BREZTRI - AstraZeneca Pharmaceuticals LP

BREZTRI AEROSPHERE is indicated for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adult patients.

BREZTRI AEROSPHERE is indicated for the maintenance treatment of asthma in adult and pediatric patients 12 years of age and older.

BREZTRI AEROSPHERE is not indicated for the relief of acute bronchospasm [see Warnings and Precautions (5.1, 5.2)].

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.

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.

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.

Use of long-acting beta₂-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.

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.

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 beta₂-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 beta₂-agonist/corticosteroid combination (asthma only) or an inhaled short-acting beta₂-agonist (COPD or asthma).

When beginning treatment with BREZTRI AEROSPHERE, patients who have been taking inhaled, short‑acting beta₂‑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 beta₂‑agonist/corticosteroid combination (asthma only) or an inhaled, short acting beta₂‑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 beta₂-agonist becomes less effective or the patient needs more inhalations of short-acting beta₂-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.

As with other inhaled drugs containing beta₂-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)].

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.

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.

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.

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 [FEV₁] 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.

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.

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)].

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.

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)].

Formoterol fumarate, like other beta₂-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.

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) ].

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)].

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.

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.

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 beta₂-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

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. Beta₂-agonist therapies may produce transient hyperglycemia in some patients.

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.

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.

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.

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) ].

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)].

Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate the hypokalemic effect of beta₂-adrenergic agonists such as formoterol, a component of BREZTRI AEROSPHERE.

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 beta₂-agonists, especially when the recommended dose of the beta₂-agonist is exceeded.

BREZTRI AEROSPHERE, as with other beta₂-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.

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 beta₂-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.

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) ].

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/m² 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/m² 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/m² 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/m² 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/m² basis at maternal inhalation doses up to 250 mcg/kg/day).

In a peri-and post-natal development study, rats dosed from gestation day 15 to postpartum day 21, budesonide had no effects on delivery, but did affect growth and development of offspring. Offspring survival was reduced, and surviving offspring had decreased mean body weights at birth and during lactation at doses 0.3 times the MRHDID and higher (on a mcg/m² basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

Formoterol Fumarate

In a fertility and reproduction study, male rats were orally dosed for at least 9 weeks and females for 2 weeks prior to pairing and throughout the mating period. Females were either dosed up to gestation day 19 or up until weaning of their offspring. Males were dosed up to 25 weeks. Umbilical hernia was observed in rat fetuses at oral doses 1500 times the MRHDID (on a mcg/m² basis at maternal oral doses of 3000 mcg/kg/day and higher). Brachygnathia was observed in rat fetuses at a dose 8000 times the MRHDID (on a mcg/m² basis at a maternal oral dose of 15,000 mcg/kg/day). Pregnancy was prolonged at a dose 8000 times the MRHDID (on a mcg/m² basis at a maternal oral dose of 15,000 mcg/kg/day). Fetal and pup deaths occurred at doses approximately 1500 times the MRHDID and higher (on a mcg/m² basis at oral doses of 3000 mcg/kg/day and higher) during gestation.

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6 to 15, no structural abnormalities, embryocidal effects, or developmental effects were seen at doses up to 350 times the MRHDID (on a mcg/m² basis with maternal inhalation doses up to 690 mcg/kg/day).

In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6 to 18, subcapsular cysts on the liver were observed in the fetuses at a dose 61,000 times the MRHDID (on a mcg/m² basis with a maternal oral dose of 60,000 mcg/kg/day). No teratogenic effects were observed at doses up to 3500 times the MRHDID (on a mcg/m² basis at maternal oral doses up to 3500 mcg/kg/day).

In a pre- and post-natal development study, pregnant female rats received formoterol at oral doses of 0, 210, 840, and 3400 mcg/kg/day from gestation day 6 (completion of implantation) through the lactation period. Pup survival was decreased from birth to postpartum day 26 at doses 110 times the MRHDID and higher (on a mcg/m² basis at maternal oral doses of 210 mcg/kg/day and higher), although there was no evidence of a dose-response relationship. There were no treatment-related effects on the physical, functional, and behavioral development of rat pups.

Glycopyrrolate

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6 to 17, glycopyrrolate produced no structural abnormalities or effects on fetal survival; however, slight reductions of fetal body weight in the presence of maternal toxicity at the highest tested dose that was 1350 times the MRHDID (on a mcg/m² basis at a maternal subcutaneous dose of 10,000 mcg/kg/day). Fetal body weights were unaffected with doses up to 135 times the MRHDID (on a mcg/m² basis with maternal subcutaneous doses up to 1000 mcg/kg/day). Maternal toxicity was observed with doses 135 times the MRHDID and higher (on a mcg/m² basis with maternal subcutaneous doses of 1000 mcg/kg/day and higher).

