Mylan Pharmaceuticals Inc.
Budesonide and formoterol fumarate
GenericGeneric for Breyna
ID: 00378750332
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Aerosol
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TL;DR â Quick Summary
Key facts from the full medication guide below
đŠēWhat it's for
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.
đHow to take it
For oral inhalation only. Treatment of asthma in patients 12 years and older: 2 inhalations of BREYNA 80 mcg/4.5 mcg or 160 mcg/4.5 mcg twice daily. Starting dosage is based on asthma severity. (2.2) Treatment of asthma in patients aged 6 to less than 12 years: 2 inhalations of BREYNA 80 mcg/4.5 mcg twice daily. (2.2) Maintenance treatment in COPD: 2 inhalations of BREYNA 160 mcg/4.5 mcg twice daily.
âšī¸Common side effects
LABA use may result in the following: Serious asthma-related events hospitalizations, intubations, death [see Warnings and Precautions (5.1)]. Cardiovascular and central nervous system effects [see Warnings and Precautions (5.12)].
â ī¸Serious risks
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.
đInteractions & cautions
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)].
đĻStorage & missed dose
BREYNA (budesonide and formoterol fumarate dihydrate) Inhalation Aerosol is available in two strengths and is supplied in the following package sizes: Dosage Forms and Strengths Package Size NDC BREYNA Inhalations 80 mcg/4.5 mcg 120 0378-7502-32 BREYNA Inhalations 160 mcg/4.5 mcg 120 0378-7503-32 Each strength 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.
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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.
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.
For oral inhalation only. Treatment of asthma in patients 12 years and older: 2 inhalations of BREYNA 80 mcg/4.5 mcg or 160 mcg/4.5 mcg twice daily. Starting dosage is based on asthma severity. (2.2) Treatment of asthma in patients aged 6 to less than 12 years: 2 inhalations of BREYNA 80 mcg/4.5 mcg twice daily. (2.2) Maintenance treatment in COPD: 2 inhalations of BREYNA 160 mcg/4.5 mcg twice daily. (2.3)
BREYNA should be administered as 2 inhalations twice daily (morning and evening, approximately 12 hours apart), every day by the orally inhaled route only. After inhalation, the patient should rinse the mouth with water without swallowing. Prime BREYNA before using for the first time by releasing two test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well before each spray and releasing two test sprays into the air away from the face. More frequent administration or a higher number of inhalations (more than 2 inhalations twice daily) of the prescribed strength of BREYNA is not recommended as some patients are more likely to experience adverse effects with higher doses of formoterol. Patients using BREYNA should not use additional LABA for any reason [see Warnings and Precautions (5.3 , 5.12) ].
If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.
This was a 12-month, active-control study which included 811 subjects treated with budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg or formoterol 4.5 mcg, each administered as 2 inhalations twice daily. The study was conducted to evaluate for COPD exacerbation reduction in patients with COPD. COPD exacerbations were defined as worsening of COPD that required a course of oral steroids for treatment and/or hospitalization. This study randomized 407 subjects to budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg and 404 to formoterol 4.5 mcg of which 61% were male and 83% were Caucasian. They had a mean age of 63 years and a median smoking history of 45 pack years, with 36% identified as current smokers. At run-in, the mean post-bronchodilator % predicted normal FEV1 was 37.8% (range: 11.75% to 76.50%), and a history of at least 1 COPD exacerbation in the previous year treated with systemic corticosteroids and/or antibiotics. In Study 3, subjects treated with budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg, two inhalations twice daily had a significantly lower annual rate of moderate/severe COPD exacerbations compared with formoterol 4.5 mcg with a reduction of 26% (95% CI: 9%, 39%). In Study 4, a significantly lower annual rate of exacerbations was also observed in subjects treated with budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg compared with formoterol 4.5 mcg with a reduction of 35% (95% CI: 20%, 47%) (Table 8). Table 8. Chronic Obstructive Pulmonary Disease Exacerbations n Number of patients included in efficacy analysis set. n Annual Rate Estimate Rate Ratio Budesonide and Formoterol Fumarate Dihydrate Inhalation Aerosol 160 mcg/4.5 mcg vs. Formoterol 4.5 mcg Treatment Estimate 95% CI Study 3 Budesonide and Formoterol Fumarate Dihydrate Inhalation Aerosol 160 mcg/4.5 mcg 606 0.94 0.74 0.61, 0.91 Formoterol 4.5 mcg 613 1.27 Study 4 Budesonide and Formoterol Fumarate Dihydrate Inhalation Aerosol 160 mcg/4.5 mcg 404 0.68 0.65 0.53, 0.80 Formoterol 4.5 mcg 403 1.05 Health-related quality of life was measured using the St. George s Respiratory Questionnaire (SGRQ) in both COPD exacerbation clinical studies. In Study 3, 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 mcg/4.5 mcg 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 mcg/4.5 mcg vs. formoterol 4.5 mcg. In Study 4, the responder rates at 12 months were 50% and 49% for budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg 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 mcg/4.5 mcg vs. formoterol 4.5 mcg.
