Breztri

1 INDICATIONS AND USAGE BREZTRI AEROSPHERE is a combination of budesonide, an inhaled corticosteroid (ICS); glycopyrrolate, an anticholinergic; and formoterol fumarate, a long-acting beta 2 -adrenergic agonist (LABA), indicated for: • the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adult patients. ( 1.1 ) • the maintenance treatment of asthma in adult and pediatric patients 12 years of age and older. ( 1.2 ) Limitations of Use: Not indicated for the relief of acute bronchospasm. ( 1.3 , 5.1 , 5.2 ) 1.1 Maintenance Treatment of Chronic Obstructive Pulmonary Disease BREZTRI AEROSPHERE is indicated for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adult patients. 1.2 Maintenance Treatment of Asthma BREZTRI AEROSPHERE is indicated for the maintenance treatment of asthma in adult and pediatric patients 12 years of age and older. 1.3 Limitations of Use BREZTRI AEROSPHERE is not indicated for the relief of acute bronchospasm [see Warnings and Precautions (5.1 , 5.2) ] .

2 DOSAGE AND ADMINISTRATION • For oral inhalation only. ( 2 ) • Prime BREZTRI AEROSPHERE before first time use and re-prime if not used for more than 7 days. ( 2.1 ) • Maintenance treatment of COPD: 2 inhalations of BREZTRI AEROSPHERE 160 mcg/9 mcg/4.8 mcg twice daily administered by oral inhalation. ( 2.2 ) • Maintenance treatment of asthma: 2 inhalations of BREZTRI AEROSPHERE 160 mcg/18 mcg/4.8 mcg twice daily administered by oral inhalation. ( 2.3 ) 2.1 Preparation and Administration Information BREZTRI AEROSPHERE should be administered as 2 inhalations twice daily, in the morning and in the evening, by oral inhalation. Do not take more than two inhalations twice daily. After inhalation, rinse mouth with water without swallowing [see Warnings and Precautions (5.4) ] . Priming Before Use Priming BREZTRI AEROSPHERE is essential to ensure appropriate drug content in each actuation. Prime BREZTRI AEROSPHERE before using for the first time. Prime BREZTRI AEROSPHERE by releasing 4 sprays into the air away from the face, shaking well before each spray. Re-prime BREZTRI AEROSPHERE if the inhaler has not been used for more than 7 days, is dropped, or after weekly rinsing. Prime BREZTRI AEROSPHERE by releasing 2 sprays into the air away from the face, shaking well before each spray. Dose counter BREZTRI AEROSPHERE canister has an attached dose indicator (also known as puff indicator), which indicates how many inhalations (puffs) remain. The dose indicator display has a pointer which will move after every actuation. When nearing the end of the usable inhalations, the pointer is in the yellow zone. BREZTRI AEROSPHERE should be discarded when the pointer is at zero in the red zone of the dose indicator. 2.2 Recommended Dosage for Maintenance Treatment of Chronic Obstructive Pulmonary Disease The recommended dosage of BREZTRI AEROSPHERE for treatment of COPD is budesonide 320 mcg, glycopyrrolate 18 mcg, and formoterol fumarate 9.6 mcg (administered as 2 inhalations of BREZTRI AEROSPHERE 160 mcg/9 mcg/4.8 mcg [budesonide 160 mcg, glycopyrrolate 9 mcg, and formoterol fumarate 4.8 mcg]) twice daily, in the morning and in the evening, by oral inhalation. 2.3 Recommended Dosage for Maintenance Treatment of Asthma The recommended dosage of BREZTRI AEROSPHERE for maintenance treatment of asthma is budesonide 320 mcg, glycopyrrolate 36 mcg, and formoterol fumarate 9.6 mcg (administered as 2 inhalations of BREZTRI AEROSPHERE 160 mcg/18 mcg/4.8 mcg [budesonide 160 mcg, glycopyrrolate 18 mcg, and formoterol fumarate 4.8 mcg]) twice daily, in the morning and in the evening, by oral inhalation. 2.1 Preparation and Administration Information BREZTRI AEROSPHERE should be administered as 2 inhalations twice daily, in the morning and in the evening, by oral inhalation. Do not take more than two inhalations twice daily. After inhalation, rinse mouth with water without swallowing [see Warnings and Precautions (5.4) ] . Priming Before Use Priming BREZTRI AEROSPHERE is essential to ensure appropriate drug content in each actuation. Prime BREZTRI AEROSPHERE before using for the first time. Prime BREZTRI AEROSPHERE by releasing 4 sprays into the air away from the face, shaking well before each spray. Re-prime BREZTRI AEROSPHERE if the inhaler has not been used for more than 7 days, is dropped, or after weekly rinsing. Prime BREZTRI AEROSPHERE by releasing 2 sprays into the air away from the face, shaking well before each spray. Dose counter BREZTRI AEROSPHERE canister has an attached dose indicator (also known as puff indicator), which indicates how many inhalations (puffs) remain. The dose indicator display has a pointer which will move after every actuation. When nearing the end of the usable inhalations, the pointer is in the yellow zone. BREZTRI AEROSPHERE should be discarded when the pointer is at zero in the red zone of the dose indicator. 