Breztri
budesonide, glycopyrrolate, and formoterol fumarate · Aerosol, Metered · Respiratory (inhalation)
Uses
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) ] .
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.
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 )
Contraindications
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 )
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.
Side effects
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.
Drug interactions
No formal drug interaction studies have been performed with BREZTRI AEROSPHERE.
• Strong cytochrome P450 3A4 inhibitors (e.g. ritonavir): Use with caution. May cause systemic corticosteroid effects. ( 7.1 )
• Other adrenergic drugs may potentiate effect: Use with caution. ( 7.2 )
• Diuretics, xanthine derivatives or steroids may potentiate hypokalemia or ECG changes. Use with caution. ( 7.3 , 7.4 )
• Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol fumarate on cardiovascular system. ( 7.5 )
• Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. ( 7.6 )
• Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of BREZTRI AEROSPHERE with other anticholinergic-containing drugs. ( 7.7 ) 7.1 Inhibitors of Cytochrome P450 3A4 The main route of metabolism of corticosteroids, including budesonide, a component of BREZTRI AEROSPHERE, is via cytochrome P450 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 BREZTRI AEROSPHERE 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 (5.9) ] . 7.2 Adrenergic Drugs If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of formoterol, a component of BREZTRI AEROSPHERE, may be potentiated [see Warnings and Precautions (5.3) ] . 7.3 Xanthine Derivatives, Steroids, or Diuretics Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate the hypokalemic effect of beta 2 -adrenergic agonists such as formoterol, a component of BREZTRI AEROSPHERE. 7.4 Non-Potassium Sparing Diuretics The hypokalemia and/or ECG changes that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta 2 -agonists, especially when the recommended dose of the beta 2 -agonist is exceeded. 7.5 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs BREZTRI AEROSPHERE, as with other beta 2 -agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias. 7.6 Beta-adrenergic Receptor Blocking Agents Beta-adrenergic receptor antagonists (beta-blockers) and BREZTRI AEROSPHERE may interfere with the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta 2 -agonists, but may produce severe bronchospasm in COPD and asthma patients. Therefore, patients with COPD or asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD or asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution. 7.7 Anticholinergics There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of BREZTRI AEROSPHERE with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.9 , 5.10 ) and Adverse Reactions (6.1) ]. 7.7 Anticholinergics There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of BREZTRI AEROSPHERE with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.9 , 5.10 ) and Adverse Reactions (6.1) ].
Use in specific populations
Hepatic impairment: Budesonide and formoterol fumarate systemic exposure may increase in patients with severe hepatic impairment. Monitor patients for signs of increased drug exposure. ( 8.6 , 12.3 ) Renal impairment: In patients with severe renal impairment, use should be considered only if the potential benefit of the treatment outweighs the risk ( 8.7 ). 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with BREZTRI AEROSPHERE or with two of its individual components, glycopyrrolate or formoterol fumarate, in pregnant women to inform a drug-associated risk; however, studies are available for the other component, budesonide. In animal reproduction studies, budesonide alone, administered by the subcutaneous route, caused structural abnormalities, was embryocidal, and reduced fetal weights in rats and rabbits at 0.3 and 0.75 times maximum recommended human daily inhaled dose (MRHDID), respectively, but these effects were not seen in rats that received inhaled doses up to 4 times the MRHDID. Studies of pregnant women who received inhaled budesonide alone during pregnancy have not shown increased risk of abnormalities. Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. Formoterol fumarate alone, administered by the oral route in rats and rabbits, caused structural abnormalities at 1500 and 61,000 times the MRHDID, respectively. Formoterol fumarate was also embryocidal, increased pup loss at birth and during lactation, and decreased pup weight in rats at 110 times the MRHDID. These adverse effects generally occurred at large multiples of the MRHDID when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No structural abnormalities, embryocidal, or developmental effects were seen in rats that received inhalation doses up to 350 times the MRHDID. Glycopyrrolate alone, administered by the subcutaneous route in rats and rabbits, did not cause structural abnormalities or affect fetal survival at exposures approximately 1350 and 2700 times from MRHDID, respectively. Glycopyrrolate had no effects on the physical, functional, and behavioral development of rat pups with exposures up to 1350 times the MRHDID. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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 trials that have investigated the effects of BREZTRI AEROSPHERE on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of BREZTRI AEROSPHERE during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. 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 2,534 infants whose mothers were exposed to inhaled budesonide. In this study, the rate of congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%). Animal Data Budesonide 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 of the offspring at birth and during lactation, along with a decrease in maternal body weight gain, at a dose 0.3 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 0.08 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 to 18, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities at a dose 0.75 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 25 mcg/kg/day).
