budesonide 0.1 MG/ACTUAT Nasal Spray

INDICATIONS AND USAGE Budesonide delayed-release capsules are a corticosteroid indicated for: • Treatment of mild to moderate active Crohn’s disease involving the ileum and/or the ascending colon, in patients 8 years and older. ( 1.1 ) • Maintenance of clinical remission of mild to moderate Crohn’s disease involving the ileum and/or the ascending colon for up to 3 months in adults. ( 1.2 ) 1.1 Treatment of Mild to Moderate Active Crohn’s Disease Budesonide delayed-release capsules are indicated for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon in patients 8 years of age and older. 1.2 Maintenance of Clinical Remission of Mild to Moderate Crohn’s Disease Budesonide delayed-release capsules are indicated for the maintenance of clinical remission of mild to moderate Crohn’s disease involving the ileum and/or the ascending colon for up to 3 months in adults.

DOSAGE AND ADMINISTRATION Administration Instructions ( 2.1 ): • Take once daily in the morning. • Swallow whole. Do not chew or crush. • For patients unable to swallow an intact capsule, open the capsules and empty the granules onto one tablespoonful of applesauce. Mix and consume the entire contents within 30 minutes. Do not chew or crush. Follow with 8 ounces of water. • Avoid consumption of grapefruit juice for the duration of therapy. Recommended Dosage : Mild to moderate active Crohn’s disease ( 2.2 ): • Adults: 9 mg once daily for up to 8 weeks; repeat 8 week treatment courses for recurring episodes of active disease. • Pediatrics 8 to 17 years who weigh more than 25 kg: 9 mg once daily for up to 8 weeks, followed by 6 mg once daily in the morning for 2 weeks. Maintenance of clinical remission of mild to moderate Crohn’s disease ( 2.3 ): • Adults: 6 mg once daily for up to 3 months; taper to complete cessation after 3 months. Continued treatment for more than 3 months has not been shown to provide substantial clinical benefit. • When switching from oral prednisolone, begin tapering prednisolone concomitantly with initiating budesonide delayed-release capsules. Hepatic Impairment : • Consider reducing the dosage to 3 mg once daily in adult patients with moderate hepatic impairment (Child-Pugh Class B). ( 2.4 , 5.1 , 8.6 ) 2.1 Administration Instructions • Take budesonide delayed-release capsules once daily in the morning. • Swallow budesonide delayed-release capsules whole. Do not chew or crush. • For patients unable to swallow an intact capsule, budesonide delayed-release capsules can be opened and administered as follows: 1. Place one tablespoonful of applesauce into a clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing. 2. Open the capsule(s). 3. Carefully empty all the granules inside the capsule(s) on the applesauce. 4. Mix the granules with the applesauce. 5. Consume the entire contents within 30 minutes of mixing. Do not chew or crush the granules. Do not save the applesauce and granules for future use. 6. Follow the applesauce and granules immediately with a glass (8 ounces) of cool water to ensure complete swallowing of the granules. • Avoid consumption of grapefruit juice for the duration of budesonide delayed-release capsule therapy [see Drug Interactions (7.1)] . 2.2 Treatment of Mild to Moderate Active Crohn’s Disease The recommended dosage of budesonide delayed-release capsules is: Adults : 9 mg orally once daily for up to 8 weeks. Repeated 8 week courses of budesonide delayed-release capsules 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. 2.3 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 budesonide delayed-release capsules 6 mg orally once daily for maintenance of clinical remission up to 3 months. If symptom control is still maintained at 3 months an attempt to taper to complete cessation is recommended. Continued treatment with budesonide delayed-release capsules 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 budesonide delayed-release capsules with no reported episodes of adrenal insufficiency. Since prednisolone should not be stopped abruptly, tapering should begin concomitantly with initiating budesonide delayed-release capsules treatment. 2.4 Dosage Adjustment in Adult Patients with Hepatic Impairment Consider reducing the dosage of budesonide delayed-release capsules to 3 mg once daily for adult patients with moderate hepatic impairment (Child-Pugh Class B). Avoid use in patients with severe hepatic impairment (Child-Pugh Class C) [see Warnings and Precautions (5.1), Use in Specific Populations (8.6)] .