2.2 Recommended Dosage for Maintenance Treatment of Chronic Obstructive Pulmonary Disease The recommended dosage of BREZTRI AEROSPHERE for treatment of COPD is budesonide 320 mcg, glycopyrrolate 18 mcg, and formoterol fumarate 9.6 mcg (administered as 2 inhalations of BREZTRI AEROSPHERE 160 mcg/9 mcg/4.8 mcg [budesonide 160 mcg, glycopyrrolate 9 mcg, and formoterol fumarate 4.8 mcg]) twice daily, in the morning and in the evening, by oral inhalation. 2.3 Recommended Dosage for Maintenance Treatment of Asthma The recommended dosage of BREZTRI AEROSPHERE for maintenance treatment of asthma is budesonide 320 mcg, glycopyrrolate 36 mcg, and formoterol fumarate 9.6 mcg (administered as 2 inhalations of BREZTRI AEROSPHERE 160 mcg/18 mcg/4.8 mcg [budesonide 160 mcg, glycopyrrolate 18 mcg, and formoterol fumarate 4.8 mcg]) twice daily, in the morning and in the evening, by oral inhalation.

3 DOSAGE FORMS AND STRENGTHS Inhalation aerosol: a pressurized metered dose inhaler with an attached dose indicator, a yellow plastic actuator, a white mouthpiece, and a grey plastic dust cap that delivers a combination of: • 160 mcg/9 mcg/4.8 mcg (budesonide 160 mcg, glycopyrrolate 9 mcg, and formoterol fumarate 4.8 mcg) per inhalation. • 160 mcg/18 mcg/4.8 mcg (budesonide 160 mcg, glycopyrrolate 18 mcg, and formoterol fumarate 4.8 mcg) per inhalation. Inhalation aerosol: Pressurized metered dose inhaler with a combination of: • 160 mcg/9 mcg/4.8 mcg (budesonide 160 mcg, glycopyrrolate 9 mcg, and formoterol fumarate 4.8 mcg) per inhalation. ( 3 ) • 160 mcg/18 mcg/4.8 mcg (budesonide 160 mcg, glycopyrrolate 18 mcg, and formoterol fumarate 4.8 mcg) per inhalation. ( 3 )

4 CONTRAINDICATIONS BREZTRI AEROSPHERE is contraindicated in the following conditions: • Primary treatment of status asthmaticus or other acute episodes of COPD or asthma where intensive measures are required [see Warnings and Precautions (5.2) ] . • Hypersensitivity to budesonide, glycopyrrolate, formoterol, or any of the excipients [see Warnings and Precautions (5.11) and Description (11) ] . • Primary treatment of status asthmaticus or other acute episodes of asthma or COPD requiring intensive measures. ( 4 ) • Hypersensitivity to budesonide, glycopyrrolate, formoterol fumarate, or to any of the excipients. ( 4 )

5 WARNINGS AND PRECAUTIONS • LABA as monotherapy (without an inhaled-corticosteroid) is associated with an increased risk of serious asthma-related events. ( 5.1 ) • Do not initiate in acutely deteriorating COPD or asthma. Do not use to relieve acute symptoms. ( 5.2 ) • Do not use in combination with an additional therapy containing a LABA because of the risk of overdose. ( 5.3 ) • Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 ) • Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. ( 5.5 ) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; 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. ( 5.6 ) • Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREZTRI AEROSPHERE. ( 5.7 ) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, consider appropriate therapy. ( 5.8 ) • If paradoxical bronchospasm occurs, discontinue BREZTRI AEROSPHERE and institute alternative therapy. ( 5.10 ) • Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.12 ) • Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.13 ) • Monitor growth in pediatric patients. ( 5.14 ) • Glaucoma and cataracts may occur with long-term use of ICS. Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to contact a healthcare provider immediately if symptoms occur. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use BREZTRI AEROSPHERE long term. ( 5.15 ) • Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to contact a healthcare provider immediately if symptoms occur. ( 5.16 ) • Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.17 ) • Be alert to hypokalemia and hyperglycemia. ( 5.18 ) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death Use of long-acting beta 2 -adrenergic agonists (LABA) as monotherapy [without inhaled corticosteroid (ICS)] for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When a LABA is used in fixed‑dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone (see Serious Asthma-Related Events with ICS/LABA) . Available data do not suggest an increased risk of death with use of LABA in patients with COPD. Serious Asthma-Related Events with ICS/LABA Four large, 26-week, randomized, blinded, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared to ICS alone in patients with asthma. Three trials included adult and adolescent patients aged ≥12 years: one trial compared budesonide/formoterol to budesonide; one trial compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder; and one trial compared mometasone furoate/formoterol to mometasone furoate. The fourth trial included pediatric patients 4 to 11 years of age and compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder. BREZTRI AEROSPHERE is not indicated for patients 4 to 11 years of age. The primary safety endpoint for all four trials was serious asthma‑related events (hospitalizations, intubations and death). A blinded adjudication committee determined whether events were asthma-related. The three adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk of 2.7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the three adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS. Table 1: Meta-analysis of Serious Asthma-Related Events in Patients with Asthma Aged 12 Years and Older ICS/LABA (N=17,537) Randomized patients who had taken at least 1 dose of study drug. Planned treatment used for analysis. ICS (N=17,552) ICS/LABA vs ICS Hazard ratio (95% CI) Estimated using a Cox proportional hazards model of time to first event with baseline hazards stratified by each of the 3 trials. Serious asthma-related event Number of patients with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Patients can have one or more events, but only the first event was counted for analysis. A single, blinded, independent adjudication committee determined whether events were asthma-related. 116 105 1.10 (0.85, 1.44) Asthma-related death 2 0 Asthma-related intubation (endotracheal) 1 2 Asthma-related hospitalization (≥24-hour stay) 115 105 ICS=Inhaled Corticosteroid, LABA=Long-acting Beta2-adrenergic Agonist The pediatric safety trial included 6208 pediatric patients 4 to 11 years of age who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3107 (0.9%) patients randomized to ICS/LABA and 21/3101 (0.7%) patients randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared to ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27). BREZTRI AEROSPHERE is not indicated for use in pediatric patients aged 11 years and younger. Salmeterol Multicenter Asthma Research Trial (SMART) A 28-week, placebo-controlled U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; relative risk: 4.37 [95% CI 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy. 5.2 Deterioration of Disease and Acute Episodes BREZTRI AEROSPHERE should not be initiated in patients with acutely deteriorating COPD or asthma, which may be a life-threatening condition. BREZTRI AEROSPHERE has not been studied in patients with acutely deteriorating COPD or asthma. The use of BREZTRI AEROSPHERE in this setting is not appropriate. Increasing use of inhaled, short-acting beta 2 -agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate re-evaluation with reassessment of the treatment regimen, giving special consideration to the possible need for additional therapeutic options. Patients should not use more than 2 inhalations twice daily (morning and evening) of BREZTRI AEROSPHERE. BREZTRI AEROSPHERE should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREZTRI AEROSPHERE has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with either an inhaled short-acting beta 2 -agonist/corticosteroid combination (asthma only) or an inhaled short-acting beta 2 -agonist (COPD or asthma). When beginning treatment with BREZTRI AEROSPHERE, patients who have been taking inhaled, short‑acting beta 2 ‑agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREZTRI AEROSPHERE, the healthcare provider should also prescribe either an inhaled short-acting beta 2 ‑agonist/corticosteroid combination (asthma only) or an inhaled, short acting beta 2 ‑agonist (COPD or asthma) and instruct the patient on how it should be used. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREZTRI AEROSPHERE no longer controls symptoms, or the patient’s inhaled, short-acting beta 2 -agonist becomes less effective or the patient needs more inhalations of short-acting beta 2 -agonist than usual, these may be markers of deterioration of disease. In this setting, re-evaluate the patient and the COPD treatment regimen at once. The daily dosage of BREZTRI AEROSPHERE should not be increased beyond the recommended dose. 5.3 Avoid Excessive Use of BREZTRI AEROSPHERE and Avoid Use with other Long-Acting Beta 2 -Agonists As with other inhaled drugs containing beta 2 -adrenergic agents, BREZTRI AEROSPHERE should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREZTRI AEROSPHERE should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason [see Drug Interactions (7.1) ]. 5.4 Oropharyngeal Candidiasis BREZTRI AEROSPHERE contains budesonide, an ICS. Localized infections of the mouth and pharynx with Candida albicans have occurred in subjects treated with orally inhaled drug products containing budesonide. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREZTRI AEROSPHERE continues. In some cases, therapy with BREZTRI AEROSPHERE may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following administration of BREZTRI AEROSPHERE to help reduce the risk of oropharyngeal candidiasis. 5.5 Pneumonia Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap. In a 52-week trial of subjects with COPD (n = 8,529), the incidence of confirmed pneumonia was 4.2% for BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg (n = 2144), 3.5% for budesonide, glycopyrrolate and formoterol fumarate [BGF MDI 160 mcg/18 mcg/9.6 mcg] (n = 2124), 2.3% for GFF MDI 18 mcg/9.6 mcg (n = 2125) and 4.5% for BFF MDI 320 mcg/9.6 mcg (n = 2136). Fatal cases of pneumonia occurred in 2 subjects receiving BGF MDI 160 mcg/18 mcg/9.6 mcg, 3 subjects receiving GFF MDI 18 mcg/9.6 mcg, and no subjects receiving BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg. In a 24-week trial of subjects with COPD (n = 1,896), the incidence of confirmed pneumonia was 1.9% for BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg (n = 639), 1.6% for glycopyrrolate and formoterol fumarate [GFF MDI 18 mcg/9.6 mcg] (n = 625) and 1.9% for budesonide and formoterol fumarate [BFF MDI 320 mcg/9.6 mcg] (n = 320). There were no fatal cases of pneumonia in the study. 5.6 Immunosuppression and Risk of Infections Patients who are using 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 such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration 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 a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see the Prescribing Information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered. ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.7 Transferring Patients from Systemic Corticosteroid Therapy HPA Suppression/Adrenal Insufficiency Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients during and after transfer from systemic corticosteroids to less systemically available ICS. 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 BREZTRI AEROSPHERE may provide control of COPD or 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, a severe COPD or asthma exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their healthcare practitioner for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe COPD or asthma exacerbation. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREZTRI AEROSPHERE. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREZTRI AEROSPHERE. Lung function (forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [PEF]), beta-agonist use, and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Unmasking of Allergic Conditions Previously Suppressed by Systemic Corticosteroids Transfer of patients from systemic corticosteroid therapy to BREZTRI AEROSPHERE may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Corticosteroid Withdrawal Symptoms During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function. 5.8 Hypercorticism and Adrenal Suppression Inhaled budesonide is absorbed into the circulation and can be systemically active. Effects of budesonide on the HPA axis are not observed with the therapeutic doses of budesonide in BREZTRI AEROSPHERE. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9) and Drug Interactions (7.1) ] . Because of the possibility of significant systemic absorption of ICS, patients treated with BREZTRI AEROSPHERE should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects, such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, appropriate therapy should be initiated as needed. 5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of BREZTRI AEROSPHERE with long-term ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . 5.10 Paradoxical Bronchospasm As with other inhaled therapies, BREZTRI AEROSPHERE can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs following dosing with BREZTRI AEROSPHERE, it should be treated immediately with an inhaled, short-acting bronchodilator; BREZTRI AEROSPHERE should be discontinued immediately and alternative therapy should be instituted. 5.11 Hypersensitivity Reactions including Anaphylaxis Immediate hypersensitivity reactions have been reported after administration of budesonide, glycopyrrolate or formoterol fumarate, the components of BREZTRI AEROSPHERE. If signs suggesting allergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing, swelling of tongue, lips, and face), urticaria, or skin rash, BREZTRI AEROSPHERE should be stopped at once and alternative treatment should be considered [see Contraindications (4) ] . 5.12 Cardiovascular Effects Formoterol fumarate, like other beta 2 -agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles [see Clinical Pharmacology (12.2) ] . If such effects occur, BREZTRI AEROSPHERE may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Therefore, BREZTRI AEROSPHERE should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREZTRI AEROSPHERE and periodically thereafter. If significant reductions in BMD are seen and BREZTRI AEROSPHERE is still considered medically important for that patient's COPD therapy, use of therapy to treat or prevent osteoporosis should be strongly considered. In a subset of COPD patients in a 24-week trial with a 28-week safety extension that evaluated BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg and GFF MDI 18 mcg/9.6 mcg, the effects on BMD endpoints were evaluated. BMD evaluations were performed at baseline and 52-weeks using dual energy x-ray absorptiometry (DEXA) scans. Mean percent changes in BMD from baseline was -0.1% for BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg and 0.4% for GFF MDI 18 mcg/9.6 mcg [see Clinical Studies (14.1) ]. 5.14 Effect on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving BREZTRI AEROSPHERE routinely (e.g., via stadiometry) [see Use in Specific Populations (8.4) ] . 5.15 Glaucoma and Cataracts, Worsening of Narrow-Angle Glaucoma Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of ICS or with use of inhaled anticholinergics. BREZTRI AEROSPHERE should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use BREZTRI AEROSPHERE long term. In a 52-week trial that evaluated BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg, GFF MDI 18 mcg/9.6 mcg, and BFF MDI 320 mcg/9.6 mcg in subjects with COPD, the incidence of cataracts ranged from 0.7% to 1.0% across groups. 5.16 Worsening of Urinary Retention BREZTRI AEROSPHERE, like all therapies containing an anticholinergic, should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop. 5.17 Coexisting Conditions BREZTRI AEROSPHERE, like all therapies containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta 2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.18 Hypokalemia and Hyperglycemia Beta-adrenergic agonists may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Beta 2 -agonist therapies may produce transient hyperglycemia in some patients.