PULMICORT RESPULES

6 ADVERSE REACTIONS Systemic and inhaled corticosteroid use may result in the following: • Candida albicans Infection [see Warnings and Precautions (5.1) ] • Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.3) ] • Immunosuppression [see Warnings and Precautions (5.4) ] • Hypercorticism and Adrenal Suppression [see Warnings and Precautions (5.6) ] • Reduction in Bone Mineral Density [see Warnings and Precautions (5.7) ] • Growth Effects in Pediatric Patients [see Warnings and Precautions (5.8) , Use in Specific Populations (8.4) ] • Glaucoma, Increased Intraocular Pressure and Cataracts [see Warnings and Precautions (5.9) ] • Eosinophilic Conditions and Churg-Strauss Syndrome [see Warnings and Precautions (5.11) ] Most common adverse reactions (incidence > 3%) are respiratory infection, rhinitis, coughing, otitis media, viral infection, moniliasis, gastroenteritis, vomiting, diarrhea, abdominal pain, ear infection, epistaxis, conjunctivitis, rash ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1–800–236–9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The incidence of common adverse reactions is based on three double-blind, placebo-controlled, randomized U.S. clinical trials in which 945 patients, 12 months to 8 years of age, (98 patients ≥12 months and <2 years of age; 225 patients ≥2 and <4 years of age; and 622 patients ≥4 and ≤8 years of age) were treated with PULMICORT RESPULES (0.25 to 1 mg total daily dose for 12 weeks) or vehicle placebo. The incidence and nature of adverse events reported for PULMICORT RESPULES was comparable to that reported for placebo. The following table shows the incidence of adverse events in U.S. controlled clinical trials, regardless of relationship to treatment, in patients previously receiving bronchodilators and/or inhaled corticosteroids. This population included a total of 605 male and 340 female patients and 78.4% were Caucasian, 13.8% African American, 5.5% Hispanic and 2.3% Other. Table 1 – Adverse Reactions occurring at an incidence of ≥3% in at least one active treatment group where the incidence was higher with PULMICORT RESPULES than placebo Adverse Events Vehicle Placebo (n=227) % PULMICORT RESPULES Total Daily Dose 0.25 mg (n=178) % 0.5 mg (n=223) % 1 mg (n=317) % Respiratory System Disorder Respiratory Infection 36 34 35 38 Rhinitis 9 7 11 12 Coughing 5 5 9 8 Resistance Mechanism Disorders Otitis Media 11 12 11 9 Viral Infection 3 4 5 3 Moniliasis 2 4 3 4 Gastrointestinal System Disorders Gastroenteritis 4 5 5 5 Vomiting 3 2 4 4 Diarrhea 2 4 4 2 Abdominal Pain 2 3 2 3 Hearing and Vestibular Disorders Ear Infection 4 2 4 5 Platelet, Bleeding and Clotting Disorders Epistaxis 1 2 4 3 Vision Disorders Conjunctivitis 2 <1 4 2 Skin and Appendages Disorders Rash 3 <1 4 2 The information below includes all adverse reactions by system organ class with an incidence of 1 to < 3%, in at least one PULMICORT RESPULES treatment group where the incidence was higher with PULMICORT RESPULES than with placebo, regardless of relationship to treatment. Blood and lymphatic system disorders: cervical lymphadenopathy Ear and labyrinth disorders: earache General disorders and administration site conditions: fatigue, flu-like disorder Immune system disorders: allergic reaction Infections and infestations: eye infection, herpes simplex, external ear infection, infection Injury, poisoning and procedural complication: fracture Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: hyperkinesia Psychiatric disorders: emotional lability Respiratory, thoracic, and mediastinal disorders: chest pain, dysphonia, stridor Skin and subcutaneous tissue disorders: contact dermatitis, eczema, pustular rash, pruritus, purpura The incidence of reported adverse events was similar between the 447 PULMICORT RESPULES-treated (mean total daily dose 0.5 to 1 mg) and 223 conventional therapy-treated pediatric asthma patients followed for one year in three open-label studies. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of PULMICORT RESPULES. 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. Some of these adverse reactions may also have been observed in clinical studies with PULMICORT RESPULES. Endocrine disorders: symptoms of hypocorticism and hypercorticism [see Warnings and Precautions (5.6) ] Eye disorders: cataracts, glaucoma, increased intraocular pressure [see Warnings and Precautions (5.9) ] General disorders and administration site conditions: fever, pain Immune system disorders: immediate and delayed hypersensitivity reactions including, anaphylaxis, angioedema, bronchospasm, rash, contact dermatitis, and urticaria [see Contraindications (4) , Warnings and Precautions (5.10) ] Infection and Infestation: sinusitis, pharyngitis, bronchitis Musculoskeletal and connective tissue disorders: avascular necrosis of the femoral head, osteoporosis, growth suppression Nervous system disorders: headache Psychiatric disorders: psychiatric symptoms including psychosis, depression, aggressive reactions, irritability, nervousness, restlessness, and anxiety Respiratory, thoracic, and mediastinal disorders: cough, dysphonia and throat irritation Skin and subcutaneous tissue disorders: skin bruising, facial skin irritation Cases of growth suppression have been reported for inhaled corticosteroids including post-marketing reports for PULMICORT RESPULES [see Warnings and Precautions (5.8) , Use in Specific Populations (8.4) ] .

