Breyna 80/4.5

— THERAPEUTIC CATEGORIES —
  • Asthma/COPD
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Breyna 80/4.5 Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Budesonide 80mcg, formoterol fumarate dihydrate 4.5mcg; per inh; pressurized metered-dose inhaler.

    Pharmacological Class

    Corticosteroid + long-acting beta-2 agonist (LABA).

    See Also

    How Supplied

    Inhaler—10.3g (120 inh)

    How Supplied

    Breyna is supplied as a pressurized aluminum canister with an attached counting device, a blue plastic actuator body with a blue mouthpiece, and attached grey dust cap. 

    • Breyna is available as 80mcg/4.5mcg or 160mcg/4.5mcg strengths in 120-count inhalations.

    • Each 120 inhalation canister has a net fill weight of 10.3 grams. 

    • Each canister is packaged in a foil overwrap pouch with a desiccant sachet and placed into a carton.

    Storage

    Store at controlled room temperature 20°C to 25°C (68°F to 77°F) [see USP]. Store the inhaler with the mouthpiece down.

    Manufacturer

    Mylan Inc.

    Mechanism of Action

    Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. Inflammation is an important component in the pathogenesis of COPD and asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (eg, histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non–allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in COPD and asthma. Formoterol fumarate is a long-acting selective beta2-adrenergic agonist with a rapid onset of action. Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol, 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 (cAMP). Increased cAMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

    Breyna 80/4.5 Indications

    Indications

    Treatment of asthma in patients ≥6yrs old not adequately controlled on a long-term asthma control medication [eg, inhaled corticosteroid (ICS)] or whose disease warrants initiation of both an ICS and LABA.

    Limitations of Use

    Not for relief of acute bronchospasm.

    Breyna 80/4.5 Dosage and Administration

    Adult

    Allow approx. 12hrs between doses. Asthma: Base initial dose on asthma severity. 2 inh of 80/4.5 or 160/4.5 twice daily (AM & PM). If insufficient response after 1–2 weeks using 80/4.5 strength, may switch to 160/4.5 strength. Max 2 inh of 160/4.5 twice daily. Titrate to lowest effective strength after adequate response. COPD: 2 inh of 160/4.5 twice daily. Rinse mouth after use.

    Adult

    Asthma

    • Allow approx. 12 hours between doses. Rinse mouth after use. 

    • If symptoms arise between doses, an inhaled short-acting beta2-agonist should be used for immediate relief.

    • For patients 12 years of age and older:

      • 2 inhalations of 80/4.5 or 160/4.5 twice daily (AM & PM). Starting dosages are based upon the patients’ asthma severity or level of control of asthma symptoms, and risk of exacerbations on current inhaled corticosteroids (ICS).

      • Maximum recommended dose: 2 inhalations of 160mcg/4.5mcg twice daily.

      • Improvement in asthma control can occur within 15 minutes of administration. Maximum benefit may not be achieved for 2 weeks or longer after starting treatment. Higher doses may provide additional asthma control if patients do not respond adequately to the starting dose after 2 weeks of therapy. 

      • If insufficient response after 1–2 weeks using 80/4.5 strength, may switch to 160/4.5 strength.

      • If a dosage regimen fails to provide adequate control of asthma, re-evaluate and additional therapeutic options should be considered (eg, replacing the current strength with a higher strength, initiating an ICS and long-acting beta2-agonist (LABA) combination product, or initiating oral corticosteroids).

    COPD

    • Allow approx. 12 hours between doses. Rinse mouth after use. 

    • If symptoms arise between doses, an inhaled short-acting beta2-agonist should be used for immediate relief.

    • For patients 12 years of age and older:

      • 2 inh of 160/4.5 twice daily. 

    Children

    Allow approx. 12hrs between doses. Asthma: <6yrs: not established. 6–<12yrs: 2 inh of 80/4.5 twice daily (AM & PM). Rinse mouth after use. COPD: not indicated.