For patients with COPD the recommended dose is BREYNA 160 mcg/4.5 mcg, two inhalations twice daily. If shortness of breath occurs in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.
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. Metered-dose inhaler containing a combination of budesonide (80 mcg or 160 mcg) and formoterol fumarate dihydrate (4.5 mcg) as an inhalation aerosol. (3)
The use of BREYNA is contraindicated in the following conditions: Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required. Hypersensitivity to any of the ingredients in BREYNA. Primary treatment of status asthmaticus or acute episodes of asthma or COPD requiring intensive measures (4) Hypersensitivity to any of the ingredients in BREYNA (4)
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)
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 ).
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.
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.
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.
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%).
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.
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.
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.
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)].
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.
Immediate hypersensitivity reactions may occur after administration of BREYNA, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm.
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.
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.
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)].
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.
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.
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.
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.
LABA use may result in the following: Serious asthma-related events hospitalizations, intubations, death [see Warnings and Precautions (5.1)]. Cardiovascular and central nervous system effects [see Warnings and Precautions (5.12)]. Systemic and inhaled corticosteroid use may result in the following: Candida albicans infection [see Warnings and Precautions (5.4)] Pneumonia or lower respiratory tract infections in patients with COPD [see Warnings and Precautions (5.5)] Immunosuppression [see Warnings and Precautions (5.6)] Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8)] Growth effects in pediatric patients [see Warnings and Precautions (5.14)] 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. Most common adverse reactions (incidence 3%) are: Asthma: nasopharyngitis, headache, upper respiratory tract infection, pharyngolaryngeal pain, sinusitis, influenza, back pain, nasal congestion, stomach discomfort, vomiting, and oral candidiasis. (6.1) COPD: nasopharyngitis, oral candidiasis, bronchitis, sinusitis, upper respiratory tract infections. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
The safety data described below reflect exposure to budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg in 1783 patients. Budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg was studied in two placebo-controlled lung function studies (6 and 12 months in duration), and two active-controlled exacerbation studies (6 and 12 months in duration) in patients with COPD. The incidence of common adverse events in Table 3 below is based upon pooled data from two double-blind, placebo-controlled lung function clinical studies (6 and 12 months in duration) in which 771 adult COPD patients (496 males and 275 females) 40 years of age and older were treated with budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg, two inhalations twice daily. Of these patients 651 were treated for 6 months and 366 were treated for 12 months. The budesonide and formoterol fumarate dihydrate inhalation aerosol group was composed of mostly Caucasian (93%) patients with a mean age of 63 years, and a mean percent predicted FEV1 at baseline of 33%. Control arms for comparison included 2 inhalations of budesonide HFA (MDI) 160 mcg, formoterol (DPI) 4.5 mcg or placebo (MDI and DPI) twice daily. Table 3 includes all adverse events that occurred at an incidence of 3% in the budesonide and formoterol fumarate dihydrate inhalation aerosol group and more commonly than in the placebo group. In considering these data, the increased average duration of patient exposure to budesonide and formoterol fumarate dihydrate inhalation aerosol should be taken into account, as incidences are not adjusted for an imbalance of treatment duration. Table 3. Adverse Reactions Occurring at an Incidence of 3% and More Commonly Than Placebo in the Budesonide and Formoterol Fumarate Dihydrate Inhalation Aerosol Group: Pooled Data From Two Double-blind, Placebo-controlled Clinical COPD Trials Treatment All treatments were administered as 2 inhalations twice daily. Budesonide and Formoterol Fumarate Dihydrate Inhalation Aerosol Budesonide Formoterol Placebo Adverse Event 160 mcg/4.5 mcg N = 771 % 160 mcg N = 275 % 4.5 mcg N = 779 % N = 781 % Nasopharyngitis 7.3 3.3 5.8 4.9 Oral candidiasis 6.0 4.4 1.2 1.8 Bronchitis 5.4 4.7 4.5 3.5 Sinusitis 3.5 1.5 3.1 1.8 Upper respiratory tract infection viral 3.5 1.8 3.6 2.7 Average Duration of Exposure (days) 255.2 157.1 240.3 223.7 Lung infections other than pneumonia (mostly bronchitis) occurred in a greater percentage of subjects treated with budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg compared with placebo (7.9% vs. 5.1%, respectively). There were no clinically important or unexpected patterns of abnormalities observed for up to 1 year in chemistry, hematology, ECG, ECG (Holter) monitoring, HPA-axis, bone mineral density and ophthalmology assessments. The safety findings from the two double-blind, active-controlled exacerbations studies (6 and 12 months in duration) in which 1012 adult COPD patients (616 males and 396 females) 40 years of age and older were treated with budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg, two inhalations twice daily were consistent with the lung function studies.