WARNINGS AND PRECAUTIONS • Localized Infections: Candida albicans infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise patients to rinse the mouth following inhalation ( 5.1 ) • Deterioration of Asthma or Acute Episodes: PULMICORT FLEXHALER should not be used for relief of acute symptoms. Patients require immediate re-evaluation during rapidly deteriorating asthma ( 5.2 ) • Hypersensitivity Reactions: Anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT FLEXHALER. Discontinue PULMICORT FLEXHALER if such reactions occur ( 5.3 ) • Immunosuppression: Potential worsening of infections (e.g., existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients ( 5.4 ) • Transferring Patients from Systemic Corticosteroid Therapy: Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to PULMICORT FLEXHALER ( 5.5 ) • Hypercorticism and Adrenal Suppression: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, reduce PULMICORT FLEXHALER slowly ( 5.6 ) • Reduction in Bone Mineral Density with Long term Administration: Monitor patients with major risk factors for decreased bone mineral content ( 5.8 ) • Effects on Growth: Monitor growth of pediatric patients ( 5.9 ) • Glaucoma and Cataracts: Close monitoring is warranted ( 5.10 ) • Paradoxical Bronchospasm: Discontinue PULMICORT FLEXHALER and institute alternative therapy if paradoxical bronchospasm occurs ( 5.11 ) • Eosinophilic Conditions and Churg-Strauss Syndrome: Be alert to eosinophilic conditions ( 5.12 ) 5.1 Local Effects In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with PULMICORT FLEXHALER. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while treatment with PULMICORT FLEXHALER continues, but at times, therapy with PULMICORT FLEXHALER may need to be interrupted. Patients should rinse the mouth after inhalation of PULMICORT FLEXHALER. 5.2 Deterioration of Asthma or Acute Episodes PULMICORT FLEXHALER is not a bronchodilator and is not indicated for the rapid relief of bronchospasm or other acute episodes of asthma. Patients should be instructed to contact their physician immediately if episodes of asthma not responsive to their usual doses of bronchodilators occur during the course of treatment with PULMICORT FLEXHALER. During such episodes, patients may require therapy with oral corticosteroids. An inhaled short acting beta 2 -agonist, not PULMICORT FLEXHALER, should be used to relieve acute symptoms such as shortness of breath. When prescribing PULMICORT FLEXHALER, the physician must also provide the patient with an inhaled, short-acting beta 2 -agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of PULMICORT FLEXHALER. 5.3 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT FLEXHALER. Discontinue PULMICORT FLEXHALER if such reactions occur [see Contraindications (4) , Adverse Reactions (6) ] . PULMICORT FLEXHALER contains small amounts of lactose, which contains trace levels of milk proteins. It is possible that cough, wheezing, or bronchospasm may occur in patients who have a severe milk protein allergy [see Contraindications (4) , Adverse Reactions (6.2) ] . 5.4 Immunosuppression 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 children or adults using corticosteroids. In 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 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 to chicken pox, 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. The immune responsiveness to varicella vaccine was evaluated in pediatric patients with asthma ages 12 months to 8 years 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., beta 2 -agonists, leukotriene receptor antagonists, cromones). The percentage of patients developing a seroprotective antibody titer of ≥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-corticosteroid asthma therapy (90%). No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination. 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. 5.5 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who are transferred from systemically active corticosteroids to PULMICORT FLEXHALER 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 FLEXHALER 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 FLEXHA

CONTRAINDICATIONS The use of budesonide inhalation suspension is contraindicated in the following conditions: • Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. • Hypersensitivity to budesonide or any of the ingredients of budesonide inhalation suspension [see Warnings and Precautions ( 5.3 ), Description ( 11 ), Adverse Reactions ( 6.2 )]. • Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. ( 4 ) • Hypersensitivity to any of the ingredients in budesonide inhalation suspension. ( 4 )