    Children

    Asthma

    • Allow approx. 12 hours between doses. Rinse mouth after use. 

    • If symptoms arise between doses, an inhaled short-acting beta2-agonist should be used for immediate relief.

    • For patients 6 to less than 12 years of age and older:

      • 2 inhalations of 80/4.5 twice daily (AM & PM).

    Breyna 80/4.5 Contraindications

    Contraindications

    Primary treatment of status asthmaticus or acute attacks of asthma or COPD requiring intensive measures.

    Breyna 80/4.5 Boxed Warnings

    Not Applicable

    Breyna 80/4.5 Warnings/Precautions

    Warnings/Precautions

    LABA monotherapy (without ICS) can increase risk of asthma-related events (death, hospitalizations, intubations). Do not initiate in rapidly or acutely deteriorating COPD or asthma. Not for use with other long-acting β2-agonists. Do not exceed recommended dose. Prescribe a short-acting, inhaled β2-agonist for acute symptoms; monitor for increased need. Monitor for signs/symptoms of pneumonia. Immunosuppressed. Tuberculosis. Systemic infections. Ocular herpes simplex. If exposed to chickenpox or measles, consider immune globulin prophylaxis or antiviral ­treatment. Monitor for adrenal insufficiency when transferring from systemic steroids. May need supplemental systemic corticosteroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack. May unmask previously suppressed allergic conditions. Reevaluate periodically. Monitor for hypercorticism and HPA axis suppression (if occurs, discontinue gradually), growth in children, intraocular pressure, glaucoma, or cataracts. Discontinue if paradoxical bronchospasm occurs; use alternative therapy. Cardiovascular disease (esp. coronary insufficiency, arrhythmias, hypertension). Eosinophilic conditions. Convulsive disorders. Thyrotoxicosis. Hyperresponsiveness to sympathomimetics. Diabetes. Ketoacidosis. Hypokalemia. Hyperglycemia. Hepatic impairment; monitor. Assess bone mineral density if risk factors exist (eg, osteoporosis, postmenopausal). Labor & delivery. Pregnancy. Nursing mothers.

    Warnings/Precautions

    Serious Asthma-Related Events – Hospitalizations, Intubations and Death

    • Increased risk for asthma-related death when use of LABA as monotherapy (without ICS) for asthma. Moreover, use of LABA as monotherapy increases the risk for asthma-related hospitalization in pediatric and adolescent patients.

    Serious Asthma-Related Events with ICS/LABA

    • Four large, 26-week, clinical safety trials evaluated the risk for serious asthma-related events when LABA were used in fixed-dose combination with ICS vs ICS alone in patients with asthma. 

      • In the 3 adult and adolescent trials, ICS/LABA met its pre-specified objective and demonstrated noninferiority to ICS alone. A meta-analysis of the 3 trials did not show a significant increase in risk for a serious asthma-related event with ICS/LABA fixed-dose combination vs ICS alone.

      • In the pediatric safety trial, there were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk for a serious asthma-related event vs ICS.

    Salmeterol Multicenter Asthma Research Trial (SMART)

    • In a 28-week, placebo-controlled US trial, the safety of salmeterol was compared with placebo in addition to the usual asthma therapy. Findings showed an increase in asthma-related deaths among patients-treated with salmeterol. The use of background ICS was not required in this trial.

    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. 

    Deterioration of Disease and Acute Asthma Episodes

    • Do not initiate Breyna 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.

    • A marker of deteriorating asthma is an increased use of inhaled, short-acting beta2-agonists; immediately re-evaluate patient if this occurs.

    • Do not use Breyna for the relief of acute symptoms (eg, as rescue therapy for the treatment of acute episodes of bronchospasm.

    • When beginning treatment with Breyna, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (eg, 4 times a day) should be instructed to discontinue the regular use of these drugs.

    Excessive Use of Breyna and Use with Other Long-Acting Beta2-Agonists

    • Do not use more often than the recommended, at higher doses than recommended, or in conjunction with other medications containing LABA.

