Breyna aerosol, metered Aerosol, Metered Uses, Dosage & Side Effects

BREYNA is a combination product containing a corticosteroid and a long-acting beta2-adrenergic agonist indicated for: • Treatment of asthma in patients 6 years of age and older. (1.1)

• Maintenance treatment of airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and/or emphysema. (1.2)

Important limitations: • Not indicated for the relief of acute bronchospasm. (1.1, 1.2) 1.1 Treatment of Asthma

BREYNA is indicated for the treatment of asthma in patients 6 years of age and older.

BREYNA should be used for patients not adequately controlled on a long-term asthma-control medication such as an inhaled corticosteroid (ICS) or whose disease warrants initiation of treatment with both an inhaled corticosteroid and long-acting beta2-adrenergic agonist (LABA).

Important Limitations of Use: • BREYNA is NOT indicated for the relief of acute bronchospasm. 1.2 Maintenance Treatment of Chronic Obstructive Pulmonary Disease

BREYNA 160 mcg/4.5 mcg is indicated for the maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and/or emphysema.

BREYNA 160 mcg/4.5 mcg is also indicated to reduce exacerbations of COPD. BREYNA 160 mcg/4.5 mcg is the only strength indicated for the treatment of COPD.

Important Limitations of Use: • BREYNA is NOT indicated for the relief of acute bronchospasm.

The use of BREYNA is contraindicated in the following conditions:

1. •Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.
2. •Hypersensitivity to any of the ingredients in BREYNA.

LABA use may result in the following:

1. •Serious asthma-related events – hospitalizations, intubations, death [see Warnings and Precautions (5.1)].
2. •Cardiovascular and central nervous system effects [see Warnings and Precautions (5.12)].

Systemic and inhaled corticosteroid use may result in the following:

1. •Candida albicans infection [see Warnings and Precautions (5.4)]
2. •Pneumonia or lower respiratory tract infections in patients with COPD [see Warnings and Precautions (5.5)]
3. •Immunosuppression [see Warnings and Precautions (5.6)]
4. •Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8)]
5. •Growth effects in pediatric patients [see Warnings and Precautions (5.14)]
6. •Glaucoma and cataracts [see Warnings and Precautions (5.15)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

• Serious asthma-related events: Long-acting beta2-adrenergic agonists as monotherapy increase the risk. (5.1)

• Deterioration of disease and acute episodes: Do not initiate in acutely deteriorating asthma or COPD or to treat acute symptoms. (5.2)

• Use with additional long-acting beta2-agonist: Do not use in combination because of risk of overdose. (5.3)

• Localized infections: Candida albicans

infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. (5.4)

• Pneumonia: Increased risk in patients with COPD. Monitor patients for signs and symptoms of pneumonia and other potential lung infections. (5.5)

• Immunosuppression: Potential worsening of infections (e.g., existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or 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)

• Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to BREYNA. (5.7)

• Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue BREYNA slowly. (5.8)

• Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased systemic corticosteroid effects. Exercise caution when used with BREYNA. (5.9)

• Paradoxical bronchospasm: Discontinue BREYNA and institute alternative therapy if paradoxical bronchospasm occurs. (5.10)

• Patients with cardiovascular or central nervous system disorders: Use with caution because of beta-adrenergic stimulation. (5.12)

• Decreases in bone mineral density: Assess bone mineral density initially and periodically thereafter. (5.13)

• Effects on growth: Monitor growth of pediatric patients. (5.14)

• Glaucoma and cataracts: Close monitoring is warranted. (5.15)

• Metabolic effects: Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. (5.16, 5.18)

• Coexisting conditions: Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.17) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations and Death

Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see

Salmeterol Multicenter Asthma Research Trial (SMART)

]. 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. When LABA are 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 to ICS alone (see Serious Asthma-Related Events with ICS/LABA). 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 (budesonide and formoterol fumarate dihydrate inhalation aerosol) to budesonide [see Clinical Studies (14.1)]; 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. 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 = Inhaled Corticosteroid, LABA = Long-acting Beta2-adrenergic Agonist

ICS/LABA

(N = 17,537)

Randomized patients who had taken at least 1 dose of study drug. Planned treatment used for analysis.