Pregnancy
8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with BREZTRI AEROSPHERE or with two of its individual components, glycopyrrolate or formoterol fumarate, in pregnant women to inform a drug-associated risk; however, studies are available for the other component, budesonide. In animal reproduction studies, budesonide alone, administered by the subcutaneous route, caused structural abnormalities, was embryocidal, and reduced fetal weights in rats and rabbits at 0.3 and 0.75 times maximum recommended human daily inhaled dose (MRHDID), respectively, but these effects were not seen in rats that received inhaled doses up to 4 times the MRHDID. Studies of pregnant women who received inhaled budesonide alone during pregnancy have not shown increased risk of abnormalities. Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. Formoterol fumarate alone, administered by the oral route in rats and rabbits, caused structural abnormalities at 1500 and 61,000 times the MRHDID, respectively. Formoterol fumarate was also embryocidal, increased pup loss at birth and during lactation, and decreased pup weight in rats at 110 times the MRHDID. These adverse effects generally occurred at large multiples of the MRHDID when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No structural abnormalities, embryocidal, or developmental effects were seen in rats that received inhalation doses up to 350 times the MRHDID. Glycopyrrolate alone, administered by the subcutaneous route in rats and rabbits, did not cause structural abnormalities or affect fetal survival at exposures approximately 1350 and 2700 times from MRHDID, respectively. Glycopyrrolate had no effects on the physical, functional, and behavioral development of rat pups with exposures up to 1350 times the MRHDID. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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 trials that have investigated the effects of BREZTRI AEROSPHERE on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of BREZTRI AEROSPHERE during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. 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 2,534 infants whose mothers were exposed to inhaled budesonide. In this study, the rate of congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%). Animal Data Budesonide 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 of the offspring at birth and during lactation, along with a decrease in maternal body weight gain, at a dose 0.3 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 0.08 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 to 18, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities at a dose 0.75 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 8 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 up to 4 times the MRHDID (on a mcg/m 2 basis at maternal inhalation doses up to 250 mcg/kg/day).
Pediatric use
8.4 Pediatric Use The safety and effectiveness of BREZTRI AEROSPHERE have been established for the maintenance treatment of asthma in pediatric patients 12 years of age and older. Use of BREZTRI AEROSPHERE for this indication is supported by evidence from two adequate and well-controlled studies (KALOS and LOGOS) in adults and pediatric patients 12 years of age and older, in which 30 pediatric patients 12 years to less than 18 years of age were treated with BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg twice daily by oral inhalation [see Adverse Reactions (6.1) and Clinical Studies (14.2) ] . The safety and effectiveness of BREZTRI AEROSPHERE in pediatric patients less than 12 years of age have not been established. Controlled clinical studies have shown that ICS agents, including budesonide, one of the components of BREZTRI AEROSPHERE, may cause a reduction in growth velocity in pediatric patients. The effects of long-term treatment of pediatric patients with ICS on final adult height are not known. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained [see Warnings and Precautions (5.14) ] .
Geriatric use
8.5 Geriatric Use Based on available data, no adjustment of the dosage of BREZTRI AEROSPHERE in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. In the COPD trials, ETHOS and KRONOS, 1100 subjects and 343 subjects, respectively, aged 65 years and older were administered BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg twice daily [see Clinical Studies (14.1) ] . In both trials, no overall differences in safety or effectiveness were observed between these subjects and younger subjects. In the asthma trials, KALOS and LOGOS, 141 subjects and 124 subjects, respectively, aged 65 years and older were administered BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg twice daily [see Clinical Studies (14.2) ] . In both trials, no overall differences in safety or effectiveness were observed between these subjects and younger subjects.
Overdosage
10 OVERDOSAGE BREZTRI AEROSPHERE contains budesonide, glycopyrrolate, and formoterol fumarate; therefore, the risks associated with overdosage for the individual components described below apply to BREZTRI AEROSPHERE. Treatment of overdosage consists of discontinuation of BREZTRI AEROSPHERE together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. Cardiac monitoring is recommended in case of overdosage. Budesonide If used at excessive doses for prolonged periods, systemic corticosteroid effects, such as hypercorticism may occur [see Warnings and Precautions (5.8) ] . Glycopyrrolate High doses of glycopyrrolate, a component of BREZTRI AEROSPHERE, may lead to anticholinergic signs and symptoms such as nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular pressure (causing pain, vision disturbances or reddening of the eye), obstipation, or difficulties in voiding. Formoterol Fumarate An overdose of formoterol fumarate would likely lead to an exaggeration of effects that are typical for beta 2 -agonists: seizures, angina, hypertension, hypotension, tachycardia, atrial and ventricular tachyarrhythmias, nervousness, headache, tremor, palpitations, muscle cramps, nausea, dizziness, sleep disturbances, metabolic acidosis, hyperglycemia, hypokalemia. As with all sympathomimetic medications, cardiac arrest, and even death may be associated with overdosage of formoterol fumarate.