    • Do not use an additional LABA for any reason, including prevention of exercise-induced bronchospasm or the treatment of asthma or COPD.

    Local Effects

    • Localized infections with Candida albicans may occur in the mouth and pharynx in some patients.

    • If these infections develop, patients may require treatment with appropriate local or systemic antifungal therapy and/or interruption of treatment.

    • Rinse mouth after each inhalation. 

    Pneumonia and Other Lower Respiratory Tract Infections

    • Risk for development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap.

    Immunosuppression

    • If exposed to chicken pox, 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, may consider treatment with antiviral agents.

    • Use caution in patients with active or quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral or parasitic infections; or ocular herpes simplex. 

    Transferring Patients from Systemic Corticosteroid Therapy

    • Use particular care when transferring patients from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency may occur.

    • The most susceptible patients are those who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent).

    • A number of months are required for recovery of HPA-axis function after withdrawal from systemic corticosteroids. During this period of HPA-axis suppression, patients exposed to trauma, surgery, infection, or other conditions associated with severe electrolyte loss may exhibit signs and symptoms of adrenal insufficiency.

    • During periods of stress, a severe COPD exacerbation, or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and contact their physicians. These patients should carry a medical identification card.

    • If oral corticosteroids are required, patients should be weaned slowly from systemic corticosteroid use after transferring to Breyna. For these patients, accomplish prednisone reduction by reducing the daily prednisone dose by 2.5mg on a weekly basis during Breyna therapy. Monitor carefully lung function (FEV1 or AM PEF), beta-agonist use, and asthma or COPD symptoms during withdrawal of oral corticosteroids. Observe for signs and symptoms of adrenal insufficiency.

    • Transfer from systemic corticosteroid therapy to Breyna may unmask conditions previously suppressed by the systemic corticosteroid therapy.

    Hypercorticism and Adrenal Suppression  

    • Use particular care when observing patients post-operatively or during periods of stress for evidence of inadequate adrenal response

    • Systemic corticosteroid effects may occur, including hypercorticism, and adrenal suppression (including adrenal crisis), particularly when budesonide is administered at higher than recommended doses over prolonged periods of time. Reduce dose of Breyna slowly if these effects occur.

    Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

    • Use caution when considering using ketoconazole and other known strong CYP3A4 inhibitors  (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) with Breyna because it may potentiate systemic exposure to budesonide. 

    Paradoxical Bronchospasm and Upper Airway Symptoms 

    • Discontinue treatment and institute alternative therapy if paradoxical bronchospasm occurs, and treat immediately with a fast-acting inhaled bronchodilator.

    Immediate Hypersensitivity Reactions 

    • Immediate hypersensitivity reactions may occur, including urticaria, angioedema, rash, and bronchospasm. 

    Cardiovascular and Central Nervous System Effects

    • Use with caution in patients with cardiovascular disorders (esp. coronary insufficiency, arrhythmias, hypertension). Consider discontinuing treatment if significant cardiovascular effects occur.

    • Beta2-agonists can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic and/or diastolic blood pressure, and/or symptoms. ECG changes have also been reported.

    Reduction in Bone Mineral Density

    • Decreases in bone mineral density (BMD) have been observed with long-term administration of inhaled corticosteroids.

    • Monitor and treat appropriately in patients with major risk factors for decreased BMD, such as prolonged immobilization, family history of osteoporosis, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids).

    Effects on Growth

    • May cause a reduction in growth velocity when administered to pediatric patients.

    • Monitor growth routinely if administered to pediatric patients. These systemic effects can be minimized by titrating each patient to their lowest effective dose.

    Glaucoma and Cataracts

    • Monitor closely in patients with a change in vision or with a history of increased  intraocular pressure, glaucoma, and/or cataracts.

    Eosinophilic Conditions and Churg-Strauss Syndrome 

    • In rare cases, may present with systemic eosinophilic conditions.

    • Health care providers should be alert to eosinophilia, vasculitis rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.