4 CONTRAINDICATIONS The use of PULMICORT RESPULES 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 PULMICORT RESPULES [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 PULMICORT RESPULES ( 4 )

11 DESCRIPTION Budesonide, the active component of PULMICORT RESPULES ® , 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 C 25 H 34 O 6 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 10 3 . PULMICORT RESPULES is a sterile suspension for inhalation via jet nebulizer and contains the active ingredient budesonide (micronized), and the inactive ingredients disodium edetate, sodium chloride, sodium citrate, citric acid, polysorbate 80, and Water for Injection. Three dose strengths are available in single-dose ampules (Respules™ ampules): 0.25 mg, 0.5 mg, and 1 mg per 2 mL RESPULES ampule. For PULMICORT RESPULES, like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the jet nebulizer utilized, and compressor performance. Using the Pari-LC-Jet Plus Nebulizer/Pari Master compressor system, under in vitro conditions, the mean delivered dose at the mouthpiece (% nominal dose) was approximately 17% at a mean flow rate of 5.5 L/min. The mean nebulization time was 5 minutes or less. PULMICORT RESPULES should be administered from jet nebulizers at adequate flow rates, via face masks or mouthpieces [see Dosage and Administration (2) ] . Chemical Structure for Pulmicort Respules

2 DOSAGE AND ADMINISTRATION The recommended starting dose and highest recommended dose of PULMICORT RESPULES, based on prior asthma therapy, are listed in the following table. Previous Therapy Recommended Starting Dose Highest Recommended Dose Bronchodilators alone 0.5 mg total daily dose administered either once daily or twice daily in divided doses 0.5 mg total daily dose Inhaled Corticosteroids 0.5 mg total daily dose administered either once daily or twice daily in divided doses 1 mg total daily dose Oral Corticosteroids 1 mg total daily dose administered either as 0.5 mg twice daily or 1 mg once daily 1 mg total daily dose Recommended dosing based on previous therapy ( 2 ). Start with the lowest recommended dose: • Bronchodilators alone: 0.5 mg once daily or 0.25 mg twice daily • Inhaled corticosteroids: 0.5 mg once daily or 0.25 mg twice daily up to 0.5 mg twice daily • Oral corticosteroids: 0.5 mg twice daily or 1 mg once daily • In symptomatic children not responding to non-steroidal therapy, a starting dose of 0.25 mg once daily may be considered • If once-daily treatment does not provide adequate control, the total daily dose should be increased and/or administered as a divided dose. Once asthma stability is achieved, titrate the dose downwards • For inhalation use via compressed air driven jet nebulizers only (not for use with ultrasonic devices). Not for injection. ( 2.2 ) 2.1 Dosing Recommendations Dosing recommendations based on previous therapy are as follows: • Bronchodilators alone: 0.5 mg once daily or 0.25 mg twice daily • Inhaled corticosteroids: 0.5 mg once daily or 0.25 mg twice daily up to 0.5 mg twice daily • Oral corticosteroids: 0.5 mg twice daily or 1 mg once daily In symptomatic children not responding to non-steroidal therapy, a starting dose of 0.25 mg once daily may be considered. If once-daily treatment does not provide adequate control, the total daily dose should be increased and/or administered as a divided dose. In all patients, it is desirable to downward-titrate to the lowest effective dose once asthma stability is achieved. 2.2 Directions for Use PULMICORT RESPULES should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask. Ultrasonic nebulizers are not suitable for the adequate administration of PULMICORT RESPULES and, therefore, are NOT recommended. The effects of mixing PULMICORT RESPULES with other nebulizable medications have not been adequately assessed. PULMICORT RESPULES should be administered separately in the nebulizer [see Patient Counseling Information (17.1) ]. A Pari-LC-Jet Plus Nebulizer (with face mask or mouthpiece) connected to a Pari Master compressor was used to deliver PULMICORT RESPULES to each patient in 3 U.S. controlled clinical studies. The safety and efficacy of PULMICORT RESPULES delivered by other nebulizers and compressors have not been established.

1 INDICATIONS AND USAGE PULMICORT RESPULES ® is an inhaled corticosteroid indicated for: • Maintenance treatment of asthma and as prophylactic therapy in children 12 months to 8 years of age ( 1 ) Limitations of Use: Not indicated for the relief of acute bronchospasm ( 1 ) 1.1 Maintenance Treatment of Asthma PULMICORT RESPULES is indicated for the maintenance treatment of asthma and as prophylactic therapy in children 12 months to 8 years of age. Limitations of Use : • PULMICORT RESPULES is NOT indicated for the relief of acute bronchospasm.