ICS

(N = 17,552)

ICS/LABA vs ICS

Hazard Ratio (95% CI)

Estimated using a Cox proportional hazards model of time to first event with baseline hazards stratified by each of the 3 trials.

Serious asthma-related event

Number of patients with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Patients can have one or more events, but only the first event was counted for analysis. A single, blinded, independent adjudication committee determined whether events were asthma-related.

116

105

1.10 (0.85, 1.44)

Asthma-related death

2

0

Asthma-related intubation (endotracheal)

1

2

Asthma-related hospitalization (≥24-hour stay)

115

105

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). 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. Formoterol Monotherapy Studies

Clinical studies with formoterol used as monotherapy suggested a higher incidence of serious asthma exacerbation in patients who received formoterol than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the difference in serious asthma exacerbations between treatment groups. 5.2 Deterioration of Disease and Acute Episodes

BREYNA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. BREYNA has not been studied in patients with acutely deteriorating asthma or COPD. The initiation of BREYNA 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 replacing the current strength of BREYNA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 2 inhalations twice daily (morning and evening) of BREYNA.

BREYNA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not BREYNA, should be used to relieve acute symptoms such as shortness of breath.

When beginning treatment with BREYNA, patients who have been taking oral or inhaled, short- acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs. 5.3 Excessive Use of BREYNA and Use with Other Long-Acting Beta2-Agonists

As with other inhaled drugs containing beta2-adrenergic agents, BREYNA 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 BREYNA should not use an additional LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced bronchospasm (EIB) or the treatment of asthma or COPD. 5.4 Local Effects

In clinical studies, the development of localized infections of the mouth and pharynx with

Candida albicans

has occurred in patients treated with budesonide and formoterol fumarate dihydrate inhalation aerosol. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while treatment with BREYNA continues, but at times therapy with BREYNA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. 5.5 Pneumonia and Other Lower Respiratory Tract Infections

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap. Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids.

In a 6-month lung function study of 1704 patients with COPD, there was a higher incidence of lung infections other than pneumonia (e.g., bronchitis, viral lower respiratory tract infections, etc.) in patients receiving budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg (7.6%) than in those receiving budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg (3.2%), formoterol 4.5 mcg (4.6%) or placebo (3.3%). Pneumonia did not occur with greater incidence in the budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg group (1.1 %) compared with placebo (1.3%). In a 12-month lung function study of 1964 patients with COPD, there was also a higher incidence of lung infections other than pneumonia in patients receiving budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg (8.1%) than in those receiving budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg (6.9%), formoterol 4.5 mcg (7.1%) or placebo (6.2%). Similar to the 6-month study, pneumonia did not occur with greater incidence in the budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg group (4.0%) compared with placebo (5.0%). 5.6 Immunosuppression

Patients who are on 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 exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see the respective package inserts for complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents may be considered. The immune responsiveness to varicella vaccine was evaluated in pediatric patients with asthma ages 12 months to 8 years with budesonide inhalation suspension.

An open-label, nonrandomized clinical study examined the immune responsiveness to varicella vaccine in 243 asthma patients 12 months to 8 years of age who were treated with budesonide inhalation suspension 0.25 mg to 1 mg daily (n = 151) or noncorticosteroid asthma therapy (n = 92) (i.e., beta2-agonists, leukotriene receptor antagonists, cromones). The percentage of patients developing a seroprotective antibody titer of ≥ 5.0 (gpELISA value) in response to the vaccination was similar in patients treated with budesonide inhalation suspension (85%), compared to patients treated with noncorticosteroid asthma therapy (90%). No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination.

Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.7 Transferring Patients From Systemic Corticosteroid Therapy

Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. 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 BREYNA may provide control of 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 asthma attack or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians 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 asthma attack, or a severe COPD exacerbation.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREYNA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREYNA. Lung function (mean forced expiratory volume in 1 second [FEV1] or morning peak expiratory flow [PEF]), beta-agonist use, and asthma or COPD symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to inhaled corticosteroids or BREYNA may unmask conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function. 5.8 Hypercorticism and Adrenal Suppression

Budesonide, a component of BREYNA, will often help control asthma and COPD symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since budesonide is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of BREYNA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with BREYNA 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, particularly when budesonide is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of BREYNA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms. 5.9 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors

Caution should be exercised when considering the coadministration of BREYNA with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur

[see

Drug Interactions (7.1)

and Clinical Pharmacology (12.3)]. 5.10 Paradoxical Bronchospasm and Upper Airway Symptoms

As with other inhaled medications, BREYNA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREYNA, it should be treated immediately with an inhaled, short-acting bronchodilator, BREYNA should be discontinued immediately, and alternative therapy should be instituted. 5.11 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of BREYNA, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm. 5.12 Cardiovascular and Central Nervous System Effects

Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see Overdosage (10)]. Therefore, BREYNA, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Formoterol, a component of BREYNA, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of formoterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. 5.13 Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. 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 BREYNA and periodically thereafter. If significant reductions in BMD are seen and BREYNA is still considered medically important for that patient’s COPD therapy, use of medication to treat or prevent osteoporosis should be strongly considered.

Effects of treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg, budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg, formoterol 4.5 mcg, or placebo on BMD was evaluated in a subset of 326 patients (females and males 41 to 88 years of age) with COPD in the 12-month lung function study. BMD evaluations of the hip and lumbar spine regions were conducted at baseline and 52 weeks using dual energy x-ray absorptiometry (DEXA) scans. Mean changes in BMD from baseline to end of treatment were small (mean changes ranged from -0.01 - 0.01 g/cm2). ANCOVA results for total spine and total hip BMD based on the end of treatment time point showed that all geometric LS Mean ratios for the pairwise treatment group comparisons were close to 1, indicating that overall, BMD for total hip and total spine regions for the 12‑month time point were stable over the entire treatment period. 5.14 Effect on Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving BREYNA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including BREYNA, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2.2) and Use in Specific Populations (8.4)]. 5.15 Glaucoma and Cataracts

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long-term administration of inhaled corticosteroids, including budesonide, a component of BREYNA. Therefore, close monitoring is warranted in patients with a change in vision or with history of increased intraocular pressure, glaucoma, and/or cataracts.

Effects of treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg, budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg, formoterol 4.5 mcg, or placebo on development of cataracts or glaucoma were evaluated in a subset of 461 patients with COPD in the 12-month lung function study. Ophthalmic examinations were conducted at baseline, 24 weeks, and 52 weeks. There were 26 subjects (6%) with an increase in posterior subcapsular score from baseline to maximum value (> 0.7) during the randomized treatment period. Changes in posterior subcapsular scores of > 0.7 from baseline to treatment maximum occurred in 11 patients (9.0%) in the budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg group, 4 patients (3.8%) in the budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg group, 5 patients (4.2%) in the formoterol group, and 6 patients (5.2%) in the placebo group. 5.16 Eosinophilic Conditions and Churg-Strauss Syndrome

In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between budesonide and these underlying conditions has not been established. 5.17 Coexisting Conditions

BREYNA, like all medications 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. 5.18 Hypokalemia and Hyperglycemia

Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology (12.2)]. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with budesonide and formoterol fumarate dihydrate inhalation aerosol at recommended doses.

BREYNA is available as a metered-dose inhaler containing a combination of budesonide (80 mcg or 160 mcg) and formoterol fumarate dihydrate (4.5 mcg) as an inhalation aerosol in the following two strengths: 80 mcg/4.5 mcg and 160 mcg/4.5 mcg. Each dosage strength contains 120 actuations per/canister. Each strength of BREYNA is supplied with a blue plastic actuator with a grey dust cap.

Caution should be exercised when considering the coadministration of BREYNA with 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)].

In clinical studies, concurrent administration of budesonide and formoterol fumarate dihydrate inhalation aerosol and other drugs, such as short-acting beta₂-agonists, intranasal corticosteroids, and antihistamines/decongestants has not resulted in an increased frequency of adverse reactions. No formal drug interaction studies have been performed with budesonide and formoterol fumarate dihydrate inhalation aerosol.

A single-dose crossover study was conducted to compare the pharmacokinetics of eight inhalations of the following: budesonide, formoterol, and budesonide plus formoterol administered concurrently. The results of the study indicated that there was no evidence of a pharmacokinetic interaction between the two components of budesonide and formoterol fumarate dihydrate inhalation aerosol.