrazeneca-us.com or call AstraZeneca at 1-800-236-9933. What are the Ingredients of RHINOCORT AQUA (budesonide) Nasal Spray? Active ingredient: budesonide Inactive ingredients: Microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose anhydrous, polysorbate 80, disodium edetate, potassium sorbate, and purified water, and hydrochloric acid. Patient Instructions for Use For use in your nose only. Do not spray in your eyes or mouth. Read the Patient Instructions for Use carefully before you start to use RHINOCORT AQUA (budesonide) Nasal Spray. If you have any questions, ask your healthcare provider Figure A How to prime your RHINOCORT AQUA (budesonide) Nasal Spray Before you use RHINOCORT AQUA (budesonide) Nasal Spray, the bottle must be primed. To prime RHINOCORT AQUA (budesonide) Nasal Spray: 1. Pull to remove the green protective cap off the nasal spray unit. 2. Shake the bottle gently for a few seconds before each use. 3. Hold the bottle firmly, as shown in Figure B, with your index and middle finger on either side of the spray tip and your thumb underneath the bottle. Figure B 4. Activate the pump by quickly and firmly pressing down on the white collar while holding the base of the bottle with your thumb. 5. Before your first use of RHINOCORT AQUA (budesonide) Nasal Spray, shake the bottle gently. The pump must be primed by pressing down on the white collar 8 times. The pump is now ready to use. If used daily the pump does not need to be reprimed. If not used for 2 days in a row, reprime with 1 spray or until a fine spray appears. If not used for more than 14 days, rinse the spray tip of the pump using the cleaning steps listed at the end of this leaflet. After cleaning reprime with 2 sprays or until a fine spray appears. Each bottle of RHINOCORT AQUA (budesonide) Nasal Spray contains enough medicine for you to spray medicine from the bottle 120 times after the bottle is primed. You should not use the bottle of RHINOCORT AQUA (budesonide) Nasal Spray after 120 sprays. Additional sprays after 120 may not contain the right amount of medicine. You should keep track of the number of sprays you use from each bottle of RHINOCORT AQUA Nasal Spray and throw away any remaining medicine that may be left in the bottle. Refill your prescription monthly. How to use your RHINOCORT AQUA (budesonide) Nasal Spray Follow these instructions for daily use of RHINOCORT AQUA (budesonide) Nasal Spray: Gently blow your nose to clear your nostrils, if necessary. Shake the bottle gently for a few seconds and remove the green protective cap. Hold the bottle firmly with your index and middle finger on either side of the spray tip and your thumb underneath the bottle (See Figure C). Figure C 4. Insert the spray tip into your nostril (the tip should not reach far into your nose). Close the other nostril with a finger and lean your head slightly forward so the spray will aim toward the back of your nose (See Figure D). Figure D 5. For each spray, activate the pump by quickly and firmly pressing down on the white collar while holding the base of the bottle with your thumb. Breathe gently inward through the nostril. 6. After spraying into your nostril, lean your head backward for a few seconds (See Figure E). Figure E 7. If a second spray is needed in the same nostril, repeat steps 3 through 6. 8. Repeat steps 3 through 7 for your other nostril. 9. Avoid blowing your nose for 15 minutes after you use RHINOCORT AQUA (budesonide) Nasal Spray. 10. Wipe the spray tip with a clean tissue (See Figure F), and replace the green protective cap. Store the bottle in an upright position. Figure F How to clean your RHINOCORT AQUA (budesonide) Nasal Spray Figure G Rinse the green protective cap and the spray tip regularly. To do this: Remove the green protective cap and lift off the spray tip (See Figure G). Wash only the green protective cap and the spray tip in warm water and rinse them in cold tap water. 3. Allow the green protective cap and the spray tip to air-dry completely before reassembling the nasal spray. If the spray tip becomes blocked, it can be cleared by repeating Steps 1 through 3. Do not unblock the nasal applicator with a pin or other sharp object. For additional information about RHINOCORT AQUA (budesonide) ® Nasal Spray, please call the AstraZeneca Information Center, Monday through Friday, 8 am - 6 pm ET, excluding holidays at 1-800-236-9933.

PATIENT INFORMATION Patient's Instructions For Use Please read this leaflet carefully before you start to take your medicine. It provides a summary of information on your medicine. Following these instructions helps to ensure that you are inhaling the medication correctly. FOR FURTHER INFORMATION ASK YOUR DOCTOR OR PHARMACIST. WHAT YOU SHOULD KNOW ABOUT PULMICORT TURBUHALER (budesonide) Your doctor has prescribed PULMICORT TURBUHALER 200 mcg. It contains a medication called budesonide, which is a synthetic corticosteroid. Corticosteroids are natural substances found in the body that help fight inflammation. They are used to treat asthma because they reduce the swelling and irritation in the walls of the small air passages in the lungs and ease breathing problems. When inhaled regularly, corticosteroids also help to prevent attacks of asthma. PULMICORT TURBUHALER (budesonide) treats the inflammation—the “quiet part” of asthma that you cannot hear, see, or feel. When inflammation is left untreated, your asthma symptoms and attacks can increase. PULMICORT TURBUHALER (budesonide) works to prevent and reduce your asthma symptoms and attacks. IMPORTANT POINTS TO REMEMBER ABOUT PULMICORT TURBUHALER (budesonide) MAKE SURE that this medicine is suitable for you (see “BEFORE USING YOUR PULMICORT TURBUHALER (budesonide) ”). It is important that you inhale each dose as your doctor has advised. Use your Turbuhaler as directed by your doctor. DO NOT STOP TREATMENT OR REDUCE YOUR DOSE EVEN IF YOU FEEL BETTER, unless told to do so by your doctor. DO NOT inhale more doses or use your Turbuhaler more often than instructed by your doctor. This medicine is NOT intended to provide rapid relief of your breathing difficulties during an asthma attack. It must be taken at regular intervals as recommended by your doctor, and not as an emergency measure. Your doctor may prescribe additional medication (such as bronchodilators) for emergency relief if an acute an asthma attack does not respond to the additional medication, you require more of the additional medication than usual. If you also use another medicine by inhalation, you should consult your doctor for instructions on when to use it in relation to using your PULMICORT TURBUHALER (budesonide) . BEFORE USING YOUR PULMICORT TURBUHALER (budesonide) TELL YOUR DOCTOR BEFORE STARTING TO TAKE THIS MEDICINE IF YOU: are pregnant (or intending to become pregnant), are breast-feeding a baby, are allergic to budesonide or any other orally inhaled corticosteroid, have any infections, have or had tuberculosis, have osteoporosis, have recently been around anyone with chicken pox or measles, are planning to have surgery, have been taking an oral corticosteroid medicine like prednisone. You may have to follow