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Serious asthma-related events – hospitalizations, intubations, death [see Warnings and Precautions (5.1) ] • Oropharyngeal candidiasis infection [see Warnings and Precautions (5.4) ] • Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5) ] • Immunosuppression and risk of infections [see Warnings and Precautions (5.6) ] • Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8) ] • Paradoxical bronchospasm [see Warnings and Precautions (5.10) ] • Hypersensitivity reactions including anaphylaxis [see Contraindications (4) and Warnings and Precautions (5.11) ] • Cardiovascular effects [see Warnings and Precautions (5.12) ] • Reduction in bone mineral density [see Warnings and Precautions (5.13) ] • Growth effects in pediatric patients [see Warnings and Precautions (5.14) ] • Worsening of narrow-angle glaucoma and cataracts [see Warnings and Precautions (5.15) ] • Worsening of urinary retention [see Warnings and Precautions (5.16) ] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. • COPD: Most common adverse reactions (incidence ≥ 2%) are upper respiratory tract infection, pneumonia, back pain, oral candidiasis, influenza, muscle spasm, urinary tract infection, cough, sinusitis and diarrhea. ( 6.1 ) • Asthma: Most common adverse reactions (incidence ≥ 2%) are nasopharyngitis, pneumonia, and headache. ( 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 Chronic Obstructive Pulmonary Disease The safety of BREZTRI AEROSPHERE in COPD is based on the safety data from one 52-week exacerbation trial (ETHOS) and one 24-week lung function trial with a 28-week safety extension study, resulting in up to 52 weeks of treatment (KRONOS). In ETHOS and KRONOS, a total of 2783 subjects have received at least 1 dose of BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg [see Clinical Studies (14.1) ]. In ETHOS and KRONOS, subjects received one of the following treatments: BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg, glycopyrrolate and formoterol fumarate (GFF MDI 18 mcg/9.6 mcg), or budesonide and formoterol fumarate (BFF MDI 320 mcg/9.6 mcg). Each treatment was administered twice daily. In ETHOS, a 52-week, randomized, double-blind clinical trial, a total of 2144 subjects with COPD received at least 1 dose of BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg (mean age: 64.7 years, 84.9% Caucasian, 59.7% male across all treatments) [see Clinical Studies (14.1) ] . In KRONOS, a 24-week, randomized, double-blind clinical trial, with a 28-week long-term safety extension resulting in up to 52 weeks of treatment, a total of 639 subjects received at least 1 dose of BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg (mean age: 65.2 years, 50.1% Caucasian, 71.2% male across all treatments) [see Clinical Studies (14.1) ] . The incidence of adverse reactions from the 52-week trial (ETHOS) is presented in Table 2 for subjects treated with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg, GFF MDI 18 mcg/9.6 mcg, or BFF MDI 320 mcg/9.6 mcg. Table 2: Adverse Reactions Occurring at an Incidence of ≥ 2% of Subjects with COPD and More Common in BREZTRI AEROSPHERE Compared to GFF MDI and/or BFF MDI (ETHOS) Adverse Reaction BREZTRI AEROSPHERE BREZTRI AEROSPHERE = budesonide/glycopyrrolate/formoterol fumarate 320 mcg/18 mcg/9.6 mcg; GFF MDI = glycopyrrolate/formoterol fumarate 18 mcg/9.6 mcg; BFF MDI = budesonide/formoterol fumarate 320 mcg/9.6 mcg; all treatments were administered twice daily. 320 mcg/18 mcg/9.6 mcg N=2144 (%) GFF MDI 18 mcg/9.6 mcg N=2125 (%) BFF MDI 320 mcg/9.6 mcg N=2136 (%) Upper Respiratory Tract Infection 123 (5.7) 102 (4.8) 115 (5.4) Pneumonia 98 (4.6) 61 (2.9) 107 (5.0) Back pain 67 (3.1) 55 (2.6) 64 (3.0) Oral candidiasis 65 (3.0) 24 (1.1) 57 (2.7) Influenza 63 (2.9) 42 (2.0) 61 (2.9) Muscle spasms 60 (2.8) 19 (0.9) 53 (2.5) Urinary tract infection 58 (2.7) 60 (2.8) 41 (1.9) Cough 58 (2.7) 50 (2.4) 51 (2.4) Sinusitis 56 (2.6) 47 (2.2) 55 (2.6) Diarrhea 44 (2.1) 37 (1.7) 38 (1.8) In 24-week data from KRONOS, adverse reactions that occurred in subjects treated with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg (n=639) at an incidence of ≥ 2% included dysphonia (3.1%) and muscle spasms (3.3%). Asthma The safety of BREZTRI AEROSPHERE for the