<?xml version="1.0" encoding="UTF-8"?><section ID="ID_ae0da34e-3fe1-4aa6-9c9a-636445464a10">
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<title>5 WARNINGS AND PRECAUTIONS </title>
<effectiveTime value="20220126"/>
<excerpt>
<highlight>
<text>
<list listType="unordered">
<item>
<caption>•</caption>LABA as monotherapy (without an inhaled-corticosteroid) is associated with an increased risk of serious asthma-related events. <linkHtml href="#ID_dd402fd5-90bb-49bc-b3d5-dd0447747fae">(5.1)</linkHtml>
</item>
<item>
<caption>•</caption>Do not initiate in acutely deteriorating COPD. Do not use to relieve acute symptoms. <linkHtml href="#ID_7eb68c23-e515-43a4-bae9-30a962d4cb0c">(5.2)</linkHtml>
</item>
<item>
<caption>•</caption>Do not use in combination with an additional therapy containing a LABA because of the risk of overdose. <linkHtml href="#ID_c8a2f965-e64e-4534-b947-ee781f942031">(5.3)</linkHtml>
</item>
<item>
<caption>•</caption>
<content styleCode="italics">Candida albicans</content> 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. <linkHtml href="#ID_caf8216d-58e4-4644-8663-5d5f9588cbd9">(5.4)</linkHtml>
</item>
<item>
<caption>•</caption>Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. <linkHtml href="#ID_0f08c8da-8d80-4e93-8517-37aa9656fca2">(5.5)</linkHtml>
</item>
<item>
<caption>•</caption>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. <linkHtml href="#ID_7c9c2bb5-c1e2-4545-80d4-28b12f75f141">(5.6)</linkHtml>
</item>
<item>
<caption>•</caption>Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREZTRI AEROSPHERE. <linkHtml href="#ID_41dc0685-68a8-45e9-81d0-69e5bf769b77">(5.7)</linkHtml>
</item>
<item>
<caption>•</caption>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. <linkHtml href="#ID_f09d5c93-a024-4475-bd62-f5d020996751">(5.8)</linkHtml>
</item>
<item>
<caption>•</caption>If paradoxical bronchospasm occurs, discontinue BREZTRI AEROSPHERE and institute alternative therapy. <linkHtml href="#ID_435dc595-3ed5-49b9-9500-1449be38ad1a">(5.10)</linkHtml>
</item>
<item>
<caption>•</caption>Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. <linkHtml href="#ID_89d0a77f-8395-4490-9edc-6852191cb472">(5.12)</linkHtml>
</item>
<item>
<caption>•</caption>Assess for decrease in bone mineral density initially and periodically thereafter. <linkHtml href="#ID_7c24b6c1-82ec-440f-ae95-f4643ec187d7">(5.13)</linkHtml>
</item>
<item>
<caption>•</caption>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. <linkHtml href="#ID_f68c5100-c44e-4047-8339-5cc8d4aaf362">(5.14)</linkHtml>
</item>
<item>
<caption>•</caption>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. <linkHtml href="#ID_681ddc4e-cb52-4ad4-bdb8-d59f52b923e8">(5.15)</linkHtml>
</item>
<item>
<caption>•</caption>Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. <linkHtml href="#ID_910c7b89-3778-4eda-b28c-bfc7ffb7d82f">(5.16)</linkHtml>
</item>
<item>
<caption>•</caption>Be alert to hypokalemia and hyperglycemia. <linkHtml href="#ID_a720db62-6e2e-4b09-9287-89d41594d1eb">(5.17)</linkHtml>
</item>
</list>
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</excerpt>
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<title>5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death </title>
<text>
<paragraph>The safety and efficacy of BREZTRI AEROSPHERE in patients with asthma have not been established. BREZTRI AEROSPHERE is not indicated for the treatment of asthma. </paragraph>
<paragraph>Use of long-acting beta<sub>2</sub>-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.</paragraph>
<paragraph>Available data do not suggest an increased risk of death with use of LABA in patients with COPD.</paragraph>
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<title>5.2 Deterioration of Disease and Acute Episodes </title>
<text>
<paragraph>BREZTRI AEROSPHERE should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. BREZTRI AEROSPHERE has not been studied in patients with acutely deteriorating COPD. The use of BREZTRI AEROSPHERE in this setting is not appropriate.</paragraph>
<paragraph>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 an inhaled short-acting beta<sub>2</sub>-agonist.</paragraph>
<paragraph>When beginning treatment with BREZTRI AEROSPHERE, patients who have been taking inhaled, short-acting beta<sub>2</sub>-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 an inhaled, short acting beta<sub>2</sub>-agonist and instruct the patient on how it should be used. Increasing inhaled beta<sub>2</sub>-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. </paragraph>
<paragraph>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<sub>2</sub>-agonist becomes less effective or the patient needs more inhalations of short-acting beta<sub>2</sub>-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.</paragraph>
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<title>5.3 Avoid Excessive Use of BREZTRI AEROSPHERE and Avoid Use with other Long-Acting Beta<sub>2</sub>-Agonists </title>
<text>
<paragraph>As with other inhaled drugs containing beta<sub>2</sub>-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 <content styleCode="italics">[see <linkHtml href="#ID_98434b7b-de57-43de-b640-0630f032b802">Drug Interactions (7.1)</linkHtml>].</content>
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<effectiveTime value="20200723"/>
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<title>5.4 Oropharyngeal Candidiasis </title>
<text>
<paragraph>BREZTRI AEROSPHERE contains budesonide, an ICS. Localized infections of the mouth and pharynx with <content styleCode="italics">Candida albicans</content> 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.</paragraph>
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<title>5.5 Pneumonia </title>
<text>
<paragraph>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. </paragraph>
<paragraph>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). </paragraph>
<paragraph>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. </paragraph>
<paragraph>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.</paragraph>