    Coexisting Conditions

    • Use with caution in patients with convulsive disorders or thyrotoxicosis. Use with caution in patients who are unusually responsive to sympathomimetic amines.

    • Doses of the related beta2-agonist albuterol, when given intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 

    Hypokalemia and Hyperglycemia

    • Beta-agonists may produce significant hypokalemia in some patients.

    • This is usually transient and does not require supplementation.

    Pregnancy Considerations

    Risk Summary

    • There are no adequate and well-controlled studies on the use of Breyna or its individual components, formoterol fumarate, in pregnant women.

    Clinical Considerations

    • Disease-Associated Maternal and/or Embryofetal Risk: Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control of asthma. 

    • Labor or Delivery: Use only during labor if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility.

    Nursing Mother Considerations

    Risk Summary

    • There is no available data on the effects of Breyna on the breastfed child or the effects on milk production. 

    • Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Breyna and any potential adverse effects on the breastfed child from Breyna or from the underlying maternal condition. 

    Pediatric Considerations

    • The safety and effectiveness of Breyna in asthma patients less than 6 years of age have not been established.

    • May cause a reduction in growth velocity when administered to pediatric patients.

    • Monitor growth routinely if administered to pediatric patients. These systemic effects can be minimized by titrating each patient to their lowest effective dose.

    Geriatric Considerations

    No adjustment of the dosage of Breyna in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. 

    Renal Impairment Considerations

    Formal pharmacokinetic studies have not been conducted in patients with renal impairment.

    Hepatic Impairment Considerations

    • Formal pharmacokinetic studies have not been conducted in patients with hepatic impairment.

    • Hepatic impairment may lead to accumulation of budesonide and formoterol fumarate in plasma. Monitor closely in patients with hepatic disease.

    Breyna 80/4.5 Pharmacokinetics

    Absorption

    Budesonide:

    • Peak concentration is reached within 20 minutes.

    Formoterol fumarate:

    • Peak plasma concentrations are reached within 5 to 10 minutes.

    Distribution

    Budesonide:

    • Volume of distribution: ~3 L/kg. 85% to 90% plasma protein bound.

    Formoterol fumarate:

    • Plasma protein binding for the RR and SS enantiomers of formoterol was 46% and 58%, respectively.

    Metabolism

    Budesonide:

    • Peak concentration is reached within 20 minutes.

    Formoterol fumarate:

    • Peak plasma concentrations are reached within 5 to 10 minutes.

    Elimination

    Budesonide:

    • Excreted in urine and feces. Approximately 60% of an intravenous radiolabeled dose was recovered in the urine.

    • Terminal half-life was 2 to 3 hours.

    Formoterol fumarate:

    • Excreted in urine (62%) and feces (24%).

     

    Breyna 80/4.5 Interactions

    Interactions

    Caution with concomitant strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin), during or within 2 weeks of discontinuing MAOIs or tricyclic antidepressants, β-blockers (consider cardioselective), K+-depleting diuretics.

    Breyna 80/4.5 Adverse Reactions

    Adverse Reactions

    Nasopharyngitis, pharyngolaryngeal pain, sinusitis, nasal congestion, oral candidiasis, headache, upper respiratory infection, flu, back pain, stomach discomfort, vomiting; hypersensitivity reactions. COPD: also bronchitis.

    Breyna 80/4.5 Clinical Trials

    Clinical Trials

    Asthma

    Study 1: Clinical Study with Budesonide and Formoterol fumarate dihydrate inhalation aerosol 160/4.5

    • The 12-week study compared budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5, the free combination of budesonide 160 mcg plus formoterol 4.5 mcg in separate inhalers, budesonide 160 mcg, formoterol 4.5 mcg, and placebo in 596 patients 12 years of age and older. Each component was administered as 2 inhalations twice daily.

    • The coprimary efficacy endpoints were 12-hour-average post-dose FEV1 at week 2, and pre-dose FEV1 averaged over the course of the study. 