In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6 to 18, glycopyrrolate produced no structural abnormalities or effects on fetal survival; however, slight reductions of fetal body weight in the presence of maternal toxicity at the highest tested dose that was 2700 times the MRHDID (on a mcg/m² basis at a maternal subcutaneous dose of 10,000 mcg/kg/day). Fetal body weights were unaffected with doses up to 270 times the MRHDID (on a mcg/m² basis with maternal subcutaneous doses up to 1000 mcg/kg/day). Maternal toxicity was observed with doses 270 times the MRHDID and higher (on a mcg/m² basis with maternal subcutaneous doses of 1000 mcg/kg/day and higher).

In a pre- and post-natal development study, pregnant female rats received glycopyrrolate at doses of 100, 1000, and 10,000 mcg/kg/day from gestation day 6 through the lactation period. Pup body weight gain was slightly reduced from birth through the lactation period at a dose 1350 times the MRHDID (on a mcg/m² basis with a maternal subcutaneous dose of 10,000 mcg/kg/day); however, pup body weight gain was unaffected after weaning. There were no treatment-related effects on the physical, functional, and behavioral development of pups with doses up to 1350 times the MRHDID (on a mcg/m² basis with maternal subcutaneous doses up to 10,000 mcg/kg/day). Maternal toxicity was observed from gestation days 6 to 18 with doses 135 times the MRHDID and higher (on a mcg/m² basis with maternal subcutaneous doses of 1000 mcg/kg/day and higher).

Risk Summary

There are no available data on the effects of BREZTRI AEROSPHERE, budesonide, glycopyrrolate, or formoterol fumarate on the breastfed child or on milk production. Budesonide, like other ICS, is present in human milk [see Data]. There are no available data on the presence of glycopyrrolate or formoterol fumarate in human milk. Formoterol fumarate and glycopyrrolate have been detected in the plasma of undosed rat pups suckling from exposed dams [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BREZTRI AEROSPHERE and any potential adverse effects on the breast-fed child from BREZTRI AEROSPHERE or from the underlying maternal condition.

Data

Human Data

Human data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother. For BREZTRI AEROSPHERE, the dose of budesonide available to the infant in breast milk, as a percentage of the maternal dose, would be expected to be similar.

There is no available human data for formoterol or glycopyrrolate.

Animal Data

In the fertility and reproduction study in rats, plasma levels of formoterol were measured in pups on post-natal day 15 [see Use in Specific Populations (8.1)]. It was estimated that the maximum plasma concentration that the pups received from the maternal animal, at the highest dose of 15 mg/kg, after nursing was 4.4% (0.24 nmol/L for a litter vs. 5.5 nmol/L for the mother).

In the reproductive/developmental toxicity study in rats, plasma levels of glycopyrrolate were measured in pups on post-natal day 4. The maximum concentration in the pups was 6% of the maternal dose of 10 mg/kg/day (pup plasma concentration of 96 ng/mL at 1 hour after dosing corresponded with 1610 ng/mL in the dam at 0.5 hours after dosing).

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)].

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.

Formal pharmacokinetic studies using BREZTRI AEROSPHERE have not been conducted in patients with hepatic impairment. However, since budesonide and formoterol fumarate are predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide and formoterol fumarate in plasma. Therefore, patients with severe hepatic disease should be closely monitored.

Formal pharmacokinetic studies using BREZTRI AEROSPHERE have not been conducted in patients with renal impairment. In patients with severe renal impairment (creatinine clearance of ≤30 mL/min/1.73 m²) or end-stage renal disease requiring dialysis, BREZTRI AEROSPHERE should only be used if the expected benefit outweighs the potential risk [see Clinical Pharmacology (12.3)].

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 beta₂-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 beta₂-adrenergic agonist (beta₂-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 beta₂-receptors than at beta₁-receptors. The in vitro binding selectivity to beta₂- over beta₁-adrenoceptors is higher for formoterol than for albuterol (5 times), whereas salmeterol has a higher (3 times) beta₂-selectivity ratio than formoterol.

Although beta₂-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta₁-receptors are the predominant receptors in the heart, there are also beta₂-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 beta₂-agonists may have cardiac effects.

The pharmacologic effects of beta₂-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.