10 OVERDOSAGE The potential for acute toxic effects following overdose of PULMICORT RESPULES is low. If inhaled corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism or growth suppression may occur [see Warnings and Precautions (5.6) ] .

7 DRUG INTERACTIONS Strong Cytochrome P450 3A4 Inhibitors (e.g., ritonavir): Use with caution. May cause increased systemic corticosteroid effects ( 5.12 , 7.1 ) 7.1 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 a CYP3A4 inhibitor may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the coadministration of PULMICORT RESPULES 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 (5.12) , Clinical Pharmacology (12.3) ] .

12 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 PULMICORT RESPULES 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 (85-95%) 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 PULMICORT RESPULES can occur within 2-8 days of beginning treatment, although maximum benefit may not be achieved for 4-6 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 PULMICORT RESPULES 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 PULMICORT RESPULES treatment at recommended doses. In the subgroup of children age 6 months to 2 years (n=21) receiving a total daily dose of PULMICORT RESPULES 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 PULMICORT RESPULES or placebo once daily. A total of 28, 17, and 31 patients in the PULMICORT RESPULES 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 PULMICORT RESPULES versus placebo. However, 7 patients in this study (4 of whom received PULMICORT RESPULES 0.5 mg, 2 of whom received PULMICORT RESPULES 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 PULMICORT RESPULES, the cortisol values were near the cutoff value of 500 nmol/L. The effects of PULMICORT RESPULES 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 PULMICORT RESPULES (1 and 2 mg twice daily) showed statistically significantly reduced (43-52%) urinary cortisol excretion compared to the run-in period. The highest recommended dose of PULMICORT RESPULES, 1 mg total daily dose, did not show statistically significantly reduced urinary cortisol excretion compared to the run-in period. PULMICORT RESPULES, 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 4-6 years of age, the total absolute bioavailability (i.e., lung + oral) following administration of PULMICORT RESPULES 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 PULMICORT RESPULES. Distribution: In asthmatic children 4-6 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 85-90% bound to plasma proteins, the degree of binding being constant over the concentration range (1-100 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/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 difference between the in vitro and in vivo metabolic patterns has been detected. Negligible metabolic inactivation was observed in human lung and serum preparations. Excretion/Elimination: Budesonide is primarily cleared by the liver. Budesonide is excreted in urine and feces in the form of metabolites. In adults, approximately 60% of an intravenous radiolabeled dose was recovered in the urine. No unchanged budesonide was detected in the urine. In asthmatic children 4-6 years of age, the terminal half-life of budesonide after nebulization is 2.3 hours, and the systemic clearance is 0.5 L/min, which is approximately 50% greater than in healthy adults after adjustment for differences in weight. Special Populations: No differences in pharmacokinetics due to race, gender, or age have been identified. 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 adults. Nursing Mothers: The disposition of budesonide when delivered by 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 is 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 breast-feeding (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 (8.2) ] . 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 (5.12) , Drug Interactions (7.1) ] . Cimetidine: At recommended doses, cimetidine, a non-specific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.

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 PULMICORT RESPULES 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 (85-95%) 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 PULMICORT RESPULES can occur within 2-8 days of beginning treatment, although maximum benefit may not be achieved for 4-6 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 PULMICORT RESPULES 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 PULMICORT RESPULES treatment at recommended doses. In the subgroup of children age 6 months to 2 years (n=21) receiving a total daily dose of PULMICORT RESPULES 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 PULMICORT RESPULES or placebo once daily. A total of 28, 17, and 31 patients in the PULMICORT RESPULES 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 PULMICORT RESPULES versus placebo. However, 7 patients in this study (4 of whom received PULMICORT RESPULES 0.5 mg, 2 of whom received PULMICORT RESPULES 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 PULMICORT RESPULES, the cortisol values were near the cutoff value of 500 nmol/L. The effects of PULMICORT RESPULES 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 PULMICORT RESPULES (1 and 2 mg twice daily) showed statistically significantly reduced (43-52%) urinary cortisol excretion compared to the run-in period. The highest recommended dose of PULMICORT RESPULES, 1 mg total daily dose, did not show statistically significantly reduced urinary cortisol excretion compared to the run-in period. PULMICORT RESPULES, 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 4-6 years of age, the total absolute bioavailability (i.e., lung + oral) following administration of PULMICORT RESPULES 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 PULMICORT RESPULES. Distribution: In asthmatic children 4-6 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 85-90% bound to plasma proteins, the degree of binding being constant over the concentration range (1-100 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/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 difference between the in vitro and in vivo metabolic patterns has been detected. Negligible metabolic inactivation was observed in human lung and serum preparations. Excretion/Elimination: Budesonide is primarily cleared by the liver. Budesonide is excreted in urine and feces in the form of metabolites. In adults, approximately 60% of an intravenous radiolabeled dose was recovered in the urine. No unchanged budesonide was detected in the urine. In asthmatic children 4-6 years of age, the terminal half-life of budesonide after nebulization is 2.3 hours, and the systemic clearance is 0.5 L/min, which is approximately 50% greater than in healthy adults after adjustment for differences in weight. Special Populations: No differences in pharmacokinetics due to race, gender, or age have been identified. 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 adults. Nursing Mothers: The disposition of budesonide when delivered by 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 is 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 breast-feeding (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 (8.2) ] . 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 (5.12) , Drug Interactions (7.1) ] . Cimetidine: At recommended doses, cimetidine, a non-specific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.