specific instructions to avoid health risks associated with stopping the use of these types of medicines. In some circumstances, this medicine may not be suitable and your doctor may wish to prescribe a different medicine. Make sure that your doctor knows what other medicines you are taking including prescription and non-prescription medicines, as well as any vitamins or dietary and herbal supplements. WHAT ARE THE POSSIBLE SIDE EFFECTS OF PULMICORT TURBUHALER (budesonide) ? As with all inhaled corticosteroids, you should be aware of the following side effects: Increased wheezing right after taking PULMICORT TURBUHALER (budesonide) . Always have a short-acting bronchodilator medicine with you to treat sudden wheezing. Short-acting bronchodilator medicines help to relax the muscles around the airways in your lungs. Wheezing happens when the muscles around the airways tighten. This makes it hard to breathe. In severe cases, wheezing can stop your breathing and cause death if not treated right away. Immune system effects and a higher chance of infections. Eye problems including glaucoma and cataracts. Eye examinations should be considered while using PULMICORT TURBUHALER (budesonide) . A child's growth should be checked regularly while taking PULMICOR TURBUHALER because of the potential for slowed growth. Based on clinical trials, the most common side effects reported by patients using PULMICORT TURBUHALER (budesonide) are: respiratory infection headache flu symptoms sore throat sinusitis These are not all of the possible side effects of PULMICORT TURBUHALER (budesonide) . For more information, ask your doctor, healthcare professional, or pharmacist. USING YOUR PULMICORT TURBUHALER (budesonide) Follow the instructions shown in the section “HOW TO USE YOUR PULMICORT TURBUHALER”. If you have any problems, tell your doctor or pharmacist. It is important that you inhale each dose as directed by your doctor. The pharmacy label will usually tell you what dose to take and how often. If it doesn't, or you are not sure, ask your doctor or pharmacist. DOSAGE Use as directed by your doctor. It is VERY IMPORTANT that you follow your doctor's instructions as to how many inhalations to take and how often to use your PULMICORT TURBUHALER (budesonide) . DO NOT inhale more doses or use your PULMICORT TURBUHALER (budesonide) more often than your doctor advises. It may take 1 to 2 weeks or longer before you feel maximum improvement, so IT IS VERY IMPORTANT THAT YOU USE PULMICORT TURBUHALER (budesonide) REGULARLY. DO NOT STOP TREATMENT OR REDUCE YOUR DOSE EVEN IF YOU ARE FEELING BETTER, unless told to do so by your doctor. If you miss a dose, just take your regularly scheduled next dose when it is due. DO NOT DOUBLE the dose. HOW TO USE YOUR PULMICORT TURBUHALER (budesonide) Read the complete instructions carefully and use only as directed. PRIMING INSTRUCTIONS: Before you use a new PULMICORT TURBUHALER (budesonide) for the first time, you should prime it. To do this, turn the cover and lift off. Hold PULMICORT TURBUHALER (budesonide) upright (with mouthpiece up), then twist the brown grip fully to the right and back again to the left. Repeat. Now you are ready to take your first dose (see instructions for “TAKING A DOSE”). You do not have to prime it any other time after this, even if you put it aside for a prolonged period of time. TAKING A DOSE: LOADING A DOSE Twist the cover and lift off. In order to provide the correct dose, PULMICORT TURBUHALER (budesonide) must be held in the upright position (mouthpiece up) whenever a dose of medication is being loaded. Twist the brown grip fully to the right as far as it will go. Twist it back again fully to the left. You will hear a click. INHALING THE DOSE When you are inhaling, PULMICORT TURBUHALER (budesonide) must be held in the upright (mouthpiece up) or horizontal position. Turn your head away from the inhaler and breathe out. Do not shake the inhaler after loading it. Place the mouthpiece between your lips and inhale deeply and forcefully. You may not taste or feel the medication. Do not chew or bite on the mouthpiece. Remove the inhaler from your mouth and exhale. Do not blow or exhale into the mouthpiece. If more than one dose is required, just repeat the steps above. When you are finished, place the cover back on the inhaler and twist shut. Rinse your mouth with water. Do not swallow. Keep your PULMICORT TURBUHALER (budesonide) clean and dry at all times. Do not use PULMICORT TURBUHALER (budesonide) if it has been damaged or if the mouthpiece has become detached. STORING YOUR PULMICORT TURBUHALER (budesonide) After each use, place the white cover back on and twist it firmly into place. Keep PULMICORT TURBUHALER (budesonide) in a dry place at controlled room temperature, 68-77°F (20-25°C). Keep your PULMICORT TURBUHALER (budesonide) in a secure place out of the reach of young children. DO NOT use after the date shown on the body of your Turbuhaler. HOW TO KNOW WHEN YOUR PULMICORT TURBUHALER (budesonide) IS EMPTY The label on the box or cover will tell you how many doses are in your PULMICORT TURBUHALER. Your PULMICORT TURBUHALER (budesonide) has a convenient dose indicator window just below the mouthpiece. When a red mark appears at the top of the window, there are 20 doses of medicine remaining. Now is the time to get your next PULMICORT TURBUHALER (budesonide) . When the red mark reaches the bottom of the window, your inhaler should be discarded as it may no longer deliver the correct amount of medication. (You may still hear a sound if you shake it—this sound is not the medicine. This sound is produced by the drying agent inside the Turbuhaler.) Remember, you will get a new inhaler each time you refill your prescription. Do not immerse it in water to find out if it is empty. Simply check your dose indicator window. FURTHER INFORMATION ABOUT PULMICORT TURBUHALER (budesonide) PULMICORT TURBUHALER (budesonide) delivers your medicine as a very fine powder. Because of this, you may not taste, smell, or feel any medication entering your lungs when inhaling from PULMICORT TURBUHALER (budesonide) This does not mean that you are not getting your medication. PULMICORT TURBUHALER (budesonide) should not be used with a spacer. PULMICORT TURBUHALER contains only budesonide and does not contain any inactive ingredients. PULMICORT TURBUHALER (budesonide) is specially designed to deliver only one dose at a time, no matter how often you click the brown grip. If you accidentally blow into your inhaler after loading a dose, simply follow the instructions for loading a new dose. This leaflet does not contain the complete information about your medicine. If you have any questions, or are not sure about something, then you should ask your doctor or pharmacist. You may want to read this leaflet again. Please DO NOT THROW IT AWAY until you have finished your medicine. REMEMBER: This medicine has been prescribed for you by your doctor. DO NOT give this medicine to anyone else. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR DOCTOR. If you have further questions about the use of PULMICORT TURBUHALER (budesonide) , call: 1-800-236-9933.