    • Patients receiving budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 had significantly greater mean improvements from baseline in pre-dose FEV1 at the end of treatment (0.19 L, 9.4%), compared with budesonide 160 mcg (0.10 L, 4.9%), formoterol 4.5 mcg (-0.12 L, -4.8%), and placebo (-0.17 L, -6.9%).

    • Treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol achieved a clinically meaningful improvement in pre-dose FEV1 at the end of treatment (0.19 L, 9.4%), vs budesonide 160 mcg (0.10 L, 4.9%), formoterol 4.5 mcg (-0.12 L, -4.8%), and placebo (-0.17 L, -6.9%).

    • Patients treated with budesonide and formoterol fumarate dihydrate inhalation aerosol also had clinically meaningful improvement in overall asthma-specific quality of life, as defined by a mean difference between treatment groups of >0.5 points in change from baseline in overall AQLQ score (difference in AQLQ score of 0.70 [95% CI 0.47, 0.93], compared to placebo).

    Study 2: Clinical Study with Budesonide and Formoterol fumarate dihydrate inhalation aerosol 80/4.5

    • The 12-week study was similar in design to Study 1, and compared budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5, budesonide 80 mcg, formoterol 4.5 mcg, and placebo in 480 patients 12 years of age and older with mild to moderate asthma. Each component was administered as 2 inhalations twice daily. 

    • Efficacy results were similar to those observed in Study 1.

    Onset and Duration of Action and Progression of Improvement in Asthma Control

    • Two pivotal clinical studies evaluated the onset of action and progression of improvement in asthma control. 

    • The median time to onset of clinically significant bronchodilation (>15% improvement in FEV1) was seen within 15 minutes. Maximum improvement in FEV1 occurred within 3 hours, and clinically significant improvement was maintained over 12 hours. 

    • After the first dose of budesonide and formoterol fumarate dihydrate inhalation aerosol, asthma symptoms and albuterol rescue use as well as improvement in morning and evening PEF occurred within 1 day. Improvement in these variables was maintained over the 12 weeks of therapy.

    • No diminution in the 12-hour bronchodilator effect was observed with either budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 or budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5, as assessed by FEV1, following 12 weeks of therapy or at the last available visit.

    Patients with Asthma 6 to less than 12 years of age

    • The efficacy of budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 in children 6 to less than 12 years of age was evaluated in a clinical program which included: 1) a budesonide dose confirmatory study, 2) a formoterol dose finding study, and 3) an efficacy and safety study of the budesonide and formoterol fumarate dihydrate inhalation aerosol combination product.

    • Budesonide 80mcg was selected based on a 6-week, randomized, double-blind, placebo-controlled study in 304 pediatric patients (152 budesonide, 152 placebo) 6 to less than 12 years of age with asthma. Compared to placebo, treatment with budesonide 80 mcg achieved a statistically significantly greater improvement in the change from baseline to the treatment period average in pre-dose morning PEF and the change in pre-dose morning FEV1.

    • Formoterol dose selection was based on a randomized, single dose, placebo-controlled, active-controlled (Foradil Aerolizer 12 mcg), 5-way cross-over study in which doses of 2.25, 4.5 and 9 mcg formoterol were administered in combination with budesonide in 54 pediatric patients 6 to less than 12 years of age with asthma. Compared to the active control, treatment with formoterol achieved dose response for FEV1 averaged over 12 hours post-dose and the 9 mcg group achieved numerically similar results.

    • A 12-week, randomized, double-blind, multicenter confirmatory efficacy study compared budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 to budesonide pMDI 80 mcg administered as 2 inhalations twice daily in 184 pediatric patients 6 to less than 12 years of age with a documented clinical diagnosis of asthma. Results showed that treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 achieved a statistically significant improvement in 1-hour post-dose FEV1 of 0.28 L at week 12 from baseline compared with 0.17 L for budesonide 80 mcg (mean difference, 0.12 L; 95% CI, 0.03-0.20). Moreover, budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 achieved improvement from baseline to week 12 for 1-hour post-dose clinic PEF (mean difference, 25.5 L/min/ 95% CI, 10.9-40.0). Bronchodilatory effects were evidence from the first assessment at 15 minutes on day 1 and were maintained at week 12. The estimated mean difference between budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 and budesonide with respect to change from baseline to Week 12 in 15 minutes post-dose clinic FEV1 was 0.10 L (95% CI, 0.02-0.18). 