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3 DOSAGE FORMS AND STRENGTHS PULMICORT RESPULES is available in three strengths, each containing 2 mL: 0.25 mg/2 mL, 0.5 mg/2 mL, and 1 mg/2 mL. PULMICORT RESPULES is supplied in sealed aluminum foil envelopes containing one plastic strip of five single-dose RESPULES ampules together with patient instructions for use. There are 30 RESPULES ampules in a carton. Each single-dose RESPULES ampule contains 2 mL of sterile liquid suspension. Inhalation suspension: 0.25 mg/2 mL, 0.5 mg/2 mL, 1 mg/2 mL ( 3 )

PULMICORT RESPULES Budesonide BUDESONIDE BUDESONIDE EDETATE DISODIUM SODIUM CHLORIDE SODIUM CITRATE, UNSPECIFIED FORM POLYSORBATE 80 WATER ANHYDROUS CITRIC ACID PULMICORT RESPULES Budesonide BUDESONIDE BUDESONIDE EDETATE DISODIUM SODIUM CHLORIDE SODIUM CITRATE, UNSPECIFIED FORM POLYSORBATE 80 WATER ANHYDROUS CITRIC ACID PULMICORT RESPULES Budesonide BUDESONIDE BUDESONIDE EDETATE DISODIUM SODIUM CHLORIDE SODIUM CITRATE, UNSPECIFIED FORM POLYSORBATE 80 WATER ANHYDROUS CITRIC ACID

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg (approximately 0.2 and 0.04 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis) and in female rats at oral doses up to 50 mcg/kg (approximately 0.5 and 0.1 times, respectively, MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 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 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 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 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) in these two studies 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 equivalent to and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 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. Fertility and reproductive performance were unaffected in rats at subcutaneous doses up to 80 mcg/kg approximately equivalent to the MRHDID in adults on a mcg/m2 basis. However, it caused a decrease in prenatal viability and viability in the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg and above approximately 0.2 times than the MRHDID in adults on a mcg/m2 basis. No such effects were noted at 5 mcg/kg (approximately 0.05 times the MRHDID in adults on a mcg/m2 basis).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg (approximately 0.2 and 0.04 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis) and in female rats at oral doses up to 50 mcg/kg (approximately 0.5 and 0.1 times, respectively, MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 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 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 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 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) in these two studies 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 equivalent to and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 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. Fertility and reproductive performance were unaffected in rats at subcutaneous doses up to 80 mcg/kg approximately equivalent to the MRHDID in adults on a mcg/m2 basis. However, it caused a decrease in prenatal viability and viability in the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg and above approximately 0.2 times than the MRHDID in adults on a mcg/m2 basis. No such effects were noted at 5 mcg/kg (approximately 0.05 times the MRHDID in adults on a mcg/m2 basis).

NDA020929

PULMICORT RESPULES

Budesonide

0186-1989

HUMAN PRESCRIPTION DRUG

RESPIRATORY (INHALATION)

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – 0.25 mg/2 mL NDC 0186-1988-04 Pulmicort Respules® (budesonide inhalation suspension) FOR INHALATION ONLY. Rx only Each single-dose Respules™ ampule delivers 2 mL of a sterile suspension containing 0.25 mg of micronized budesonide plus disodium edetate, sodium chloride, polysorbate 80, citric acid, sodium citrate and Water for Injection. Once a RESPULES ampule is opened, use the contents immediately. For use only in a jet nebulizer. Do NOT use in an ultrasonic nebulizer. Pulmicort Respules 0.25 mg/2 mL Carton Label 30 single-dose RESPULES ampules per carton