PATIENT INFORMATION ENTOCORT® EC (EN-toe-cort EE CEE) (budesonide) Capsules Read this Patient Information before you start taking ENTOCORT EC 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 is ENTOCORT EC? ENTOCORT EC is a prescription corticosteroid medicine used to treat mild to moderate Crohn’s disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon): in people 8 years of age and older with active Crohn’s disease in adults to help keep symptoms from coming back for up to 3 months It is not known if ENTOCORT EC is safe and effective in children under 8 years of age, or in children 8 to 17 years of age who weigh 55 pounds (25 kg) or less, for the treatment of mild to moderate active Crohn’s disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon). It is not known if ENTOCORT EC is safe and effective in children to help keep symptoms of mild to moderate Crohn’s disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon) from coming back. Who should not take ENTOCORT EC? Do not take ENTOCORT EC if: you are allergic to budesonide or any of the ingredients in ENTOCORT EC. See the end of this leaflet for a complete list of ingredients in ENTOCORT EC. What should I tell my healthcare provider before taking ENTOCORT EC? Before you take ENTOCORT EC 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. ENTOCORT EC may harm your unborn baby. Talk to your healthcare provider about the possible risk to your unborn baby if you take ENTOCORT EC when you are pregnant. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during your treatment with ENTOCORT EC. are breastfeeding or plan to breastfeed. It is not known if ENTOCORT EC 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 ENTOCORT EC. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ENTOCORT EC and other medicines may affect each other causing side effects. How should I take ENTOCORT EC? Take ENTOCORT EC exactly as your healthcare provider tells you. Your healthcare provider will tell you how many ENTOCORT EC capsules to take. Your healthcare provider may change your dose if needed. Take ENTOCORT EC 1 time each day in the morning. Take ENTOCORT EC capsules whole. Do not chew or crush ENTOCORT EC capsules before swallowing. If you take too much ENTOCORT EC call your healthcare provider right away or go to the nearest hospital emergency room. What should I avoid while taking ENTOCORT EC? Do not drink grapefruit juice during your treatment with ENTOCORT EC. Drinking grapefruit juice can increase the level of ENTOCORT EC in your blood. What are the possible side effects of ENTOCORT EC? ENTOCORT EC may cause serious side effects, including: Effects of having too much corticosteroid medicine in your blood (hypercorticism). Longtime use of ENTOCORT EC 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: acne bruise easily rounding of your face (moon face) ankle swelling thicker or more hair on your body and face a fatty pad or hump between your shoulders (buffalo hump) pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms Adrenal suppression. When ENTOCORT EC is 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 ENTOCORT EC. Worsening of allergies. If you take certain other corticosteroid medicines to treat allergies, switching to ENTOCORT EC 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 ENTOCORT EC. Increased risk of infection. ENTOCORT EC weakens 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 ENTOCORT EC. 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 ENTOCORT EC, including: fever chills pain feeling tired aches nausea and vomiting The most common side effects of ENTOCORT EC in adults include: headache stomach area (abdominal) pain infection in your air passages (respiratory infection) gas nausea vomiting back pain tiredness indigestion pain dizziness The most common side effects of ENTOCORT EC in children 8 to 17 years of age, who weigh more than 55 pounds (25 kg), are similar to the most common side effects in adults. 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 ENTOCORT EC. 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 Perrigo at 1-866-634-9120. How should I store ENTOCORT EC? Store ENTOCORT EC at room temperature between 68°F to 77°F (20°C to 25°C). Keep ENTOCORT EC in a tightly closed container. Keep ENTOCORT EC and all medicines out of the reach of children. General information about the safe and effective use of ENTOCORT EC Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ENTOCORT EC for a condition for which it was not prescribed. Do not give ENTOCORT EC 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 ENTOCORT EC that is written for health professionals. What are the ingredients in ENTOCORT EC? Active ingredient: budesonide Inactive ingredients: ethylcellulose, acetyltributyl citrate, methacrylic acid copolymer type C, triethyl citrate, antifoam M, polysorbate 80, talc, and sugar spheres. The capsule shell contains: gelatin, iron oxide, and titanium dioxide. This Patient Information has been approved by the U.S. Food and Drug Administration.

OVERDOSE Acute overdosage with this dosage form is unlikely since one 120 spray bottle of RHINOCORT AQUA (budesonide) Nasal Spray 32 mcg only contains approximately 5.4 mg of budesonide. Chronic overdosage may result in signs/symptoms of hypercorticism [see WARNINGS AND PRECAUTIONS]. CONTRAINDICATIONS RHINOCORT AQUA (budesonide) Nasal Spray is contraindicated in patients with hypersensitivity to any of its ingredients [see WARNINGS AND PRECAUTIONS].

OVERDOSE The potential for acute toxic effects following overdose of PULMICORT TURBUHALER (budesonide) is low. If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur (see PRECAUTIONS). PULMICORT TURBUHALER at twice the highest recommended dose (3200 mcg daily) administered for 6 weeks caused a significant reduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%). The corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma cortisol response to ACTH. The minimal inhalation lethal dose in mice was 100 mg/kg (approximately 320 times the maximum recommended daily inhalation dose in adults and approximately 380 times the maximum recommended daily inhalation dose in children on a mcg/m2 basis). There were no deaths following the administration of an inhalation dose of 68 mg/kg in rats (approximately 430 times the maximum recommended daily inhalation dose in adults and approximately 510 times the maximum recommended daily inhalation dose in children on a mcg/m2 basis). The minimal oral lethal dose was 200 mg/kg in mice (approximately 630 times the maximum recommended daily inhalation dose in adults and approximately 750 times the maximum recommended daily inhalation dose in children on a mcg/m2 basis) and less than 100 mg/kg in rats (approximately 630 times the maximum recommended daily inhalation dose in adults and approximately 750 times the maximum recommended daily inhalation dose in children based on a mcg/m2 basis). Post-marketing experience showed that patients experiencing acute overdose of inhaled budesonide commonly remained asymptomatic. The use of excessive doses (up to 6400 mcg daily) for prolonged periods showed systemic corticosteroid effects such as hypercorticism. CONTRAINDICATIONS PULMICORT TURBUHALER (budesonide) is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. Hypersensitivity to budesonide contraindicates the use of PULMICORT TURBUHALER (budesonide) .

OVERDOSE 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. CONTRAINDICATIONS ENTOCORT EC is contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of ENTOCORT EC. Serious hypersensitivity reactions, including anaphylaxis have occurred [see ADVERSE REACTIONS].