Cardiac Electrophysiology

A TQT study was not performed with BREZTRI AEROSPHERE as budesonide is not known to affect the QT interval. However, the potential for QTc interval prolongation with glycopyrrolate/formoterol fumarate was assessed in a double-blind, single-dose, placebo- and positive-controlled crossover trial in 69 healthy subjects. The largest mean (90% upper confidence bound) differences from placebo in baseline-corrected QTcI for 2 inhalations of glycopyrrolate/formoterol fumarate 9/4.8 mcg and glycopyrrolate/formoterol fumarate 72/19.2 mcg, were 3.1 (4.7) ms and 7.6 (9.2) ms, respectively, and excluded the clinically relevant threshold of 10 ms. A dose-dependent increase in heart rate was also observed. The largest mean (90% upper confidence bound) differences from placebo in baseline-corrected heart rate were 3.3 (4.9) beats/min and 7.6 (9.5) beats/min seen within 10 minutes of dosing with 2 inhalations of glycopyrrolate/formoterol fumarate 9/4.8 mcg and glycopyrrolate/formoterol fumarate 72/19.2 mcg, respectively.

Chronic Obstructive Pulmonary Disease

The effects of BREZTRI AEROSPHERE on cardiac rhythm in subjects with COPD was assessed using 24-hour Holter monitoring at Week 16 in ETHOS.

The Holter monitoring population in ETHOS included 180 subjects on BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg, 160 subjects on glycopyrrolate and formoterol fumarate (GFF MDI 18 mcg/9.6 mcg), and 183 subjects on budesonide/formoterol fumarate (BFF MDI 320 mcg/9.6 mcg). No clinically meaningful effects on cardiac rhythm were observed.

Asthma

The effects of BREZTRI AEROSPHERE on cardiac rhythm in subjects with asthma was assessed using 24-hour Holter monitoring at Week 4 or Week 24 in KALOS.

The Holter monitoring population in KALOS included 44 subjects on BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg, 56 subjects on budesonide and formoterol fumarate (BFF MDI) 320 mcg/9.6 mcg, and 36 subjects on budesonide/formoterol fumarate (BUD/FORM MDI) 320 mcg/9 mcg. No clinically meaningful effects on cardiac rhythm were observed.

HPA Axis Effects

Effects of BREZTRI AEROSPHERE on the HPA axis were assessed by measurement of 24-hour serum cortisol at Baseline and Week 24 in subjects with COPD. The geometric mean ratio (Week 24/Baseline) was 0.86 (Co-efficient of variation (CV) =39%) and 0.94 (CV=36.6%) for BREZTRI AEROSPHERE 320 mcg/18mcg/9.6mcg and GFF MDI 18 mcg/9.6 mcg, respectively.

Linear pharmacokinetics were demonstrated for budesonide (80 to 320 mcg), glycopyrrolate (18 to 144 mcg), and formoterol fumarate (2.4 to 38.4 mcg). Pharmacokinetic information for glycopyrrolate and formoterol fumarate is for the active moieties, glycopyrronium and formoterol, respectively. The pharmacokinetics of budesonide, glycopyrronium, and formoterol from BREZTRI AEROSPHERE are comparable to the pharmacokinetics of budesonide, glycopyrronium, and formoterol when administered as budesonide/formoterol or glycopyrrolate/formoterol in studies of healthy subjects (single dose) and subjects with COPD (repeated dose).

The pharmacokinetics of the individual components of BREZTRI AEROSPHERE are presented below.

Absorption

Budesonide: Following inhaled administration of BREZTRI AEROSPHERE in subjects with COPD or asthma, C_max occurred within 20 to 40 minutes. Steady state is estimated to be achieved after approximately 1 day of repeated dosing of BREZTRI AEROSPHERE via population pharmacokinetic analysis in subjects with COPD and the AUC_0-12 is approximately 1.3 times higher than after the first dose.

Glycopyrrolate: Following inhaled administration of BREZTRI AEROSPHERE in subjects with COPD or asthma, C_max occurred within 2 to 6 minutes. Steady state is estimated to be achieved after approximately 3 days of repeated dosing of BREZTRI AEROSPHERE via population pharmacokinetic analysis in subjects with COPD and the AUC_0-12 is approximately 1.8 times higher than after the first dose.

Formoterol Fumarate: Following inhaled administration of BREZTRI AEROSPHERE in subjects with COPD or asthma, C_max occurred within 20 to 90 minutes. Steady state is estimated to be achieved after approximately 2 days of repeated dosing with BREZTRI AEROSPHERE via population pharmacokinetic analysis in subjects with COPD and the AUC_0-12 is approximately 1.4 times higher than after the first dose.

Distribution

Budesonide: The estimated budesonide apparent volume of distribution at steady-state in subjects with COPD is approximately 1200 L, via population pharmacokinetic analysis. Over the concentration range of 1-100 nmol/L, mean plasma protein binding of budesonide ranged from 86% to 87%.