17 PATIENT COUNSELING INFORMATION 17.1 Administration with a Jet Nebulizer Patients should be advised that PULMICORT RESPULES should be administered with a jet nebulizer connected to a compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask. Ultrasonic nebulizers are not suitable for the adequate administration of PULMICORT RESPULES and, therefore, are not recommended. The effects of mixing PULMICORT RESPULES with other nebulizable medications have not been adequately assessed. PULMICORT RESPULES should be administered separately in the nebulizer [see Dosage and Administration (2) ] . 17.2 Oral Candidiasis Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with PULMICORT RESPULES, but at times therapy with PULMICORT RESPULES may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised [see Warnings and Precautions (5.1) ] . 17.3 Not for Acute Symptoms PULMICORT RESPULES is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta 2 -agonist such as albuterol. (The healthcare professional should provide that patient with such medication and instruct the patient in how it should be used). Patients should be instructed to notify their healthcare professional immediately if they experience any of the following: • Decreasing effectiveness of inhaled, short-acting beta 2 - agonists • Need for more inhalations than usual of inhaled, short-acting beta 2 -agonists • Significant decrease in lung function as outlined by the physician Patients should not stop therapy with PULMICORT RESPULES without physician/provider guidance since symptoms may recur after discontinuation [see Warnings and Precautions (5.2) ]. 17.4 Hypersensitivity Including Anaphylaxis Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT RESPULES. Discontinue PULMICORT RESPULES if such reactions occur [see Contraindications (4) , Warning and Precautions (5.3) ] . 17.5 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. If exposure to such a person occurs, and the child has not had chicken pox or been properly vaccinated, a physician should be consulted without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.4) ]. 17.6 Hypercorticism and Adrenal Suppression Patients should be advised that PULMICORT RESPULES may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to PULMICORT RESPULES [see Warnings and Precautions (5.6) ] . 17.7 Reduction in Bone Mineral Density Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk [see Warnings and Precautions (5.7) ] . 17.8 Reduced Growth Velocity Patients should be informed that orally inhaled corticosteroids, including PULMICORT RESPULES, may cause a reduction in growth velocity when administered to pediatric patients. Healthcare professionals should closely follow the growth of children and adolescents taking corticosteroids by any route [see Warnings and Precautions (5.8) ] . 17.9 Ocular Effects Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered [see Warnings and Precautions (5.9) ] . 17.10 Use Daily Patients should be advised to use PULMICORT RESPULES at regular intervals once or twice a day, since its effectiveness depends on regular use. Maximum benefit may not be achieved for 4 to 6 weeks or longer after starting treatment. If symptoms do not improve in that time frame or if the condition worsens, patients should be instructed to contact their healthcare professional. See accompanying Patient Information and Instructions for Use.