SIDE EFFECTS Systemic and intranasal corticosteroids use may result in the following: Epistaxis, Candida albicans infection, nasal septum perforation, and impaired wound healing [see WARNINGS AND PRECAUTIONS]. Hypersensitivity Including Anaphylaxis [see WARNINGS AND PRECAUTIONS]. Immunosuppression [see WARNINGS AND PRECAUTIONS]. Hypercorticism and Adrenal Suppression [see WARNINGS AND PRECAUTIONS]. Growth Effect [see WARNINGS AND PRECAUTIONS and Use in Specific Populations]. Glaucoma and Cataracts [see WARNINGS AND PRECAUTIONS]. 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. The incidence of common adverse reactions in Table 1 is based upon two U.S. and five non-U.S. controlled clinical trials in 1,526 patients with seasonal or perennial rhinitis in adults and children ≥ 6 years treated with RHINOCORT AQUA (budesonide) Nasal Spray at doses up to 400 mcg once daily for 3-6 weeks. This population included 745 females and 781 males with a mean age of 31 years (range of 6-85 years, 349 were 6 < 18 years). The racial distribution of patients receiving RHINOCORT AQUA (budesonide) Nasal Spray was 93% white, 3% black and 4% other. Table 1 describes adverse reactions occurring at an incidence of 2% or greater and more commonly among RHINOCORT AQUA (budesonide) Nasal Spray-treated patients than in placebo-treated patients in controlled clinical trials. Table 1. Adverse Reactions occurring at an incidence ≥ 2% and more commonly than placebo in the RHINOCORT AQUA (budesonide) Nasal Spray group in patients 6 years and older Adverse Event RHINOCORT AQUA Nasal Spray Placebo Vehicle Epistaxis 8% 5% Pharyngitis 4% 3% Bronchospasm 2% 1% Coughing 2% < 1% Nasal Irritation 2% < 1% A similar adverse reaction profile was observed in the subgroup of pediatric patients 6 to 12 years of age. These patients are included in Table 1. Two to three percent (2-3%) of patients in clinical trials discontinued because of adverse reactions. Systemic corticosteroid side effects were not reported during controlled clinical studies with RHINOCORT AQUA (budesonide) Nasal Spray. If recommended doses are exceeded, or if individuals are particularly sensitive, symptoms of hypercorticism, ie, Gushing's Syndrome, and adrenal suppression could occur. Post-marketing Experience The following adverse reactions have been reported during post-approval use of RHINOCORT AQUA (budesonide) Nasal Spray. 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: immediate and delayed hypersensitivity reactions (including anaphylactic reaction, urticaria, rash, dermatitis, angioedema and pruritus), [see WARNINGS AND PRECAUTIONS and CONTRAINDICATIONS] Eye disorders: glaucoma, increased intraocular pressure, cataracts [see WARNINGS AND PRECAUTIONS] Respiratory, thoracic, and mediastinal disorders: nasal septum perforation, anosmia, pharynx disorders (throat irritation, throat pain, swollen throat, burning throat, and itchy throat), and wheezing Cardiac disorders: palpitations Musculoskeletal and connective tissue disorders: growth suppression [see WARNINGS AND PRECAUTIONS and Use In Specific Populations] DRUG INTERACTIONS Inhibitors of Cytochrome P450 3A4 The main route of metabolism of corticosteroids, including budesonide, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the co-administration of RHINOCORT AQUA (budesonide) Nasal Spray with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir clarithromycin, indinavir itraconazole, nefazodone nelfinavir-saquinavir, telithromycin) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

SIDE EFFECTS The following adverse reactions were reported in patients treated with PULMICORT TURBUHALER (budesonide) . The incidence of common adverse events is based upon double-blind, placebo-controlled US clinical trials in which 1116 adult and pediatric patients age 6-70 years (472 females and 644 males) were treated with PULMICORT TURBUHALER (budesonide) (200 to 800 mcg twice daily for 12 to 20 weeks) or placebo. The following table shows the incidence of adverse events in patients previously receiving bronchodilators and/or inhaled corticosteroids in US controlled clinical trials. This population included 232 male and 62 female pediatric patients (age 6 to 17 years) and 332 male and 331 female adult patients (age 18 years and greater). Adverse Events with ≥ 3% Incidence reported by Patients on PULMICORT TURBUHALER (budesonide) PULMICORT TURBUHALER Adverse Event Placebo N=284 % 200 mcg twice daily N=286 % 400 mcg twice daily N=289 % 800 mcg twice daily N=98 % Respiratory System Respiratory infection 17 20 24 19 Pharyngitis 9 10 9 5 Sinusitis 7 11 7 2 Voice alteration 0 1 2 6 Body As A Whole Headache 7 14 13 14  Flu syndrome 6 6 6 14 Pain 2 5 5 5 Back pain 1 2 3 6 Fever 2 2 4 0 Digestive System Oral candidiasis 2 2 4 4 Dyspepsia 2 1 2 4 Gastroenteritis 1 1 2 3 Nausea 2 2 1 3 Average Duration of Exposure (days) 59 79 80 80 The table above includes all events (whether considered drug-related or non-drug-related by the investigators) that occurred at a rate of ≥3% in any one PULMICORT TURBUHALER (budesonide) group and were more common than in the placebo group. In considering these data, the increased average duration of exposure for PULMICORT TURBUHALER (budesonide) patients should be taken into account. The following other adverse events occurred in these clinical trials using PULMICORT TURBUHALER (budesonide) with an incidence of 1 to 3% and were more common on PULMICORT TURBUHALER (budesonide) than on placebo. Body As A Whole:neck pain Cardiovascular: syncope Digestive: abdominal pain, dry mouth, vomiting Metabolic and Nutritional: weight gain Musculoskeletal: fracture, myalgia Nervous: hypertonia, migraine Platelet, Bleeding and Clotting: ecchymosis Psychiatric: insomnia Resistance Mechanisms: infection Special Senses: taste perversion In a 20-week trial in adult asthmatics who previously required oral corticosteroids, the effects of PULMICORT TURBUHALER (budesonide) 400 mcg twice daily (N=53) and 800 mcg twice daily (N=53) were compared with placebo (N=53) on the frequency of reported adverse events. Adverse events, whether considered drug-related or non-drug-related by the investigators, reported in more than five patients in the PULMICORT TURBUHALER (budesonide) group and which occurred more frequently with PULMICORT TURBUHALER (budesonide) than placebo are shown below (% PULMICORT TURBUHALER (budesonide) and % placebo). In considering these data, the increased average duration of exposure for PULMICORT TURBUHALER (budesonide) patients (78 days for PULMICORT TURBUHALER (budesonide) vs. 41 days for placebo) should be taken into account. Body As A Whole: asthenia (9% and 2%) headache (12% and 2%) pain (10% and 2%) Digestive: dyspepsia (8% and 0%)nausea (6% and 0%)oral candidiasis (10% and 0%) Musculoskeletal: arthralgia (6% and 0%) Respiratory: cough increased (6% and 2%) respiratory infection (32% and 13%) rhinitis (6% and 2%) sinusitis (16% and 11%) Patients Receiving PULMICORT TURBUHALER (budesonide) Once Daily The adverse event profile of once-daily administration of PULMICORT TURBUHALER (budesonide) 200 mcg and 400 mcg, and placebo, was evaluated in 309 adult asthmatic patients in an 18-week study. The study population included both patients previously treated with inhaled corticosteroids, and patients not previously receiving corticosteroid therapy. There was no clinically relevant difference in the pattern of adverse events following once-daily administration of PULMICORT TURBUHALER (budesonide) when compared with twice-daily dosing. Pediatric Studies: In a 12-week placebo-controlled trial in 404 pediatric patients 6 to 18 years of age previously maintained on inhaled corticosteroids, the frequency of adverse events for each age category (6 to 12 years, 13 to 18 years) was comparable for PULMICORT TURBUHALER (budesonide) (at 100, 200 and 400 mcg twice daily) and placebo. There were no clinically relevant differences in the pattern or severity of adverse events in children compared with those reported in adults. Adverse Event Reports From Other Sources: Rare adverse events reported in the published literature or from worldwide marketing experience with any formulation of inhaled budesonide include: immediate and delayed hypersensitivity reactions including rash, contact dermatitis, urticaria, angioedema and bronchospasm; symptoms of hypocorticism and hypercorticism; glaucoma, cataracts; psychiatric symptoms including depression, aggressive reactions, irritability, anxiety and psychosis. DRUG INTERACTIONS In clinical studies, concurrent administration of budesonide and other drugs commonly used in the treatment of asthma has not resulted in an increased frequency of adverse events. The main route of metabolism of budesonide, as well as other corticosteroids, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a potent inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of other known inhibitors of CYP3A4 (eg, itraconazole, clarithromycin, erythromycin, etc.) may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Care should be exercised when budesonide is coadministered with long-term ketoconazole and other known CYP3A4 inhibitors.