Glycopyrrolate: The estimated glycopyrronium apparent volume of distribution at steady-state in subjects with COPD is approximately 5500 L, via population pharmacokinetic analysis. Over the concentration range of 2-500 nmol/L, plasma protein binding of glycopyrronium ranged from 43% to 54%.

Formoterol Fumarate: The estimated formoterol apparent volume of distribution at steady-state in subjects with COPD is approximately 2400 L, via population pharmacokinetic analysis. Over the concentration range of 10-500 nmol/L, plasma protein binding of formoterol ranged from 46% to 58%.

Elimination

Budesonide: Budesonide was excreted in urine and feces in the form of metabolites. Only negligible amounts of unchanged budesonide have been detected in the urine. The effective half-life of budesonide in subjects with COPD derived via population pharmacokinetic analysis was approximately 5 hours.

Glycopyrrolate: After IV administration of a 0.2 mg radiolabeled glycopyrronium, 85% of dose recovered was recovered in urine 48 hours post-dose and some of radioactivity was also recovered in bile. The effective half-life of glycopyrronium in subjects with COPD derived via population pharmacokinetics analysis was approximately 15 hours.

Formoterol Fumarate: The excretion of formoterol was studied in six healthy subjects following simultaneous administration of radiolabeled formoterol via the oral and IV routes. In that study, 62% of the drug related radioactivity of formoterol was excreted in the urine while 24% was eliminated in the feces. The effective half-life of formoterol in subjects with COPD derived via population pharmacokinetics analysis was approximately 10 hours.

Metabolism

Budesonide: In vitro studies with human liver homogenates have shown that budesonide was rapidly and extensively metabolized. Two major metabolites formed via CYP3A4 catalyzed biotransformation have been isolated and identified as 16α-hydroxyprednisolone and 6ß-hydroxybudesonide. The corticosteroid activity of each of these two metabolites was less than 1% of that of the parent compound. No qualitative differences between the in vitro and in vivo metabolic patterns were detected. Negligible metabolic inactivation was observed in human lung and serum preparations.

Glycopyrrolate: Based on information from the published literature, and an in vitro human hepatocyte study, metabolism plays a minor role in the overall elimination of glycopyrronium. CYP2D6 was found to be the predominant enzyme involved in the metabolism of glycopyrronium.

Formoterol Fumarate: The primary metabolism of formoterol is by direct glucuronidation and by O-demethylation followed by conjugation to inactive metabolites. Secondary metabolic pathways include deformylation and sulfate conjugation. CYP2D6 and CYP2C have been identified as being primarily responsible for O-demethylation.

Specific Populations

Population pharmacokinetic analysis in subjects with COPD showed no evidence of a clinically significant effect of age, sex, race/ethnicity, or body weight on the pharmacokinetics of budesonide, glycopyrronium, or formoterol.

Patients with Hepatic Impairment:

Dedicated studies of BREZTRI AEROSPHERE evaluating effect of hepatic impairment on the pharmacokinetics of budesonide, glycopyrronium, and formoterol were not conducted.

Reduced liver function may affect the elimination of corticosteroids. Budesonide pharmacokinetics was affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The intravenous budesonide pharmacokinetics were, however, similar in cirrhotic patients and in healthy subjects.

As budesonide and formoterol are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe hepatic impairment.

Patients with Renal Impairment:

Studies with BREZTRI AEROSPHERE evaluating the effect of renal impairment on the pharmacokinetics of budesonide, glycopyrronium, and formoterol were not conducted.

The effect of renal impairment on the exposure to budesonide, glycopyrronium, and formoterol for up to 24 weeks was evaluated in a population pharmacokinetic analysis. Estimated glomerular filtration rate (eGFR) varied from 31-192 mL/min representing a range of moderate to no renal impairment. Simulation of the systemic exposure (AUC_0-12) in subjects with COPD with moderate renal impairment (eGFR of 45 mL/min) indicates an approximate 68% increase for glycopyrronium compared to subjects with COPD with normal renal function (eGFR of >90 mL/min). Renal function was found not to significantly affect exposure to budesonide or formoterol after drug clearance adjusted by age or body weight in a population pharmacokinetic analysis.

Drug Interaction Studies

No pharmacokinetic interaction has been observed between budesonide, glycopyrrolate, and formoterol fumarate when administered in combination by the inhaled route. Specific drug interaction studies of BREZTRI AEROSPHERE with other co-administered drugs have not been performed.

Ketoconazole and Itraconazole: Ketoconazole and itraconazole, strong inhibitors of cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4), the main metabolic enzyme for corticosteroids, increased plasma levels of orally ingested budesonide and orally inhaled budesonide, respectively.