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<title>5.6 Immunosuppression and Risk of Infections </title>
<text>
<paragraph>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.</paragraph>
<paragraph>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.</paragraph>
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<effectiveTime value="20220126"/>
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<title>5.7 Transferring Patients from Systemic Corticosteroid Therapy </title>
<text>
<paragraph>
<content styleCode="underline">HPA Suppression/Adrenal Insufficiency</content>
</paragraph>
<paragraph>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.</paragraph>
<paragraph>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 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.</paragraph>
<paragraph>During periods of stress, or a severe COPD 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, or a severe COPD exacerbation.</paragraph>
<paragraph>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<sub>1</sub>] or morning peak expiratory flow [PEF]), beta-agonist use, and COPD 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.</paragraph>
<paragraph>
<content styleCode="underline">Unmasking of Allergic Conditions Previously Suppressed by Systemic Corticosteroids</content>
</paragraph>
<paragraph>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). </paragraph>
<paragraph>
<content styleCode="underline">Corticosteroid Withdrawal Symptoms</content>
</paragraph>
<paragraph>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.</paragraph>
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<title>5.8 Hypercorticism and Adrenal Suppression </title>
<text>
<paragraph>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 <content styleCode="italics">[see <linkHtml href="#ID_650a160f-e6dd-42d9-8820-62478e5b4a27">Warnings and Precautions (5.9)</linkHtml> and <linkHtml href="#ID_98434b7b-de57-43de-b640-0630f032b802">Drug Interactions (7.1)</linkHtml>]</content>. </paragraph>
<paragraph>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. </paragraph>
<paragraph>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.</paragraph>
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<title>5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors </title>
<text>
<paragraph>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 <content styleCode="italics">[see <linkHtml href="#ID_98434b7b-de57-43de-b640-0630f032b802">Drug Interactions (7.1)</linkHtml> and <linkHtml href="#ID_f79193d3-a1fa-4469-bd1e-1cfc34dd91e9">Clinical Pharmacology (12.3)</linkHtml>]</content>.</paragraph>
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<title>5.10 Paradoxical Bronchospasm </title>
<text>
<paragraph>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.</paragraph>
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<effectiveTime value="20200723"/>
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<title>5.11 Hypersensitivity Reactions including Anaphylaxis </title>
<text>
<paragraph>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 <content styleCode="italics">[see <linkHtml href="#ID_b0d10cc4-7c19-40ac-a7d3-138a419c249b">Contraindications (4)</linkHtml>]</content>.</paragraph>
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<effectiveTime value="20200723"/>
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<title>5.12 Cardiovascular Effects </title>
<text>
<paragraph>Formoterol fumarate, like other beta<sub>2</sub>-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 <content styleCode="italics">[see <linkHtml href="#ID_3ee1cc84-c617-4f84-a80a-1883f43308b8">Clinical Pharmacology (12.2)</linkHtml>]</content>. </paragraph>
<paragraph>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.</paragraph>
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<title>5.13 Reduction in Bone Mineral Density </title>
<text>
<paragraph>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.</paragraph>
<paragraph>In a subset of COPD patients in a 24-week trial with a 28-week safety extension that evaluated BREZTRI AEROSPHERE 320/18/9.6 mcg and GFF MDI 18/9.6 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 320/18/9.6 mcg and 0.4% for GFF MDI 18/9.6 mcg <content styleCode="italics">[see <linkHtml href="#ID_dbdeff2c-1690-4f13-b487-843839ed648f">Clinical Studies (14)].</linkHtml>
</content>
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<title>5.14 Glaucoma and Cataracts, Worsening of Narrow-Angle Glaucoma </title>
<text>
<paragraph>Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD 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. </paragraph>
<paragraph>In a 52-week trial that evaluated BREZTRI AEROSPHERE 320/18/9.6 mcg, GFF MDI 18/9.6 mcg, and BFF MDI 320/9.6 mcg in subjects with COPD, the incidence of cataracts ranged from 0.7% to 1.0% across groups.</paragraph>
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<title>5.15 Worsening of Urinary Retention </title>
<text>
<paragraph>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.</paragraph>
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<section ID="ID_910c7b89-3778-4eda-b28c-bfc7ffb7d82f">
<id root="910c7b89-3778-4eda-b28c-bfc7ffb7d82f"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>5.16 Coexisting Conditions </title>
<text>
<paragraph>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<sub>2</sub>-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.</paragraph>
</text>
<effectiveTime value="20200723"/>
</section>
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<component>
<section ID="ID_a720db62-6e2e-4b09-9287-89d41594d1eb">
<id root="a720db62-6e2e-4b09-9287-89d41594d1eb"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>5.17 Hypokalemia and Hyperglycemia </title>
<text>
<paragraph>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<sub>2</sub>-agonist therapies may produce transient hyperglycemia in some patients.</paragraph>
</text>
<effectiveTime value="20200723"/>
</section>
</component>
</section>
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