SIDE EFFECTS The following clinically significant adverse reactions are described elsewhere in labeling: Hypercorticism and adrenal axis suppression [see WARNINGS AND PRECAUTIONS] Symptoms of steroid withdrawal in those patients transferred from other systemic corticosteroids [see WARNINGS AND PRECAUTIONS] Increased risk of infection [see WARNINGS AND PRECAUTIONS] Other corticosteroid effects [see WARNINGS AND PRECAUTIONS] 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 ENTOCORT EC in 520 patients with Crohn’s disease, including 520 exposed to 9 mg per day (total daily dose) for 8 weeks and 145 exposed to 6 mg per day for one year in placebo controlled clinical trials. Of the 520 patients, 38% were males and the age range was 17 to 74 years. Treatment of Mild to Moderate Active Crohn’s Disease The safety of ENTOCORT EC was evaluated in 651 adult patients in five clinical trials of 8 weeks duration in patients with active mild to moderate Crohn’s disease. The most common adverse reactions, occurring in greater than or equal to 5% of the patients, are listed in Table 1. Table 1 Common Adverse Reactions1 in 8-Week Treatment Clinical Trials Adverse Reaction ENTOCORT EC 9 mg n=520 Number (%) Placebo n=107 Number (%) Prednisolone2 40 mg n=145 Number (%) Comparator3 n=88 Number (%) Headache 107 (21) 19 (18) 31 (21) 11 (13) Respiratory Infection 55 (11) 7 (7) 20 (14) 5 (6) Nausea 57 (11) 10 (9) 18 (12) 7 (8) Back Pain 36 (7) 10 (9) 17 (12) 5 (6) Dyspepsia 31 (6) 4 (4) 17 (12) 3 (3) Dizziness 38 (7) 5 (5) 18 (12) 5 (6) Abdominal Pain 32 (6) 18 (17) 6 (4) 10 (11) Flatulence 30 (6) 6 (6) 12 (8) 5 (6) Vomiting 29 (6) 6 (6) 6 (4) 6 (7) Fatigue 25 (5) 8 (7) 11 (8) 0 (0) Pain 24 (5) 8 (7) 17 (12) 2 (2) 1. Occurring in greater than or equal to 5% of the patients in any treated group. 2. 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. 3. This drug is not approved for the treatment of Crohn’s disease in the United States. 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 ENTOCORT EC 9 mg n=427 Number (%) Placebo n=107 Number (%) Prednisolone1 40 mg n=145 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) 2 Swollen Ankles 32 (7) 6 (6) 13 (9) Hirsutism3 22 (5) 2 (2) 5 (3) Buffalo Hump 6 (1) 2 (2) 5 (3) Skin Striae 4 (1) 2 (2) 0 (0) 1. 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. 2. Statistically significantly different from ENTOCORT EC 9 mg 3. including hair growth increased, local and hair growth increased, general Maintenance of Clinical Remission of Mild to Moderate Crohn’s Disease The safety of ENTOCORT EC was evaluated in 233 adult patients in four long-term clinical trials (52 weeks) of maintenance of clinical remission in patients with mild to moderate Crohn’s disease. A total of 145 patients were treated with ENTOCORT EC 6 mg once daily. The adverse reaction profile of ENTOCORT EC 6 mg once daily in maintenance of Crohn’s disease was similar to that of short-term treatment with ENTOCORT EC 9 mg once daily in active Crohn’s disease. In the long-term clinical trials, the following adverse reactions occurred in greater than or equal to 5% and are not listed in Table 1: diarrhea (10%); sinusitis (8%); infection viral (6%); and arthralgia (5%). Signs/symptoms of hypercorticism reported by active questioning of patients in the long-term maintenance clinical trials are displayed in Table 3. Table 3: Summary and Incidence of Signs/Symptoms of Hypercorticism in Long-Term Clinical Trials Signs/Symptom ENTOCORT EC 3 mg n=88 Number (%) ENTOCORT EC 6 mg n=145 Number (%) Placebo n=143 Number (%) Bruising Easily 4(5) 15(10) 5(4) Acne 4(5) 14(10) 3(2) Moon Face 3(3) 6(4) 0 Hirsutism 2(2) 5(3) 1(1) Swollen Ankles 2(2) 3(2) 3(2) Buffalo Hump 1(1) 1(1) 0 Skin Striae 6 (1) 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 ENTOCORT EC 9 mg (total daily dose) in short-term treatment clinical studies and/or ENTOCORT EC 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 ENTOCORT EC (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 ENTOCORT EC than with prednisolone in steroid-naïve patients, whereas no difference could be detected between treatment groups for steroid-dependent patients and previous steroid users. The incidence of symptoms associated with hypercorticism was significantly higher with prednisolone treatment. Clinical Laboratory Test Findings The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to ENTOCORT EC, were reported in greater than or equal to 1% of patients: hypokalemia, leukocytosis, anemia, hematuria, pyuria, erythrocyte sedimentation rate increased, alkaline phosphatase increased, atypical neutrophils, c-reactive protein increased and adrenal insufficiency. Pediatrics --Treatment Of Mild To Moderate Active Crohn’s Disease Adverse reactions reported in pediatric patients 8 to 17 years of age, who weigh more than 25 kg, were similar to those reactions described above in adult patients. Postmarketing Experience The following adverse reactions have been reported during post-approval use of ENTOCORT EC. 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 DRUG INTERACTIONS 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]. 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].

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Local Nasal Effects Epistaxis In clinical studies of 3 to 52 weeks' duration epistaxis was observed more frequently in patients treated with RHINOCORT AQUA (budesonide) Nasal Spray than those who received placebo [see ADVERSE REACTIONS]. Candida Infection In clinical studies with budesonide administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred. When such an infection develops, it may require treatment with appropriate local or systemic therapy and discontinuation of treatment with RHINOCORT AQUA (budesonide) Nasal Spray. Patients using RHINOCORT AQUA (budesonide) Nasal Spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa. Nasal Septal Perforation Instances of nasal septum perforation have been reported following the intranasal application of corticosteroids, including budesonide [see ADVERSE REACTIONS]. Impaired Wound Healing Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until healing has occurred. Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including anaphylactic reaction, urticaria, rash, dermatitis, angioedema and pruritus may occur [see CONTRAINDICATIONS and ADVERSE REACTIONS, Post-marketing Experience]. Immunosuppression Patients who are on drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, 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 to chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (WIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents may be considered. The clinical course of chicken pox or measles infection in patients on intranasal or inhaled corticosteroids has not been studied. While there is no data with intranasal corticosteroids, a clinical study has examined the immune responsiveness to the varicella vaccine in asthma patients 12 months to 8 years of age who were treated with budesonide inhalation suspension. An open-label, nonrandomized clinical study examined the immune responsiveness to varicella vaccine in 243 asthma patients 12 months to 8 years of age who were treated with budesonide inhalation suspension 0.25 mg to 1 mg daily (n=151) or non-corticosteroid asthma therapy (n=92) (i.e., betai-agonists, leukotriene receptor antagonists, or cromones). The percentage of patients developing a seroprotective antibody titer ≥ 5.0 (gpELISA value) in response to the vaccination was similar in patients treated with budesonide inhalation suspension (85%) compared to patients treated with non-corticosteroids asthma therapy (90%). No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination. 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. Hypothalamic-Pituitary-Adrenal Axis Effects Hypercorticism and Adrenal Suppression: When intranasal steroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of RHINOCORT AQUA (budesonide) Nasal Spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy. The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency, and in addition some patients may experience symptoms of corticosteroid withdrawal, e.g., joint and/or muscular pain, fatigue, weakness, nausea, vomiting, hypotension, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids should be weaned off slowly when transferred to topical corticosteroids and carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their symptoms. Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the co-administration of RHINOCORT AQUA Nasal Spray with ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY]. Effect on Growth Intranasal corticosteroids, including budesonide may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely of pediatric patients receiving long-term treatment with RHINOCORT AQUA (budesonide) Nasal Spray. To minimize the systemic effects of intranasal corticosteroids, including RHINOCORT AQUA (budesonide) Nasal Spray, titrate each patient's dosage to the lowest one that effectively controls his/her symptoms [see Use In Specific Populations, Pediatric Use]. Glaucoma and Cataracts Glaucoma, increased intraocular pressure and cataracts have been reported following the intranasal application of corticosteroids, including budesonide. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts [see ADVERSE REACTIONS]. Patient Counseling Information [See FDA-Approved Patient Labeling] Patients being treated with RHINOCORT AQUA (budesonide) Nasal Spray should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of the medication. It is not a disclosure of all possible adverse or intended effects. For proper use of RHINOCORT AQUA (budesonide) Nasal Spray and to attain maximum improvement, the patient should read and follow the accompanying FDA Approved Patient Labeling. Local Nasal Effects Patients should be advised that epistaxis and localized infections with Candida albicans occurred in the nose and pharynx in some patients. If candidiasis develops, it should be treated with appropriate local or systemic therapy and discontinue treatment with RHINOCORT AQUA (budesonide) Nasal spray. In addition, nasal corticosteroids are associated with nasal septal perforation and impaired wound healing. Patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use RHINOCORT AQUA (budesonide) Nasal Spray until healing has occurred [see WARNINGS AND PRECAUTIONS]. Hypersensitivity including Anaphylaxis Patients should be advised that hypersensitivity reactions including anaphylactic reaction, urticaria, rash, dermatitis, angioedema and pruritus have been reported with use of RHINOCORT AQUA (budesonide) Nasal Spray. Discontinue RHINOCORT AQUA (budesonide) Nasal Spray if such reactions occur [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Immunosuppression Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infection, or ocular herpes simplex [see WARNINGS AND PRECAUTIONS]. Reduced