Description
(budesonide, glycopyrrolate and formoterol fumarate) Inhalation Aerosol is a pressurized metered-dose inhaler that delivers a combination of micronized budesonide [an inhaled corticosteroid (ICS)], micronized glycopyrrolate (an anticholinergic), and micronized formoterol fumarate [an inhaled long-acting beta 2 -adrenergic agonist (a LABA)] for oral inhalation. Budesonide is a corticosteroid with the following chemical name: (RS)-11β, 16α, 17,21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is a white to off-white, powder which is practically insoluble in water. The molecular formula is C 25 H 34 O 6 and the molecular weight is 430.54. The structural formula is as follows: Budesonide contains nine chiral centers and is a mixture of the two epimers (22R and 22S). Glycopyrrolate is a quaternary ammonium salt with the following chemical name: (RS)-[3-(SR)-Hydroxy-1,1-dimethylpyrrolidinium bromide] α-cyclopentylmandelate. Glycopyrrolate is a powder that is freely soluble in water. The molecular formula is C 19 H 28 BrNO 3 , and the molecular weight is 398.33 g/mol. The structural formula is as follows: Glycopyrrolate contains two chiral centers and is a racemate of a 1:1 mixture of the R,S and S,R diastereomers. The active moiety, glycopyrronium, is the positively charged ion of glycopyrrolate. Formoterol fumarate has the chemical name N-[2-Hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino] ethyl]phenyl] formamide, (E)-2-butenedioate dihydrate. Formoterol fumarate is a powder that is slightly soluble in water. The molecular formula is (C 19 H 24 N 2 O 4 ) 2 ·C 4 H 4 O 4 ·2H 2 O and the molecular weight is 840.91 g/mol. The structural formula is as follows: Formoterol fumarate contains two chiral centers and consists of a single enantiomeric pair (a racemate of R,R and S,S). BREZTRI AEROSPHERE is formulated as a hydrofluoroalkane (HFA 134a) propelled pressurized metered dose inhaler containing 28 or 120 inhalations. The canister has an attached dose indicator and is supplied with a yellow plastic actuator and white mouthpiece with a grey dust cap. After priming, each actuation of the inhaler meters 170 mcg of budesonide, 9.6 or 19.1 mcg of glycopyrrolate (equivalent to 7.7 or 15.3 mcg of glycopyrronium), and 5.1 mcg of formoterol fumarate (equivalent to 4.4 mcg of formoterol) from the valve which delivers 160 mcg of budesonide, 9.0 or 18 mcg of glycopyrrolate (equivalent to 7.2 or 14.4 mcg of glycopyrronium), and 4.8 mcg of formoterol fumarate (equivalent to 4.1 mcg of formoterol) from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between actuation of the device and inspiration through the delivery system. BREZTRI AEROSPHERE also contains porous particles that form a co-suspension with the drug crystals. The porous particles are comprised of the phospholipid, 1,2-distearoyl- sn -glycero-3-phosphocholine (DSPC), and calcium chloride. Porous particles and HFA 134a are excipients in the formulation. Budesonide Chemical Structure Glycopyrrolate Chemical Structure Formoterol Fumarate Chemical Structure
Mechanism of action
12.1 Mechanism of Action BREZTRI AEROSPHERE BREZTRI AEROSPHERE contains budesonide, glycopyrrolate, and formoterol fumarate. The mechanism of action described below for the individual components applies to BREZTRI AEROSPHERE. These drugs represent three different classes of medications (a synthetic corticosteroid, an anticholinergic, and a long-acting selective beta 2 -adrenoceptor agonist) that have different effects on clinical physiology and inflammatory indices of COPD and asthma. Budesonide 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. In glucocorticoid receptor affinity studies, the 22R epimer of budesonide was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert. Inflammation is an important component in the pathogenesis of COPD and asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy. Glycopyrrolate Glycopyrrolate is a long-acting antimuscarinic agent which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of the M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methylcholine and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted more than 12 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of glycopyrrolate is predominantly a site-specific effect. Formoterol Fumarate Formoterol fumarate is a long-acting selective beta 2 -adrenergic agonist (beta 2 -agonist) with a rapid onset of action. Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta 2 -receptors than at beta 1 -receptors. The in vitro binding selectivity to beta 2 - over beta 1 -adrenoceptors is higher for formoterol than for albuterol (5 times), whereas salmeterol has a higher (3 times) beta 2 -selectivity ratio than formoterol. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -adrenoceptor agonist drugs, including formoterol fumarate, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
How supplied
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.