Cimetidine: At recommended doses, cimetidine, a non-specific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.

No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with BREZTRI AEROSPHERE; however, separate studies of budesonide, glycopyrrolate, and formoterol fumarate are described below.

Budesonide

Long-term studies were conducted in rats and mice using oral administration to evaluate the carcinogenic potential of budesonide.

In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately equivalent to the MRHDID on a mcg/m² basis). No tumorigenicity was seen in male and female rats at respective oral doses up to 25 and 50 mcg/kg (approximately equivalent to the MRHDID on a mcg/m² basis). In two additional 2-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately equivalent to the MRHDID on a mcg/m² basis). However, in the male Sprague- Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately equivalent to the MRHDID on a mcg/m² basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) in these two studies showed similar findings.

In a 91-week carcinogenicity study in mice, budesonide produced no treatment-related increases in the incidence of tumors at oral doses up to 200 mcg/kg (approximately 2 times the MRHDID on a mcg/m² basis).

Budesonide was not mutagenic or clastogenic in the Ames Salmonella/microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster, and DNA repair analysis in rat hepatocyte culture.

Fertility and reproductive performance were unaffected in rats at subcutaneous doses up to 80 mcg/kg (approximately equal to the MRHDID on a mcg/m² basis). However, it caused a decrease in prenatal viability and viability in the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg and above (0.3 times the MRHDID on a mcg/m² basis). No such effects were noted at 5 mcg/kg (0.08 times the MRHDID on a mcg/m² basis).

Glycopyrrolate

Long-term studies were conducted in mice using inhalation administration and rats using oral administration to evaluate the carcinogenic potential of glycopyrrolate.

In a 24-month inhalation carcinogenicity study in B6C3F1 mice, glycopyrrolate produced no evidence of tumorigenicity when administered to males or females at doses up to 705 and 335 mcg/kg/day, respectively (approximately 48 and 23 times the MRHDID of glycopyrrolate on a mcg/m² basis, respectively).

In a 24-month carcinogenicity study in rats, glycopyrrolate produced no evidence of tumorigenicity when administered to males or females by oral gavage at dosages up to 40,000 mcg/kg/day (approximately 5400 times the MRHDID of glycopyrrolate on a mcg/m² basis).

Glycopyrrolate was not mutagenic or clastogenic in the Ames Salmonella/microsome plate test, in vitro mammalian cell micronucleus assay in TK6 cells, or in vivo micronucleus assay in rats.

Fertility and reproductive performance indices were unaffected in male and female rats that received glycopyrrolate by the subcutaneous route at doses up to 10,000 μg/kg/day (approximately 1350 times the MRHDID on a mcg/m² basis).

Formoterol Fumarate

Long-term studies were conducted in mice using oral administration and rats using inhalation administration to evaluate the carcinogenic potential of formoterol fumarate.

In a 24-month carcinogenicity study in CD-1 mice, formoterol fumarate at oral doses of 100 mcg/kg and above (approximately 25 times MRHDID on a mcg/m² basis) caused a dose-related increase in the incidence of uterine leiomyomas.

In a 24-month carcinogenicity study in Sprague-Dawley rats, an increased incidence of mesovarian leiomyoma and uterine leiomyosarcoma were observed at the inhaled dose of 130 mcg/kg (approximately 65 times the MRHDID on a mcg/m² basis). No tumors were seen at 22 mcg/kg (approximately 10 times the MRHDID on a mcg/m² basis).

Other beta-agonist drugs have similarly demonstrated increases in leiomyomas of the genital tract in female rodents. The relevance of these findings to human use is unknown.

Formoterol fumarate was not mutagenic or clastogenic in Ames Salmonella/microsome plate test, mouse lymphoma test, chromosome aberration test in human lymphocytes, or rat micronucleus test.

A reduction in fertility and/or reproductive performance was identified in male rats treated with formoterol at an oral dose of 15,000 mcg/kg, (approximately 2600 times the MRHDID on an AUC basis). No such effect was seen at 3,000 mcg/kg (approximately 1500 times the MRHDID on a mcg/m² basis). In a separate study with male rats treated with an oral dose of 15,000 mcg/kg (approximately 8000 times the MRHDID on a mcg/m² basis), there were findings of testicular tubular atrophy and spermatic debris in the testes and oligospermia in the epididymides. No effect on fertility was detected in female rats at doses up to 15,000 mcg/kg (approximately 1400 times the MRHDID on an AUC basis).