Growth Velocity Patients should be advised that intranasal corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route [see WARNINGS AND PRECAUTIONS]. Glaucoma and Cataracts Patients should be advised that long-term use of intranasal corticosteroids, including budesonide, may increase the risk of some eye problems (cataracts and glaucoma). Patients should inform his/her healthcare provider if a change in vision is noted while using RHINOCORT AQUA (budesonide) Nasal Spray [see WARNINGS AND PRECAUTIONS]. Use Daily Patients should use RHINOCORT AQUA (budesonide) Nasal Spray at regular intervals since its effectiveness depends on its regular use. Patients may note an improvement in nasal symptoms within 10 hours of first using RHINOCORT AQUA (budesonide) Nasal Spray. Maximum benefit may not be achieved until approximately 2 week after initiation of treatment [see DOSAGE AND ADMINISTRATION]. Patients should take the medication as directed and should not exceed the prescribed dosage. The patient should contact the physician if symptoms do not improve after two weeks, or if the condition worsens. Patients who experience recurrent episodes of epistaxis (nosebleeds) or nasal septum discomfort while taking this medication should contact their physician. For proper use of RHINOCORT AQUA (budesonide) Nasal Spray and to attain maximum improvement, the patient should read and follow the accompanying patient information carefully. Do not use RHINOCORT AQUA (budesonide) Nasal Spray after the labeled number of sprays have been used (does not include priming) or after the expiration date shown on the carton or bottle label. How to use RHINOCORT AQUA (budesonide) Nasal Spray Patients should be carefully instructed on the use of this drug product to assure optimal dose delivery [see PATIENT INFORMATION]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility In a 104-week oral study in Sprague-Dawley rats, a statistically significant increase in the incidence of gliomas was observed in the male rats receiving an oral dose of budesonide 50 mcg/kg/day (approximately twice the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg (approximately equal to the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis, and in female rats at oral doses up to 50 mcg/kg approximately two times the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis). In two additional two-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately twice the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately twice the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) in these two studies showed similar findings. There was no evidence of a carcinogenic effect when budesonide was administered orally for 91-weeks to mice at doses up to 200 mcg/kg/day (approximately 3 times the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis). Budesonide was not mutagenic or clastogenic in six different test systems: Ames Salmonella/microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster, and DNA repair analysis in rat hepatocyte culture. In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 3 times the maximum recommended daily intranasal dose in adults on mcg/m2 basis). At a subcutaneous dose of 20 mcg/kg/day (less than the maximum recommended daily intranasal dose in adults on a mcg/m2 basis), decreases in maternal body weight gain, prenatal viability, and viability of the young at birth and during lactation were observed. No such effects were noted at 5 mcg/kg (less than the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). Use In Specific Populations Pregnancy Teratogenic Effects: Pregnancy Category B. The impact of budesonide on human pregnancy outcomes has been evaluated through assessments of birth registries linked with maternal usage of inhaled budesonide (i.e., PULMICORT TURBUHALER) and intranasally administered budesonide (i.e., RHINOCORT AQUA (budesonide) Nasal Spray). The results from population-based prospective cohort epidemiological studies reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995- 2001 (i.e., Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for overall congenital malformations from the use of inhaled or intranasal budesonide during early pregnancy. Congenital malformations were studied in 2,014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period), the period when most major organ malformations occur.1 The rate of overall congenital malformations was similar compared to the general population rate (3.8 % vs. 3.5%, respectively). The number of infants born with orofacial clefts and cardiac defects was similar to the expected number in the general population (4 children vs. 3.3 and 18 children vs. 17-18, respectively). In a follow-on study bringing the total number of infants to 2,534, the rate of overall congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%).2 A third study from the Swedish Medical Birth Registry of 2,968 pregnancies exposed to inhaled budesonide, the majority of which were first trimester exposures, reported gestational age, birth weight, birth length, stillbirths, and multiple births similar for exposed infants compared to nonexposed infants.3 Congenital malformations were studied in 2,113 infants born to mothers reporting the use of intranasal budesonide in early pregnancy. The rate of overall congenital malformations was similar compared to the general population rate (4.5% vs. 3.5%, respectively). The adjusted odds ratio (OR) was 1.06 (95% CI 0.86-1.31). The number of infants born with orofacial clefts was similar to the expected number in the general population (3 children vs. 3, respectively). The number of infants born with cardiac defects exceeded that expected in the general population (28 children vs. 17.8 respectively). The systemic exposure from intranasal budesonide is 6-fold less than from inhaled budesonide and an association of cardiac defects was not seen with higher exposures of budesonide. Despite the animal findings, it would appear that the possibility of fetal harm is remote if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, RHINOCORT AQUA (budesonide) Nasal Spray should be used during pregnancy only if clearly needed. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose in rabbits that was approximately 2 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis and at a subcutaneous dose in rats that was approximately 16 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis. No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation at doses up to approximately 8 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed. Nursing Mothers Budesonide is secreted in human milk. Data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother [see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations, Nursing]. No studies have been conducted in breastfeeding women specifically with RHINOCORT AQUA Nasal Spray; however, the dose of budesonide available to the infant in breast milk, as a percentage of the maternal dose, would be expected to be similar. RHINOCORT AQUA (budesonide) Nasal Spray should be used in nursing women only if clinically appropriate. Prescribers should weigh the known benefits of breastfeeding for the mother and infant against the potential risks of minimal budesonide exposure in the infant. Dosing considerations include prescription or titration to the lowest clinically effective dose and use of RHINOCORT AQUA (budesonide) Nasal Spray immediately after breastfeeding to maximize the time interval between dosing and breastfeeding to minimize infant exposure. Pediatric Use Safety and effectiveness in pediatric patients below 6 years of age have not been established. Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA)-axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for "catch-up" growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including RHINOCORT AQUA (budesonide) Nasal Spray, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks and benefits associated with alternative therapies. To minimize the systemic effects of intranasal corticosteroids, including RHINOCORT AQUA (budesonide) Nasal Spray, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. A one-year placebo-controlled clinical growth study was conducted in 229 pediatric patients (ages 4 through 8 years of age) to assess the effect of RHINOCORT AQUA (budesonide) Nasal Spray (single-daily dose of 64 mcg, the recommended starting dose for children ages 6 years and above) on growth velocity. From a population of 141 patients receiving RHINOCORT AQUA (budesonide) Nasal Spray and 67 receiving placebo, the point estimate for growth velocity with RHINOCORT AQUA (budesonide) Nasal Spray was 0.25 cm/year lower than that noted with placebo (95% confidence interval ranging from 0.59 cm/year lower than placebo to 0.08 cm/year higher than placebo). In a study of asthmatic children 5-12 years of age, those treated with budesonide administered via a dry powder inhaler 200 mcg twice daily (n=311) had a 1.1-centimeter (0.433 inch) reduction in growth compared with those receiving placebo (n=418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment. By the end of four years, children treated with budesonide dry powder inhaler and children treated with placebo had similar growth velocities. Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study. The systemic effects of inhaled corticosteroids are related to the systemic exposure to such drugs. Pharmacokinetic studies have demonstrated that in both adults and children, systemic exposure to budesonide at the highest recommended doses of RHINOCORT AQUA (budesonide) Nasal Spray would be expected to be no greater than exposure at the lowest recommended doses via a dry powder inhaler. Therefore, the systemic effects (HPA axis and growth) of budesonide delivered from RHINOCORT AQUA (budesonide) Nasal Spray would be expected to be no greater than what is reported for inhaled budesonide when administered via the dry powder inhaler. The potential for RHINOCORT AQUA (budesonide) Nasal Spray to cause growth suppression in susceptible patients or when given at doses above 64 mcg daily cannot be ruled out. The recommended dosage range in patients 6 to 11 years of age is 64 to 128 mcg per day [see DOSAGE AND ADMINISTRATION]. Geriatric Use Of the 2,461 patients in clinical studies of RHINOCORT AQUA (budesonide) Nasal Spray, 5% were 60 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, except for an adverse reaction reporting frequency of epistaxis that increased with age. Further, other reported clinical experience has not identified any other differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment Formal pharmacokinetic studies using RHINOCORT AQUA (budesonide) Nasal Spray have not been conducted in patients with hepatic impairment. However, since budesonide is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide in plasma. Therefore, patients with hepatic disease should be closely monitored.