Patient information
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Serious Asthma-Related Events Inform patients with asthma that LABA when used alone increases the risk of asthma-related hospitalization or asthma‑related death. Available data show that when ICS and LABA are used together, such as with BREZTRI AEROSPHERE, there is not a significant increase in the risk of these events [see Warnings and Precautions (5.1) ] . Not for Treatment of Acute Symptoms Inform patients that BREZTRI AEROSPHERE is not meant to relieve acute symptoms of COPD or asthma and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting beta 2 -agonist/corticosteroid for asthma or, an inhaled, short-acting beta 2 -agonist for asthma or COPD [see Warnings and Precautions (5.2) ] . Provide patients with such medication and instruct them on how it should be used. Instruct patients to seek medical attention immediately if they experience any of the following:
• Decreasing effectiveness of inhaled, short-acting beta 2 -agonist/corticosteroid combination, or inhaled, short-acting beta 2 -agonists.
• Need for more inhalations than usual of inhaled, short-acting beta 2 -agonist/corticosteroid combination, or inhaled, short-acting beta 2 -agonists.
• Significant decrease in lung function as outlined by the health care practitioner. Tell patients they should not stop therapy with BREZTRI AEROSPHERE without physician guidance since symptoms may recur after discontinuation [see Warnings and Precautions (5.2) ]. Do Not Use Additional Long-acting Beta 2 -agonists or Anticholinergics Instruct patients not to use other LABA or anticholinergic medicines [see Warnings and Precautions (5.3) ]. Oropharyngeal Candidiasis Inform patients 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 BREZTRI AEROSPHERE, but at times therapy with BREZTRI AEROSPHERE may need to be temporarily interrupted under close medical supervision. Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush [see Warnings and Precautions (5.4) ]. Pneumonia Patients with COPD have a higher risk of pneumonia; instruct them to contact their healthcare providers if they develop symptoms of pneumonia [see Warnings and Precautions (5.5) ]. Immunosuppression and Risk of Infections Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.6) ] . Hypercorticism and Adrenal Suppression Advise patients that BREZTRI AEROSPHERE may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, inform patients 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 BREZTRI AEROSPHERE [see Warnings and Precautions (5.8) ]. Paradoxical Bronchospasm As with other inhaled medicines, BREZTRI AEROSPHERE can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue BREZTRI AEROSPHERE and contact their healthcare provider right away [see Warnings and Precautions (5.10) ]. Hypersensitivity Reactions, including Anaphylaxis Advise patients that hypersensitivity reactions (e.g., anaphylaxis, angioedema, rash, urticaria) may occur after administration of BREZTRI AEROSPHERE. Instruct patients to discontinue BREZTRI AEROSPHERE if such reactions occur [see Warnings and Precautions (5.11) ] . Reduction in Bone Mineral Density Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk [see Warnings and Precautions (5.13) ]. Effect on Growth Inform patients that orally inhaled corticosteroids, a component of BREZTRI AEROSPHERE, may cause a reduction in growth velocity when administered to pediatric patients. Healthcare providers should closely follow the growth of pediatric patients taking corticosteroids by any route [see Warnings and Precautions (5.14) ] . Ocular Effects such as Cataracts or Glaucoma Inform patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations. Instruct patients to 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 if any of these signs or symptoms develops [see Warnings and Precautions (5.15) ]. Worsening of Urinary Retention Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately if any of these signs or symptoms develop [see Warnings and Precautions (5.16) ]. Risks Associated with Beta-agonist Therapy Inform patients of adverse effects associated with beta 2 -agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. Instruct patients to consult a healthcare practitioner immediately should any of these signs or symptoms develop [see Warnings and Precautions (5.12) ]. Manufactured for: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 Manufactured by: AstraZeneca Dunkerque Production (AZDP), Dunkerque, France BREZTRI and AEROSPHERE are registered trademarks of the AstraZeneca group of companies.
Label text from the FDA structured product label by AstraZeneca Pharmaceuticals LP (revised Apr 27, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Budesonide in 2 products
- Glycopyrrolate in 2 products
- Formoterol in 2 products
Breztri NDC products (2)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0310-4616 | Budesonide 160 ug/1; Glycopyrrolate 9 ug/1; Formoterol 4.8 ug/1 Aerosol, Metered | AstraZeneca Pharmaceuticals LP | NDA |
| 0310-6616 | Budesonide 160 ug/1; Glycopyrrolate 18 ug/1; Formoterol 4.8 ug/1 Aerosol, Metered | AstraZeneca Pharmaceuticals LP | NDA |
Frequently asked questions
What is Breztri used for?
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…
What are the side effects of Breztri?
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… See the full label for the complete list.
Who makes Breztri?
Breztri is listed by 1 labeler in the FDA NDC directory, including AstraZeneca Pharmaceuticals LP.