The clinical efficacy of BREZTRI AEROSPHERE has been evaluated in two (ETHOS and KRONOS) randomized, double-blind, multicenter, parallel-group trials in subjects with moderate to very severe COPD who remained symptomatic while receiving 2 or more inhaled maintenance treatments for COPD for at least 6 weeks prior to screening.

ETHOS (NCT02465567) was conducted over 52 weeks in a total of 8,588 subjects randomized (1:1:1:1) to receive BREZTRI AEROSPHERE (budesonide/glycopyrrolate/formoterol fumarate 320 mcg/18 mcg/9.6 mcg), budesonide, glycopyrrolate and formoterol fumarate (BGF MDI 160 mcg/18 mcg/9.6 mcg) (the BGF MDI 160 mcg/18 mcg/9.6 mcg dosing regimen is not approved), glycopyrrolate and formoterol fumarate (GFF MDI 18 mcg/9.6 mcg), or budesonide and formoterol fumarate (BFF MDI 320 mcg/9.6 mcg), all administered twice daily. GFF MDI and BFF MDI used the same inhaler and excipients as BREZTRI AEROSPHERE.

ETHOS was conducted in subjects with a history of 1 or more moderate or severe exacerbations in the year prior to screening, post-bronchodilator FEV₁/FVC ratio less than 0.7 and the post-bronchodilator FEV₁ less than 65% predicted normal value.

The population demographics across all treatments in ETHOS were: mean age of 65 years, 60% male, 85% Caucasian, and an average smoking history of 48 pack-years, with 41% identified as current smokers. The mean post-bronchodilator percent predicted FEV₁ was 43% (range 16% to 73%). At study entry, the most common COPD medications were ICS + long-acting muscarinic antagonist (LAMA) + LABA (39%), ICS + LABA (31%), and LAMA + LABA (14%).

In ETHOS, the primary endpoint was the rate of moderate or severe COPD exacerbations for BREZTRI AEROSPHERE compared with GFF MDI and BFF MDI.

KRONOS (NCT02497001) was conducted over 24 weeks, in a total of 1,896 subjects randomized (2:2:1:1) to receive BREZTRI AEROSPHERE (budesonide/glycopyrrolate/formoterol fumarate 320 mcg/18 mcg/9.6 mcg), glycopyrrolate and formoterol fumarate (GFF MDI 18 mcg/9.6 mcg), budesonide and formoterol fumarate (BFF MDI 320 mcg/9.6 mcg), or open-label active comparator, all administered twice daily. GFF MDI and BFF MDI used the same inhaler and excipients as BREZTRI AEROSPHERE.

KRONOS was conducted in subjects with a screening post-bronchodilator FEV₁/FVC ratio less than 0.7 and post-bronchodilator FEV₁ less than 80% predicted normal value. Subjects in KRONOS were not required to have a history of moderate or severe exacerbations in the year prior to screening.

The population demographics across all treatments in KRONOS were: mean age of 65 years, 71% male, 50% Caucasian, 45% Asian, and an average smoking history of 52 pack-years, with 40% identified as current smokers. The mean post-bronchodilator percent predicted FEV₁ was 50% (range 22% to 84%). At study entry, the most common COPD medications were ICS + LAMA + LABA (27%), ICS + LABA (38%), and LAMA + LABA (20%).

In KRONOS, the primary endpoints were FEV₁ area under the curve from 0-4 hours (FEV₁ AUC_0-4) at Week 24 for BREZTRI AEROSPHERE compared to BFF MDI and change from baseline in morning pre-dose trough FEV₁ at Week 24 for BREZTRI AEROSPHERE compared to GFF MDI.

Lung Function

In ETHOS, a subset of subjects were included in a spirometric sub-study with primary endpoints of FEV₁ AUC_0-4 at Week 24 (mL) and change from baseline in morning pre-dose trough FEV₁ at Week 24 (mL). BREZTRI AEROSPHERE demonstrated an increase in on-treatment FEV₁ AUC_0-4 and trough FEV₁ at Week 24 relative to BFF MDI and GFF MDI (Table 2). The effects on lung function (mean change from baseline in on-treatment morning pre-dose trough FEV₁) of BREZTRI AEROSPHERE compared with GFF MDI and BFF MDI were observed at all timepoints over the course of the study (Figure 1).

In KRONOS, BREZTRI AEROSPHERE demonstrated an increase in on-treatment FEV₁ AUC_0-4 at Week 24 relative to BFF MDI and an increase in mean change from baseline in morning pre-dose trough FEV₁ at Week 24 compared with GFF MDI (Table 4). The comparison of BREZTRI AEROSPHERE with GFF MDI in mean change from baseline in morning pre-dose trough FEV₁ at Week 24 was not statistically significant.