WARNINGS Particular care is needed for patients who are transferred from systemically active corticosteroids to PULMICORT TURBUHALER (budesonide) because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although PULMICORT TURBUHALER (budesonide) may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to PULMICORT TURBUHALER (budesonide) . Lung function (FEV1 or AM PEF), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to PULMICORT TURBUHALER (budesonide) may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, eg, rhinitis, conjunctivitis, arthritis, eosinophilic conditions, and eczema (see DOSAGE AND ADMINISTRATION). 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 pediatric patients or adults on immunosuppressant doses of corticosteroids. In pediatric or adult patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects 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 the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered. PULMICORT TURBUHALER (budesonide) is not a bronchodilator and is not indicated for rapid relief of bronchospasm or other acute episodes of asthma. As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing. If bronchospasm occurs following dosing with PULMICORT TURBUHALER (budesonide) , it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with PULMICORT TURBUHALER (budesonide) should be discontinued and alternate therapy instituted. Patients should be instructed to contact their physician immediately when episodes of asthma not responsive to their usual doses of bronchodilators occur during treatment with PULMICORT TURBUHALER (budesonide) . During such episodes, patients may require therapy with oral corticosteroids. PRECAUTIONS General During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, eg, joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function (see DOSAGE AND ADMINISTRATION). In responsive patients, PULMICORT TURBUHALER (budesonide) may permit control of asthma symptoms with less suppression of HPA-axis function than therapeutically equivalent oral doses of prednisone. Since budesonide is absorbed into the circulation and can be systemically active, the beneficial effects of PULMICORT TURBUHALER (budesonide) in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing PULMICORT TURBUHALER (budesonide) . Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with PULMICORT TURBUHALER (budesonide) should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism, reduced bone mineral density, and adrenal suppression may appear in a small number of patients, particularly at higher doses. If such changes occur, PULMICORT TURBUHALER (budesonide) should be reduced slowly, consistent with accepted procedures for management of asthma symptoms and for tapering of systemic steroids. Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. A reduction in growth velocity may occur as a result of inadequate control of asthma or from use of corticosteroids for treatment. The potential effects of prolonged treatment on growth velocity should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including PULMICORT TURBUHALER (budesonide) , each patient should be titrated to his/her lowest effective dose (see PRECAUTIONS, Pediatric Use). Although patients in clinical trials have received PULMICORT TURBUHALER (budesonide) on a continuous basis for periods of 1 to 2 years, the long-term local and systemic effects of PULMICORT TURBUHALER (budesonide) in human subjects are not completely known. In particular, the effects resulting from chronic use of PULMICORT TURBUHALER (budesonide) on developmental or immunological processes in the mouth, pharynx, trachea, and lung are unknown. In clinical trials with PULMICORT TURBUHALER (budesonide) , localized infections with Candida albicans occurred in the mouth and pharynx in some patients. These infections may require treatment with appropriate antifungal therapy and/or discontinuance of treatment with PULMICORT TURBUHALER (budesonide) . Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral or parasitic infections, or ocular herpes simplex. Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported following the inhaled administration of corticosteroids. Information for Patients Patients being treated with PULMICORT TURBUHALER (budesonide) should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of the medication. It is not a disclosure of all possible adverse or intended effects. For proper use of PULMICORT TURBUHALER (budesonide) and to attain maximum improvement, the patient should read and follow the accompanying Patient's Instructions for Use carefully. Patients should use PULMICORT TURBUHALER (budesonide) at regular intervals as directed since its effectiveness depends on regular use. The patient should not alter the prescribed dosage unless advised to do so by the physician. Patients should be advised that PULMICORT TURBUHALER (budesonide) is not a bronchodilator and is not intended to treat acute or life-threatening episodes of asthma. Patients should be advised that the effectiveness of PULMICORT TURBUHALER (budesonide) depends on proper use of the device and inhalation-administering technique: 1. PULMICORT TURBUHALER (budesonide) must be in the upright position (mouthpiece on top) during loading in order to provide the correct dose. 2. PULMICORT TURBUHALER (budesonide) must be primed when the unit is used for the very first time. To prime the unit, it must be held in an upright position and the brown grip turned fully to the right, then turned fully to the left until it clicks. Repeat. 3. To load the first dose, the grip must be turned fully to the right and fully to the left until it clicks. 4. After the first dose, it is not necessary to prime the unit. However, it must be loaded in the upright position immediately prior to use as described above. 5. Patients should be advised not to shake the inhaler. Patients should place the mouthpiece between the lips and inhale forcefully and deeply. The powder is then delivered to the lungs. Patients should not exhale through PULMICORT TURBUHALER (budesonide) . Due to the small volume of powder, the patient may not taste or sense the presence of any medication entering the lungs when inhaling from the TURBUHALER inhaler. This lack of sensation does not indicate that the patient is not receiving benefit from PULMICORT TURBUHALER (budesonide) . Patients should be advised that rinsing the mouth with water without swallowing after each dosing may decrease the risk of the development of oral candidiasis. Patients should be instructed that they will receive a new PULMICORT TURBUHALER (budesonide) unit each time they refill their prescription. Patients should be advised to discard the whole device after the labelled number of inhalations has been used. When there are 20 doses remaining in PULMICORT TURBUHALER (budesonide) , a red mark will appear in the indicator window. PULMICORT TURBUHALER (budesonide) should not be used with a spacer. The mouthpiece should not be bitten or chewed. The cover should be replaced securely after each opening. Patients should keep PULMICORT TURBUHALER (budesonide) clean and dry at all times. Patients should be advised that improvement in asthma control following inhalation of PULMICORT TURBUHALER (budesonide) can occur within 24 hours of beginning treatment although maximum benefit may not be achieved for 1 to 2 weeks, or longer. If symptoms do not improve in that time frame, or if the condition worsens, the patient should be instructed not to increase the dosage, but to contact the physician. Patients whose systemic corticosteroids have been reduced or withdrawn should be instructed to carry a warning card indicating that they may need supplemental systemic corticosteroids during periods of stress or an asthma attack that does not respond to bronchodilators. Patients should be advised not to stop the use of PULMICORT TURBUHALER (budesonide) abruptly. Patients should be warned to avoid exposure to chicken pox or measles and if they are exposed, to consult their physicians without delay. Long-term use of inhaled corticosteroids, including budesonide, may increase the risk of some eye problems (cataracts or glaucoma). Regular eye examinations should be considered. Women considering the use of PULMICORT TURBUHALER (budesonide) should consult with their physician if they are pregnant or intend to become pregnant, or if they are breast-feeding a baby. Patients considering use of PULMICORT TURBUHALER (budesonide) should consult with their physician if they are allergic to budesonide or any other orally inhaled corticosteroid. Patients should inform their physician of other medications they are taking as PULMICORT TURBUHALER (budesonide) may not be suitable in some circumstances and the physician may wish to use a different medicine. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies were conducted in rats and mice using oral administration to evaluate the carcinogenic potential of budesonide. In a 104-week oral study in Sprague-Dawley rats, a statistically significant increase in the incidence of gliomas was observed in male rats receiving an oral dose of 50 mcg/kg/day (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m2 basis). No tumorigenicity was seen in male and female rats at respective oral doses up to 25 and 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m2 basis). In two additional two-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m2 basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m2 basis). The concurrent reference corticosteroids (prednisone and triamcinolone acetonide) in these two studies showed similar findings. There was no evidence of a carcinogenic effect when budesonide was administered orally for 91 weeks to mice at doses up to 200 mcg/kg/day (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m2 basis). Budesonide was not mutagenic or clastogenic in six different test systems: Ames Salmonella/microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster, and DNA repair analysis in rat hepatocyte culture. In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (less than the maximum recommended human daily inhalation dose on a mcg/m2 basis). At 20 mcg/kg/day (less than the maximum recommended human daily inhalation dose on a mcg/m2 basis), decreases in maternal body weight gain, prenatal viability, and viability of the young at birth and during lactation were observed. No such effects were noted at 5 mcg/kg (less than the maximum recommended human daily inhalation dose in adults on a mcg/m2 basis). Pregnancy: Teratogenic Effects Pregnancy Category B: As with other glucocorticoids, budesonide produced fetal loss, decreased pup weight, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg/day in rabbits (less than the maximum recommended human daily inhalation dose on a mcg/m2 basis) and 500 mcg/kg/day in rats (approximately 3 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation at doses up to 250 mcg/kg/day (equivalent to the maximum recommended human daily inhalation dose on a mcg/m2 basis). Experience with oral corticosteroids since their introduction in pharmacologic as opposed to physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. Studies of pregnant women, however, have not shown that PULMICORT TURBUHALER (budesonide) increases the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (i.e., Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2,014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared with the general population rate (3.8 % vs. 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs. 3.3, respectively). These same data were utilized in a second study bringing the total to 2,534 infants whose mothers were exposed to inhaled budesonide. In this study, the rate of congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%). Despite the animal findings, it would appear that the possibility of fetal harm is remote if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, PULMICORT TURBUHALER (budesonide) should be used during pregnancy only if clearly needed. Nonteratogenic Effects Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed. Nursing Mothers Corticosteroids are secreted in human milk. Because of the potential for adverse reactions in nursing infants from any corticosteroid, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Actual data for budesonide are lacking. Pediatric Use Safety and effectiveness of PULMICORT TURBUHALER (budesonide) in pediatric patients below 6 years of age have not been established. In pediatric asthma patients the frequency of adverse events observed with PULMICORT TURBUHALER (budesonide) was similar between the 6- to 12-year age group (N=172) compared with the 13- to 17-year age group (N=124). Controlled clinical studies have shown that orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids including the impact on final adult height are unknown. The potential for “catch up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. In a study of asthmatic children 5-12 years of age, those treated with PULMICORT TURBUHALER (budesonide) 200 mcg twice daily (n=311) had a 1.1-centimeter reduction in growth compared with those receiving placebo (n=418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment. By the end of four years, children treated with PULMICORT TURBUHALER (budesonide) and children treated with placebo had similar growth velocities. Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study. The growth of pediatric patients receiving orally inhaled corticosteroids, including PULMICORT TURBUHALER (budesonide) , should be monitored routinely (eg, via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks and benefits associated with alternative therapies. To minimize the systemic effects of inhaled corticosteroids, including PULMICORT TURBUHALER (budesonide) , each patient should be titrated to his/her lowest effective dose. Geriatric Use One hundred patients 65 years or older were included in the US and non-US controlled clinical trials of PULMICORT TURBUHALER (budesonide) . There were no differences in the safety and efficacy of the drug compared with those seen in 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.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS 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 ENTOCORT EC contains a corticosteroid, general warnings concerning corticosteroids should be followed [see Symptoms Of Steroid Withdrawal In Patients Transferred From Other Systemic Corticosteroids, Increased Risk Of Infection, Other Corticosteroid Effects]. Pediatric patients with Crohn’s disease have a slightly higher systemic exposure of budesonide and increased cortisol suppression than adults with Crohn’s disease [see Use In Specific Populations, CLINICAL PHARMACOLOGY]. 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, Use In Specific Populations, CLINICAL PHARMACOLOGY]. 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 ENTOCORT EC, 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 ENTOCORT EC may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. 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. 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. Patient Counseling Information Advise Patients to read the FDA-Approved patient labeling (PATIENT INFORMATION). Hypercorticism And Adrenal Axis Suppression Advise patients that ENTOCORT EC Capsules may cause hypercorticism and adrenal axis suppression and to follow a taper schedule, as instructed by their healthcare provider if transferring to ENTOCORT EC from systemic corticosteroids [see WARNINGS AND PRECAUTIONS]. Advise patients that replacement of systemic corticosteroids with ENTOCORT EC 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]. Pregnancy Advise female patients that ENTOCORT EC may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Use In Specific Populations]. Administration Advise patients to: Take ENTOCORT EC capsules once daily in the morning. Swallow ENTOCORT EC capsules whole. Do not chew or crush. Avoid consumption of grapefruit juice for the duration of their ENTOCORT EC therapy [see DRUG INTERACTIONS]. Nonclinical Toxicology 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 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 Crohn’s 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 Crohn’s 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]. 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. Lactation Risk Summary Lactation studies have not been conducted with oral budesonide, including ENTOCORT EC, 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 mother’s clinical need for ENTOCORT EC and any potential adverse effects on the breastfed infant from ENTOCORT EC, 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 ENTOCORT EC capsules 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 ENTOCORT EC, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. Pediatric Use The safety and effectiveness of ENTOCORT EC have been established in pediatric patients 8 to 17 years of age who weigh more than 25 kg for the treatment of mild to moderate active Crohn’s disease involving the ileum and/or the ascending colon. Use of ENTOCORT EC in this age group is supported by evidence from adequate and well controlled studies of ENTOCORT EC in adults, with additional data from 2 clinical studies in 149 pediatric patients treated up to 8 weeks and one pharmacokinetic study in 8 pediatric patients [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, and Clinical Studies]. The observed safety profile of ENTOCORT EC in pediatric patients is consistent with its known safety profile in adults and no new safety concerns were identified [see ADVERSE REACTIONS]. Systemic corticosteroids, including ENTOCORT EC, may cause a reduction of growth velocity in pediatric patients. Pediatric patients with Crohn’s disease have a 17% higher mean systemic exposure and cortisol suppression than adults with Crohn’s disease [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. The safety and effectiveness of ENTOCORT EC have not been established in pediatric patients less than 8 years of age for the treatment of mild to moderate active Crohn’s disease involving the ileum and/or the ascending colon. The safety and effectiveness of ENTOCORT EC have not been established in pediatric patients for the maintenance of clinical remission of mild to moderate Crohn’s disease. An open-label study to evaluate the safety and tolerability of ENTOCORT EC as maintenance treatment in pediatric patients aged 5 to 17 years was conducted, and did not establish the safety and efficacy of maintenance of clinical remission. Geriatric Use Clinical studies of ENTOCORT EC 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 ENTOCORT EC 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. 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 and CLINICAL PHARMACOLOGY]. 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]. No dosage adjustment is needed in patients with mild hepatic impairment (Child-Pugh Class A).