14 CLINICAL STUDIES Three double-blind, placebo-controlled, parallel group, randomized U.S. clinical trials of 12-weeks duration each were conducted in 1018 pediatric patients, 6 months to 8 years of age, 657 males and 361 females (798 Caucasians, 140 Blacks, 56 Hispanics, 3 Asians, 21 Others) with persistent asthma of varying disease duration (2 to 107 months) and severity. Doses of 0.25 mg, 0.5 mg, and 1 mg administered either once or twice daily were compared to placebo to provide information about appropriate dosing to cover a range of asthma severity. A Pari-LC-Jet Plus Nebulizer (with a face mask or mouthpiece) connected to a Pari Master compressor was used to deliver PULMICORT RESPULES to patients in the 3 U.S. controlled clinical trials. The co-primary endpoints were nighttime and daytime asthma symptom scores (0-3 scale). Improvements were addressed in terms of the primary efficacy variables of changes from baseline to the double-blind treatment period in nighttime and daytime asthma symptom scores (scale 0-3) as recorded in the patient diaries. Baseline was defined as the mean of the last seven days prior to randomization). The double-blind treatment period was defined as the mean over 12 week treatment period. Each of the five doses discussed below were studied in one or two, but not all three of the U.S. studies. Results of the 3 controlled clinical trials for recommended dosages of budesonide inhalation suspension (0.25 mg to 0.5 mg once or twice daily, or 1 mg once daily, up to a total daily dose of 1 mg) in 946 patients, 12 months to 8 years of age, are presented below. Statistically significant decreases in nighttime and daytime symptom scores of asthma were observed at PULMICORT RESPULES doses of 0.25 mg once daily (one study), 0.25 mg twice daily, and 0.5 mg twice daily compared to placebo. Use of PULMICORT RESPULES resulted in statistically significant decreases in either nighttime or daytime symptom scores, but not both, at doses of 1 mg once daily, and 0.5 mg once daily (one study). Symptom reduction in response to PULMICORT RESPULES occurred across gender and age. Statistically significant reductions in the need for bronchodilator therapy were also observed at all the doses of PULMICORT RESPULES studied. Improvements in lung function were associated with PULMICORT RESPULES in the subgroup of patients capable of performing lung function testing. Statistically significant increases were seen in FEV 1 [PULMICORT RESPULES 0.5 mg once daily and 1 mg once daily (one study); 0.5 mg twice daily] and morning PEF [PULMICORT RESPULES 1 mg once daily (one study); 0.25 mg twice daily; 0.5 mg twice daily] compared to placebo. A numerical reduction in nighttime and daytime symptom scores (0-3 scale) of asthma was observed within 2-8 days, although maximum benefit was not achieved for 4-6 weeks after starting treatment. The reduction in nighttime and daytime asthma symptom scores was maintained throughout the 12 weeks of the double-blind trials. Patients Not Receiving Inhaled Corticosteroid Therapy The efficacy of PULMICORT RESPULES at doses of 0.25 mg, 0.5 mg, and 1 mg once daily was evaluated in 344 pediatric patients, 12 months to 8 years of age, with mild to moderate persistent asthma (mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.07 to 1.34) who were not well controlled by bronchodilators alone. The changes from baseline to Weeks 0-12 in nighttime asthma symptom scores are shown in Figure 1. Nighttime asthma symptom scores showed statistically significant decreases in the patients treated with PULMICORT RESPULES compared to placebo. Similar decreases were also observed for daytime asthma symptom scores. Changes from baseline to the double-blind phase for the budesonide treatment groups compared to placebo were made using analysis of variance techniques. The model included terms for the respective changes from baseline as the dependent variable and terms for treatment, center and treatment by center interaction as exploratory variables (see Figures 1-3). Figure 1: A 12-Week Trial in Pediatric Patients Not on Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline p-value – 0.25 mg: 0.001, 0.5 mg: 0.010, 1.0 mg: 0.009 Patients Previously Maintained on Inhaled Corticosteroids The efficacy of PULMICORT RESPULES at doses of 0.25 mg and 0.5 mg twice daily was evaluated in 133 pediatric asthma patients, 4 to 8 years of age, previously maintained on inhaled corticosteroids (mean FEV 1 79.5% predicted; mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.04 to 1.18; mean baseline dose of beclomethasone dipropionate of 265 mcg/day, ranging between 42 to 1008 mcg/day; mean baseline dose of triamcinolone acetonide of 572 mcg/day, ranging between 200 to 1200 mcg/day). The changes from baseline to Weeks 0-12 in nighttime asthma symptom scores are shown in Figure 2. Nighttime asthma symptom scores showed statistically significant decrease in patients treated with PULMICORT RESPULES compared to placebo. Similar decreases were also observed for daytime asthma symptom scores. Statistically significant increases in FEV 1 compared to placebo were observed with PULMICORT RESPULES at a dose of 0.5 mg twice daily and in morning PEF for both doses (0.25 mg and 0.5 mg twice daily). Figure 2: A 12-Week Trial in Pediatric Patients Previously Maintained on Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline p-values: 0.25 mg: 0.022, 0.5 mg: 0.021 Patients Receiving Once-Daily or Twice-Daily Dosing The efficacy of PULMICORT RESPULES at doses of 0.25 mg once daily, 0.25 mg twice daily, 0.5 mg twice daily, and 1 mg once daily, was evaluated in 469 pediatric patients 12 months to 8 years of age (mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.13 to 1.31). Approximately 70% were not previously receiving inhaled corticosteroids. The changes from baseline to Weeks 0-12 in nighttime asthma symptom scores are shown in Figure 3. PULMICORT RESPULES at doses of 0.25 mg and 0.5 mg twice daily, and 1 mg once daily, demonstrated statistically significant decreases in nighttime asthma symptom scores compared to placebo. Similar decreases were also observed for daytime asthma symptom scores. PULMICORT RESPULES at a dose of 0.5 mg twice daily resulted in statistically significant increases compared to placebo in FEV1, and at doses of 0.25 mg and 0.5 mg twice daily and 1 mg once daily statistically significant increases in morning PEF. The evidence supports the efficacy of the same nominal dose of PULMICORT RESPULES administered on either a once-daily or twice-daily schedule. However, when all measures are considered together, the evidence is stronger for twice-daily dosing [see Dosage and Administration (2) ] . Figure 3: A 12-Week Trial in Pediatric Patients Either Maintained on Bronchodilators Alone or Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline p-values: 0.25 mg qd: 0.121, 0.25 mg bid: <0.001, 0.5 mg bid: 0.003, 1.0 mg qd: 0.005 Figure 1 Figure 2 Figure 3

8.5 Geriatric Use Of the 215 patients in 3 clinical trials of PULMICORT RESPULES in adult patients, 65 (30%) were 65 years of age or older, while 22 (10%) were 75 years of age or older. No overall differences in safety were observed between these patients and younger patients, and other reported clinical or medical surveillance experience has not identified differences in responses between the elderly and younger patients.