In both trials, there were consistent improvements in lung function in patient subgroups classified by age, sex, degree of airflow limitation (moderate, severe, and very severe), and previous ICS use.

Figure 1: Adjusted Mean Change from Baseline in Trough FEV₁ Over Time in Adult Subjects with COPD (ETHOS)*

^*The analysis excluded spirometry data collected after discontinuation of study treatment.

In KRONOS, the median time to onset on Day 1, defined as a 100 mL increase from baseline in FEV₁, was within 5 minutes in subjects receiving BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg. In ETHOS, subjects treated with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg on average used less daily rescue medication over 24 weeks compared to subjects treated with GFF MDI 18 mcg/9.6 mcg and BFF MDI 320 mcg/9.6 mcg.

Exacerbations

In ETHOS, the primary endpoint was the rate of on-treatment moderate or severe COPD exacerbations in subjects treated with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg compared with GFF MDI and BFF MDI.

Exacerbations were defined as worsening of 2 or more major symptoms (dyspnea, sputum volume, and sputum color) or worsening of any 1 major symptom together with any 1 of the following minor symptoms: cough, wheeze, sore throat, colds (nasal discharge and/or nasal congestion), and fever without other cause for at least 2 consecutive days. Exacerbations were considered to be moderate severity if treatment with systemic corticosteroids and/or antibiotics was required and were considered to be severe if they resulted in hospitalization or death.

In ETHOS, treatment with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg demonstrated a reduction in the rate of on-treatment moderate or severe COPD exacerbations over 52 weeks compared with GFF MDI and BFF MDI (see Table 5).

In KRONOS, treatment with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg reduced the annual rate of on-treatment moderate or severe COPD exacerbations compared with GFF MDI 18 mcg/9.6 mcg (rate ratio [95% CI]: 0.48 [0.37, 0.64]), and compared with BFF MDI 320 mcg/9.6 mcg (rate ratio [95% CI]: 0.82 [0.58, 1.17]). The comparison of BREZTRI AEROSPHERE with GFF MDI was not statistically significant due to failure higher in the analysis hierarchy.

Health-Related Quality of Life

In both trials, health-related quality of life was assessed using the St. George’s Respiratory Questionnaire (SGRQ) responder analysis which was defined as an improvement in SGRQ score from baseline of 4 or more.

In ETHOS, the on-treatment percentage of SGRQ responders at Week 24 was greater for subjects treated with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg (50%) compared with both GFF MDI 18 mcg/9.6 mcg (43%; odds ratio 1.4; 95% CI: 1.2, 1.5) and BFF MDI 320 mcg/9.6 mcg (45%; odds ratio 1.2; 95% CI: 1.1, 1.4). Similar differences between treatments were observed at Week 52.

In KRONOS, the on-treatment percentage of SGRQ responders at Week 24 was greater for subjects treated with BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg (50%) compared with both GFF MDI 18 mcg/9.6 mcg (44%; odds ratio 1.3; 95% CI: 1.0, 1.6) and BFF MDI 320 mcg/9.6 mcg (43%; odds ratio 1.3; 95% CI: 1.0, 1.7).

The efficacy of BREZTRI AEROSPHERE for the maintenance treatment of asthma was evaluated in two randomized, double-blind, parallel-group, active-controlled, multicenter clinical trials (KALOS [NCT04609878] and LOGOS [NCT04609904]) of 24 to 52-weeks duration. The trials enrolled adult and pediatric subjects 12 years of age and older with asthma who were inadequately controlled, defined by an Asthma Control Questionnaire (ACQ)-7 score ≥1.5 despite treatment with a medium or high dose of inhaled corticosteroid/long-acting beta₂-agonist (ICS/LABA), and pre-bronchodilator FEV₁ <80% predicted normal value for participants ≥18 years of age or <90% predicted normal value for participants 12 to <18 years of age. Subjects who met initial eligibility criteria entered a 5-week run-in period of treatment with BFF MDI 320 mcg/9.6 mcg twice daily. Subjects who remained inadequately controlled (ACQ-7 ≥1.5) were randomized (1:1:1:1) to receive a dose of BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg, BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg, BFF MDI 320 mcg/9.6 mcg, or budesonide and formoterol fumarate (BUD/FORM MDI) 320 mcg/9 mcg, all administered as two inhalations twice daily. BFF MDI used the same inhaler and aerosphere delivery platform as BREZTRI AEROSPHERE. The efficacy population is based on 1200 subjects in the KALOS trial and 1187 subjects in the LOGOS trial who received BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg or BFF MDI 320 mcg/9.6 mcg twice daily by oral inhalation.