maintenance treatment of asthma is based on the pooled safety data from two, 24 to 52-week, clinical trials (KALOS and LOGOS) [see Clinical Studies (14.2) ] . In the KALOS and LOGOS pooled safety population, a total of 1179 subjects with asthma received at least one dose of BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg. The mean duration of exposure to BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg twice daily was 45 weeks, with 678 (57%) subjects treated for at least 52 weeks. The incidence of adverse reactions (≥ 2%) from the 24 to 52-week trials (KALOS and LOGOS) is presented in Table 3 for subjects treated with BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg or BFF MDI 320 mcg/9.6 mcg. Table 3: Adverse Reactions with BREZTRI AEROSPHERE with an Incidence of ≥ 2% of Subjects with Asthma and More Common than with BFF MDI (KALOS and LOGOS) Adverse Reaction BREZTRI AEROSPHERE BREZTRI AEROSPHERE=budesonide/glycopyrrolate/formoterol fumarate 320 mcg/36 mcg/9.6 mcg; BFF MDI=budesonide/formoterol fumarate 320 mcg/9.6 mcg; all treatments were administered twice daily. 320 mcg/36 mcg/9.6 mcg N=1179 (%) BFF MDI 320 mcg/9.6 mcg N=1208 (%) Nasopharyngitis 111 (9.4) 101 (8.4) Pneumonia Consists of pneumonia, pneumonia bacterial, pneumonia fungal, pneumonia mycoplasma, pneumonia pneumococcal, pneumonia viral. 33 (2.8) 27 (2.2) Headache 26 (2.2) 15 (1.2) Additional Adverse Reactions Other adverse reactions that have been associated with one or more of the individual components of BREZTRI AEROSPHERE include: gastroesophageal reflux disease, dysphonia, oropharyngeal pain, renal and urinary tract infection, hyperglycemia, anxiety, insomnia, palpitations, nausea, hypersensitivity, depression, agitation, restlessness, nervousness, tremor, dizziness, angina pectoris, tachycardia, cardiac arrhythmias (e.g., atrial fibrillation, supraventricular tachycardia, and extrasystoles), throat irritation, bronchospasm, dry mouth, bruising, urinary retention, chest pain, sign or symptoms of systemic glucocorticoid steroid effects (e.g., hypofunctional adrenal gland), and abnormal behavior.

16 HOW SUPPLIED/STORAGE AND HANDLING BREZTRI AEROSPHERE Inhalation Aerosol: • is supplied as a pressurized aluminum canister with an attached dose indicator, a yellow plastic actuator, a white mouthpiece, and a grey plastic dust cap. • each canister of BREZTRI AEROSPHERE is packaged in a foil laminate pouch with a desiccant sachet and is placed into a carton. • each carton contains one canister and Patient Information. BREZTRI AEROSPHERE is available as presented in Table 7. Table 7: Package Information for BREZTRI AEROSPHERE Strength (budesonide/glycopyrrolate/formoterol fumarate) Number of Inhalations per Canister Net Fill Weight (g) NDC 160 mcg/9 mcg/4.8 mcg 120 10.7 0310-4616-12 160 mcg/9 mcg/4.8 mcg (institutional pack) 28 5.9 0310-4616-39 160 mcg/18 mcg/4.8 mcg 120 10.7 0310-6616-01 160 mcg/18 mcg/4.8 mcg (institutional pack) 28 5.9 0310-6616-39 The BREZTRI AEROSPHERE canister should only be used with the BREZTRI AEROSPHERE actuator, and the BREZTRI AEROSPHERE actuator should not be used with any other inhalation drug product. Dose Counter The correct amount of medication in each inhalation cannot be assured after the label number of inhalations from the canister have been used, when the dose indicator pointer is at zero in the red zone, even though the canister may not feel completely empty. BREZTRI AEROSPHERE should be discarded when the dose indicator pointer is at zero in the red zone or 3 months (for the 120-inhalation canister) or 3 weeks (for the 28-inhalation canister) after removal from the foil pouch, whichever comes first. Never immerse the canister into water to determine the amount remaining in the canister (“float test”). Storage Store at controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP]. Keep in a dry place away from heat and sunlight. For best results, the canister should be at room temperature before use. Shake well before using. Keep out of reach of children. Contents under pressure. Do not puncture. Do not use or store near heat or open flames. Exposure to temperatures above 120°F (49°C) may cause bursting. Never throw canister into fire or incinerator. Avoid spraying in eyes.