8.4 Pediatric Use Safety and effectiveness in children six months to 12 months of age has been evaluated but not established. Safety and effectiveness in children 12 months to 8 years of age have been established [see Clinical Pharmacology (12.2) , Adverse Reactions (6.1) ] . A 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 PULMICORT RESPULES or placebo once daily. Adrenal-axis function was assessed with an ACTH stimulation test at the beginning and end of the study, and mean changes from baseline in this variable did not indicate adrenal suppression in patients who received PULMICORT RESPULES versus placebo. However, on an individual basis, 7 patients in this study (6 in the PULMICORT RESPULES treatment arms and 1 in the placebo arm) experienced a shift from having a normal baseline stimulated cortisol level to having a subnormal level at Week 12 [see Clinical Pharmacology (12.2) ] . Pneumonia was observed more frequently in patients treated with PULMICORT RESPULES than in patients treated with placebo, (N = 2, 1, and 0) in the PULMICORT RESPULES 0.5 mg, 1 mg, and placebo groups, respectively. A dose dependent effect on growth was also noted in this 12-week trial. Infants in the placebo arm experienced an average growth of 3.7 cm over 12 weeks compared with 3.5 cm and 3.1 cm in the PULMICORT RESPULES 0.5 mg and 1 mg arms respectively. This corresponds to estimated mean (95% CI) reductions in 12-week growth velocity between placebo and PULMICORT RESPULES 0.5 mg of 0.2 cm (-0.6 to 1.0) and between placebo and PULMICORT RESPULES 1 mg of 0.6 cm (-0.2 to 1.4). These findings support that the use of PULMICORT RESPULES in infants 6 to 12 months of age may result in systemic effects and are consistent with findings of growth suppression in other studies with inhaled corticosteroids. Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately one centimeter per year (range 0.3 to 1.8 cm per year) and appears to be related to dose and duration of exposure. 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 budesonide administered via a dry powder inhaler 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 the 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 growth of pediatric patients receiving inhaled corticosteroids, including PULMICORT RESPULES, 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 inhaled corticosteroids, including PULMICORT RESPULES, each patient should be titrated to his/her lowest effective dose [see Dosage and Administration (2) , Warnings and Precautions (5.8) ] .