CLINICAL PHARMACOLOGY 12.1 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 these findings is unknown. The activity of budesonide inhalation suspension 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 well 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 (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. The 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 activities and systemic corticosteroid effects over a wide dose range of inhaled budesonide in a variety of formulations and delivery systems including an inhalation-driven, multi-dose dry powder inhaler and the inhalation suspension for nebulization. This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85 to 95%) and the low potency of metabolites (see below). 12.2 Pharmacodynamics The therapeutic effects of conventional doses of orally inhaled budesonide are largely explained by its direct local action on the respiratory tract. To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled budesonide, a clinical study in adult 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 administered budesonide, even though systemic budesonide exposure was comparable for both treatments, indicating that the inhaled treatment is working locally in the lung. Thus, the therapeutic effect of conventional doses of orally inhaled budesonide are largely explained by its direct action on the respiratory tract. Improvement in the control of asthma symptoms following inhalation of budesonide inhalation suspension can occur within 2 to 8 days of beginning treatment, although maximum benefit may not be achieved for 4 to 6 weeks. Budesonide administered via a dry powder inhaler has been shown in various challenge models (including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate) to decrease bronchial hyperresponsiveness in asthmatic patients. The clinical relevance of these models is not certain. Pre-treatment with budesonide administered as 1600 mcg daily (800 mcg twice daily) via a dry powder inhaler for 2 weeks reduced the acute (early-phase reaction) and delayed (late-phase reaction) decrease in FEV 1 following inhaled allergen challenge. HPA Axis Effects The effects of budesonide inhalation suspension on the hypothalamic-pituitary-adrenal (HPA) axis were studied in three, 12-week, double-blind, placebo-controlled studies in 293 pediatric patients, 6 months to 8 years of age, with persistent asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by the short cosyntropin (ACTH) stimulation test, remained intact with budesonide inhalation suspension treatment at recommended doses. In the subgroup of children age 6 months to 2 years (n=21) receiving a total daily dose of budesonide inhalation suspension equivalent to 0.25 mg (n=5), 0.5 mg (n=5), 1 mg (n=8), or placebo (n=3), the mean change from baseline in ACTH-stimulated cortisol levels showed a decline in peak stimulated cortisol at 12 weeks compared to an increase in the placebo group. These mean differences were not statistically significant compared to placebo. Another 12-week study in 141 pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent/persistent wheezing was conducted. All patients were randomized to receive either 0.5 mg or 1 mg of budesonide inhalation suspension or placebo. A total of 28, 17, and 31 patients in the budesonide inhalation suspension 0.5 mg, 1 mg, and placebo arms respectively, had an evaluation of serum cortisol levels post-ACTH stimulation both at baseline and at the end of the study. The mean change from baseline to Week 12 ACTH-stimulated minus basal plasma cortisol levels did not indicate adrenal suppression in patients treated with budesonide inhalation suspension versus placebo. However, 7 patients in this study (4 of whom received budesonide inhalation suspension 0.5 mg, 2 of whom received budesonide inhalation suspension 1 mg and 1 of whom received placebo) showed a shift from normal baseline stimulated cortisol level (≥500 nmol/L) to a subnormal level (<500 nmol/L) at Week 12. In 4 of these patients receiving budesonide inhalation suspension, the cortisol values were near the cutoff value of 500 nmol/L. The effects of budesonide inhalation suspension at doses of 0.5 mg twice daily, and 1 mg and 2 mg twice daily (2 times and 4 times the highest recommended total daily dose, respectively) on 24-hour urinary cortisol excretion were studied in 18 patients between 6 to 15 years of age with persistent asthma in a cross-over study design (4 weeks of treatment per dose level). There was a dose-related decrease in urinary cortisol excretion at 2 and 4 times the recommended daily dose. The two higher doses of budesonide inhalation suspension (1 and 2 mg twice daily) showed statistically significantly reduced (43 to 52%) urinary cortisol excretion compared to the run-in period. The highest recommended dose of budesonide inhalation suspension, 1 mg total daily dose, did not show statistically significantly reduced urinary cortisol excretion compared to the run-in period. Budesonide inhalation suspension, like other inhaled corticosteroid products, may impact the HPA axis, especially in susceptible individuals, in younger children, and in patients given high doses for prolonged periods [see Warnings and Precautions (5.5) ]. 12.3 Pharmacokinetics Absorption: In asthmatic children 4 to 6 years of age, the total absolute bioavailability (i.e., lung + oral) following administration of budesonide inhalation suspension via jet nebulizer was approximately 6% of the labeled dose. In children, a peak plasma concentration of 2.6 nmol/L was obtained approximately 20 minutes after nebulization of a 1 mg dose. Systemic exposure, as measured by AUC and C max , is similar for young children and adults after inhalation of the same dose of budesonide inhalation suspension. Distribution: In asthmatic children 4 to 6 years of age, the volume of distribution at steady-state of budesonide was 3 L/kg, approximately the same as in healthy adults. Budesonide is 85 to 90% bound to plasma proteins, the degree of binding being constant over the concentration range (1 to 100 nmol/L) achieved with, and exceeding, recommended doses. 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