    Postmarketing Safety and Efficacy Study

    • A randomized, double-blind, parallel-group, safety study compared budesonide and formoterol fumarate dihydrate inhalation aerosol with budesonide, each administered as 2 inhalations twice daily over 26 weeks (NCT01444430). The primary safety objective was to evaluate whether the addition of formoterol to budesonide therapy (budesonide and formoterol fumarate dihydrate inhalation aerosol) was non-inferior to budesonide in terms of the risk of serious asthma-related events (asthma-related hospitalization, endotracheal intubation, and death). 

    • Budesonide and formoterol fumarate dihydrate inhalation aerosol achieved noninferiority to budesonide in terms of time to first serious asthma-related events based on the pre-specified risk margin, with an estimated hazard ratio of 1.07 (95% CI, 0.70-1.65).

    • The estimated hazard ratio for time to first asthma exacerbation rate for budesonide and formoterol fumarate dihydrate inhalation aerosol relative to budesonide was 0.84 (95% CI, 0.75-0.94). This outcome was primarily driven by a reduction in systemic corticosteroid use.

     

    Chronic Obstructive Pulmonary Disease

    Lung Function

    The efficacy of budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 and budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 in the maintenance treatment of airflow obstruction in COPD patients was evaluated in two randomized, double-blind, placebo-controlled multinational studies, conducted over 6 months (Study 1) and 12 months (Study 2), in a total of 3668 patients (2416 males and 1252 females). Eligible patients were at least 40 years of age, with a FEV1 of less than or equal to 50% predicted, a clinical diagnosis of COPD with symptoms for at least 2 years, and a smoking history of at least 10 years.

    Lung Function – Study 1

    • The 6-month, placebo-controlled study evaluated the efficacy and safety of budesonide and formoterol fumarate dihydrate inhalation aerosol for the treatment of airflow obstruction in 1704 COPD patients. Patients were randomly assigned to receive: budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 (n=277), budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 (n=281), budesonide 160 mcg + formoterol 4.5 mcg (n=287), budesonide 160 mcg (n=275), formoterol 4.5 mcg (n=284), or placebo (n=300). 

    • Treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 achieved significantly greater mean improvements in pre-dose FEV1 of 0.08 L  (10.7%) averaged over the treatment period vs 0.04 L (6.9%) for formoterol 4.5 mcg and 0.01 L (2.2%) for placebo. 

    • Treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 also achieved significantly greater mean improvements in 1-hour post-dose FEV1 of 0.20 L (22.6%) averaged over the treatment period vs 0.03 L (4.9%) for budesonide 160 mcg and 0.03 L (4.1%) for placebo.

    • Treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 did not achieve a significantly greater improvement in the pre-dose FEV1 vs formoterol 4.5 mcg.

    Lung Function – Study 2

    • The 12-month, placebo-controlled study evaluated the efficacy and safety of budesonide and formoterol fumarate dihydrate inhalation aerosol for the treatment of airflow obstruction in 1964 COPD patients. Patients were randomly assigned to receive: budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 (n=494), budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 (n=494), formoterol 4.5 mcg (n=495), or placebo (n=481).

    • Treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 achieved significantly greater mean improvements in pre-dose FEV1 of 0.10 L (10.8%) averaged over the treatment period vs 0.06 L (7.2%) for formoterol 4.5 mcg and 0.01 L (2.8%) for placebo. 

    • Treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 also achieved significantly greater mean improvements in 1-hour post-dose FEV1 of 0.21 L (24.0%) averaged over the treatment period vs 0.02 L (5.2%) for placebo.

    • Treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 did not achieve a significantly greater improvement in the pre-dose FEV1 vs formoterol.

    • Median time to onset of bronchodilation, defined as an FEV1 increase of 15% or greater from baseline, occurred at 5 minutes post-dose. Maximum improvement (calculated as the average change from baseline at each timepoint) in FEV1 occurred at approximately 2 hours post-dose.

    Exacerbations – Study 3

    • The 6-month, active-controlled study evaluated the effect of budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 compared to formoterol 4.5 mcg, each administered as 2 inhalations twice daily, on the rate of moderate and severe COPD exacerbations. Patients were randomly assigned to receive either budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 (n=606) or formoterol 4.5 mcg (n=613).

    • Treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 achieved a significantly lower annual rate of moderate/severe COPD exacerbations vs formoterol 4.5 mcg with a reduction of 26% (95% CI, 9%-39%).

    • The SGRQ responder rates at 6-months (defined as an improvement in score of 4 or more as a threshold) were 40% and 33% for budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 and formoterol 4.5 mcg, respectively, with an odds ratio of 1.5 (95% CI, 1.0-2.0) for budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 vs. formoterol 4.5 mcg. 

    Exacerbations – Study 4

    • The 12-month, active-controlled study evaluated the effect of budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 compared to formoterol 4.5 mcg, each administered as 2 inhalations twice daily, on COPD exacerbations. Patients were randomly assigned to receive either budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 (n=407) or formoterol 4.5 mcg (n=404).

    • Treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 achieved a significantly lower annual rate of moderate/severe COPD exacerbations vs formoterol 4.5 mcg with a reduction of 35% (95% CI, 20%-47%).

    • The SGRQ responder rates at 12-months (defined as an improvement in score of 4 or more as a threshold) were 50% and 49% for budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 and formoterol 4.5 mcg, respectively, with an odds ratio of 1.0 (95% CI, 0.8-1.4) for budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 vs. formoterol 4.5 mcg. 

    Breyna 80/4.5 Note

    Not Applicable

    Breyna 80/4.5 Patient Counseling

    Patient Counseling

    Serious Asthma-Related Events

    • Inform patients with asthma that LABA when used alone increases the risk of asthma-related hospitalization or asthma-related death. Available data show that when ICS and LABA are used together, such as with Breyna, there is not a significant increase in the risk of these events. 

    Not for Acute Symptoms

    • Inform patients that Breyna is not meant to relieve acute symptoms of asthma of COPD and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting beta2-agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used.

    • Instruct patients to seek medical attention immediately if they experience any of the following: decreasing effectiveness of inhaled, short-acting beta2-agonists; need for more inhalations than usual of inhaled, short-acting beta2-agonists; or significant decrease in lung function as outlined by the physician.

    • Tell patients they should not stop therapy with Breyna without physician/provider guidance since symptoms may recur after discontinuation.

    Do Not Use Additional Long-acting Beta2-agonists

    • Instruct patients not to use other LABA for asthma and COPD.

    Local Effects

    • Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (ie, oral) antifungal therapy while still continuing therapy with Breyna, but at times therapy with Breyna may need to be temporarily interrupted under close medical supervision. Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush.

    Pneumonia

    • Patients with COPD have a higher risk of pneumonia; instruct them to contact their healthcare providers if they develop symptoms of pneumonia.

    Immunosuppression and Risk of Infections

    • Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

    Hypercorticism and Adrenal Suppression

    • Advise patients that Breyna may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to Breyna.

    Reduction in Bone Mineral Density

    • Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk. 

    Reduced Growth Velocity

    • Advise patients that orally inhaled corticosteroids may reduce growth velocity in pediatric patients. Physicians should closely monitor the growth of children and adolescents.

    Ocular Effects

    • Advise patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.

    Risks Associated with Beta-agonist Therapy

    • Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

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