8.1 Pregnancy Risk Summary There are no adequate well-controlled studies of PULMICORT RESPULES in pregnant women. However, there are published studies on the use of budesonide, the active ingredient in PULMICORT RESPULES, in pregnant women. In animal reproduction studies, budesonide, administered by the subcutaneous route, caused structural abnormalities, was embryocidal, and reduced fetal weights in rats and rabbits at less than the maximum recommended human daily inhalation dose (MRHDID), but these effects were not seen in rats that received inhaled doses approximately 2 times the MRHDID ( see Data ). Studies of pregnant women have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. Experience with oral corticosteroids suggests that rodents are more prone to structural abnormalities from corticosteroid exposure than humans. The estimated background risk of major birth defects and miscarriage of the indicated populations 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 In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Labor or Delivery There are no well-controlled human studies that have investigated the effects of PULMICORT RESPULES during labor and delivery. Data Human Data Studies of pregnant women have not shown that inhaled 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 2014 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 to 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 2534 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%). Animal Data In a fertility and reproduction study, male rats were subcutaneously dosed for 9 weeks and females for 2 weeks prior to pairing and throughout the mating period. Females were dosed up until weaning of their offspring. Budesonide caused a decrease in prenatal viability and viability in the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at doses 0.2 times the MRHDID (on a mcg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and above). No such effects were noted at a dose 0.05 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 5 mcg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities at doses 0.5 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 25 mcg/kg/day). In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-15, budesonide produced similar adverse fetal effects at doses approximately 5 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 500 mcg/kg/day). In another embryo-fetal development study in pregnant rats, no structural abnormalities or embryocidal effects were seen at doses approximately 2 times the MRHDID (on a mcg/m 2 basis at maternal inhalation doses up to 250 mcg/kg/day). In a peri-and post-natal development study, rats dosed from gestation day 15 to postpartum day 21, budesonide had no effects on delivery, but did have an effect on growth and development of offspring. Offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation at doses less than 0.2 times the MRHDID and higher (on a mcg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate well-controlled studies of PULMICORT RESPULES in pregnant women. However, there are published studies on the use of budesonide, the active ingredient in PULMICORT RESPULES, in pregnant women. In animal reproduction studies, budesonide, administered by the subcutaneous route, caused structural abnormalities, was embryocidal, and reduced fetal weights in rats and rabbits at less than the maximum recommended human daily inhalation dose (MRHDID), but these effects were not seen in rats that received inhaled doses approximately 2 times the MRHDID ( see Data ). Studies of pregnant women have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. Experience with oral corticosteroids suggests that rodents are more prone to structural abnormalities from corticosteroid exposure than humans. The estimated background risk of major birth defects and miscarriage of the indicated populations 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 In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Labor or Delivery There are no well-controlled human studies that have investigated the effects of PULMICORT RESPULES during labor and delivery. Data Human Data Studies of pregnant women have not shown that inhaled 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 2014 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 to 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 2534 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%). Animal Data In a fertility and reproduction study, male rats were subcutaneously dosed for 9 weeks and females for 2 weeks prior to pairing and throughout the mating period. Females were dosed up until weaning of their offspring. Budesonide caused a decrease in prenatal viability and viability in the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at doses 0.2 times the MRHDID (on a mcg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and above). No such effects were noted at a dose 0.05 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 5 mcg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities at doses 0.5 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 25 mcg/kg/day). In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-15, budesonide produced similar adverse fetal effects at doses approximately 5 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 500 mcg/kg/day). In another embryo-fetal development study in pregnant rats, no structural abnormalities or embryocidal effects were seen at doses approximately 2 times the MRHDID (on a mcg/m 2 basis at maternal inhalation doses up to 250 mcg/kg/day). In a peri-and post-natal development study, rats dosed from gestation day 15 to postpartum day 21, budesonide had no effects on delivery, but did have an effect on growth and development of offspring. Offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation at doses less than 0.2 times the MRHDID and higher (on a mcg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity. 8.2 Lactation Risk Summary There are no available data on the effects of PULMICORT RESPULES on the breastfed child or on milk production. Budesonide, like other inhaled corticosteroids, is present in human milk [see Data] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PULMICORT RESPULES and any potential adverse effects on the breastfed infant from PULMICORT RESPULES or from the underlying maternal condition. Data Human 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 (12.3) ] . 8.4 Pediatric Use Safety and effectiveness in children six months to 12 months of age has been evaluated but not established. Safety and effectiveness in children 12 months to 8 years of age have been established [see Clinical Pharmacology (12.2) , Adverse Reactions (6.1) ] . A 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 PULMICORT RESPULES or placebo once daily. Adrenal-axis function was assessed with an ACTH stimulation test at the beginning and end of the study, and mean changes from baseline in this variable did not indicate adrenal suppression in patients who received PULMICORT RESPULES versus placebo. However, on an individual basis, 7 patients in this study (6 in the PULMICORT RESPULES treatment arms and 1 in the placebo arm) experienced a shift from having a normal baseline stimulated cortisol level to having a subnormal level at Week 12 [see Clinical Pharmacology (12.2) ] . Pneumonia was observed more frequently in patients treated with PULMICORT RESPULES than in patients treated with placebo, (N = 2, 1, and 0) in the PULMICORT RESPULES 0.5 mg, 1 mg, and placebo groups, respectively. A dose dependent effect on growth was also noted in this 12-week trial. Infants in the placebo arm experienced an average growth of 3.7 cm over 12 weeks compared with 3.5 cm and 3.1 cm in the PULMICORT RESPULES 0.5 mg and 1 mg arms respectively. This corresponds to estimated mean (95% CI) reductions in 12-week growth velocity between placebo and PULMICORT RESPULES 0.5 mg of 0.2 cm (-0.6 to 1.0) and between placebo and PULMICORT RESPULES 1 mg of 0.6 cm (-0.2 to 1.4). These findings support that the use of PULMICORT RESPULES in infants 6 to 12 months of age may result in systemic effects and are consistent with findings of growth suppression in other studies with inhaled corticosteroids. Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately one centimeter per year (range 0.3 to 1.8 cm per year) and appears to be related to dose and duration of exposure. 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 budesonide administered via a dry powder inhaler 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 the 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 growth of pediatric patients receiving inhaled corticosteroids, including PULMICORT RESPULES, 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 inhaled corticosteroids, including PULMICORT RESPULES, each patient should be titrated to his/her lowest effective dose [see Dosage and Administration (2) , Warnings and Precautions (5.8) ] . 8.5 Geriatric Use Of the 215 patients in 3 clinical trials of PULMICORT RESPULES in adult patients, 65 (30%) were 65 years of age or older, while 22 (10%) were 75 years of age or older. No overall differences in safety were observed between these patients and younger patients, and other reported clinical or medical surveillance experience has not identified differences in responses between the elderly and younger patients. 8.6 Hepatic Impairment Formal pharmacokinetic studies using PULMICORT RESPULES 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.

16 HOW SUPPLIED/STORAGE AND HANDLING PULMICORT RESPULES is supplied in sealed aluminum foil envelopes containing one plastic strip of five single-dose RESPULES ampules together with patient instructions for use. There are 30 RESPULES ampules in a carton. Each single-dose RESPULES ampule contains 2 mL of sterile liquid suspension. PULMICORT RESPULES is available in three strengths, each containing 2 mL: NDC 0186–1988–04 0.25 mg/2 mL NDC 0186–1989–04 0.5 mg/2 mL NDC 0186–1990–04 1 mg/2 mL PULMICORT RESPULES should be stored upright at controlled room temperature 20-25°C (68-77°F) [see USP], and protected from light. When an envelope has been opened, the shelf life of the unused RESPULES ampules is 2 weeks when protected. After opening the aluminum foil envelope, the unused RESPULES ampules should be returned to the aluminum foil envelope to protect them from light. Any opened RESPULES ampule must be used promptly. Gently shake the RESPULES ampule using a circular motion before use. Keep out of reach of children. Do not freeze.