The demographics of the efficacy population in KALOS were: mean age of 52 years (range: 12 to 80 years), 63% female, 65% White, 24% Asian, 2% Black or African American, <1% American Indian or Alaska Native, 8% other; and 30% of Hispanic or Latino ethnicity. Subjects had a median asthma duration of 16 years (range: 1.1-74 years) and 65% of subjects reported having at least one severe exacerbation in the prior year. At baseline, the mean pre-bronchodilator percent predicted FEV₁ was 59% (standard deviation [SD] 12%), the mean reversibility was 23% (SD 19%), and the mean ACQ-5 score was 2.5 (SD 0.7).

The demographics of the efficacy population in LOGOS were: mean age of 52 years (range: 12 to 80 years), 61% female, 45% White, 38% Asian, 6% Black or African American, 1% American Indian or Alaska Native, 10% other; and 12% of Hispanic or Latino ethnicity. Subjects had a median asthma duration of 15 years (range: 1.1-76 years) and 48% of subjects reported having at least 1 severe exacerbation in the prior year. At baseline, the mean pre-bronchodilator percent predicted FEV₁ was 59% (SD 13%), the mean reversibility was 22% (SD 18%), and the mean ACQ-5 score was 2.5 (SD 0.7).

Lung Function

The primary endpoint in KALOS and LOGOS was a change from baseline in FEV₁ area under the curve from 0-3 hours (FEV₁ AUC_0-3) post-dose at Week 24 for BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg compared to BFF MDI 320 mcg/9.6 mcg.

The key secondary endpoint in KALOS and LOGOS was a change from baseline in morning pre-dose trough FEV₁ at Week 24 for BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg compared to BFF MDI 320 mcg/9.6 mcg.

In both KALOS and LOGOS, subjects receiving BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg resulted in statistically significant increases in change from baseline in FEV₁ AUC_0-3 and change from baseline in morning pre-dose trough FEV₁ compared to BFF MDI 320 mcg/9.6 mcg at Week 24 (Table 6).

AUC_0-3 = area under the curve 0 to 3 hours; BFF = budesonide and formoterol fumarate; CI = confidence interval; FEV₁ = forced expiratory volume in 1 second; LS = least squares; MDI = metered dose inhaler; N = number of subjects in treatment group; n = number of subjects with a non-missing value at Week 24.

In KALOS and LOGOS, the median time to onset of action on Day 1, defined as a 100 mL increase from baseline in FEV₁, was within 5 minutes in subjects receiving BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg.

In KALOS and LOGOS, the effects on lung function (mean change from baseline in morning pre-dose trough FEV₁) of BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg compared with BFF MDI 320 mcg/9.6 mcg were maintained over the course of both trials (Figure 2).

Figure 2: Least Squares Mean (± SE) Change from Baseline in Morning Pre-Dose Trough FEV₁ Over 24 Weeks of Treatment (KALOS and LOGOS)

Severe Exacerbations

The rate of severe asthma exacerbations endpoint was based on the pooled KALOS and LOGOS trials. A severe asthma exacerbation was defined as a deterioration of asthma symptoms that required at least 3 days of systemic corticosteroids or an emergency department or urgent care visit for asthma symptoms requiring treatment with systemic corticosteroids or resulted in in-patient hospitalization, and/or death. Asthma exacerbations were assessed over the blinded treatment period.

In the pooled efficacy analysis (KALOS and LOGOS), the adjusted mean annualized rate of severe asthma exacerbations was 0.54 for BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg (398 of 1179 patients, 34%) and 0.60 for BFF MDI 320 mcg/9.6 mcg (444 of 1208 patients, 37%).

The rate ratio of severe asthma exacerbations for BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg compared to BFF MDI 320 mcg/9.6 mcg was 0.90 (95% CI 0.78, 1.03).

Asthma Control and Health-Related Quality of Life

Asthma control was assessed at Week 24 in each trial using the Asthma Control Questionnaire (ACQ). The ACQ-7 incorporates 5 questions on symptoms, plus FEV₁, and rescue bronchodilator use. ACQ-7 responder was defined as a decrease in score of ≥0.5.

The ACQ-7 responder rate was 65% for BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg and 64% for BFF MDI 320 mcg/9.6 mcg at Week 24 (OR 1.05; 95% CI 0.82, 1.34) in KALOS. The ACQ-7 responder rate was 68% for BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg and 64% for BFF MDI 320 mcg/9.6 mcg at Week 24 (OR 1.27; 95% CI 0.98, 1.63) in LOGOS.

Responder rates with ACQ-5 (comprising the 5 questions on symptoms from ACQ-7) were similar to those with ACQ-7 at Week 24.