The following adverse reactions have been identified during post-approval use of budesonide and formoterol fumarate dihydrate inhalation aerosol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Some of these adverse reactions may also have been observed in clinical studies with budesonide and formoterol fumarate dihydrate inhalation aerosol. Cardiac Disorders: angina pectoris, tachycardia, atrial and ventricular tachyarrhythmias, atrial fibrillation, extrasystoles, palpitations Endocrine Disorders: hypercorticism, growth velocity reduction in pediatric patients Eye Disorders: cataract, glaucoma, increased intraocular pressure Gastrointestinal Disorders: oropharyngeal candidiasis, nausea Immune System Disorders: immediate and delayed hypersensitivity reactions, such as anaphylactic reaction, angioedema, bronchospasm, urticaria, exanthema, dermatitis, pruritus Metabolic and Nutrition Disorders: hyperglycemia, hypokalemia Musculoskeletal, Connective Tissue, and Bone Disorders: muscle cramps Nervous System Disorders: tremor, dizziness Psychiatric Disorders: behavior disturbances, sleep disturbances, nervousness, agitation, depression, restlessness Respiratory, Thoracic, and Mediastinal Disorders: dysphonia, cough, throat irritation Skin and Subcutaneous Tissue Disorders: skin bruising Vascular Disorders: hypotension, hypertension
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. Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. May cause increased systemic corticosteroid effects. (7.1) Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol on vascular system. (7.2) Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. (7.3) Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non-potassium-sparing diuretics may worsen with concomitant beta-agonists. (7.4)
The main route of metabolism of corticosteroids, including budesonide, a component of BREYNA, is via cytochrome P450 (CYP) 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 CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the coadministration of BREYNA 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)].
BREYNA should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of formoterol, a component of BREYNA, on the vascular system may be potentiated by these agents. In clinical trials with budesonide and formoterol fumarate dihydrate inhalation aerosol, a limited number of COPD and asthma patients received tricyclic antidepressants, and, therefore, no clinically meaningful conclusions on adverse events can be made.
Beta-blockers (including eye drops) may not only block the pulmonary effect of beta-agonists, such as formoterol, a component of BREYNA, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
The ECG changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of BREYNA with non-potassium-sparing diuretics.
Hepatic impairment: Monitor patients for signs of increased drug exposure. (8.6)
There are no available data on the effects of budesonide and formoterol fumarate dihydrate inhalation aerosol, budesonide or formoterol fumarate on the breastfed child or on milk production. Budesonide, like other inhaled corticosteroids, is present in human milk [see Data]. There are no available data on the presence of formoterol fumarate in human milk. Formoterol fumarate is present in rat milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother s clinical need for BREYNA and any potential adverse effects on the breastfed infant from BREYNA or from the underlying maternal condition.
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.
There are no well-controlled human studies that have investigated the effects of budesonide and formoterol fumarate dihydrate inhalation aerosol during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of BREYNA during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.
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 2534 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%).
Budesonide and Formoterol Fumarate Dihydrate Inhalation Aerosol In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-16, budesonide and formoterol fumarate dihydrate inhalation aerosol produced umbilical hernia in fetuses at doses less than the MRHDID (on a mcg/m2 basis at maternal inhaled doses of 12/0.66 mcg/kg/day and above). Fetal weights were reduced at approximately 5 and 3 times the MRHDID, respectively (on an AUC basis at a maternal inhaled dose of 80/4.4 mcg/kg (budesonide/formoterol)). No teratogenic or embryocidal effects were detected at doses less than the MRHDID (on a mcg/m2 basis at a maternal inhaled dose of 2.5/0.14 mcg/kg/day). 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 in the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at doses less than 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 less than 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 6-18, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities at doses less than 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 teratogenic 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 have an effect on growth and development of offspring. Offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation at doses less than 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 In a fertility and reproduction study, male rats were orally dosed for 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 1600 times and greater than 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 1600 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 6-15, no teratogenic, embryocidal or developmental effects were seen at doses up to 375 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 6-18, subcapsular cysts on the liver were observed in the fetuses at a dose 65,000 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 3800 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 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.
Safety and effectiveness of budesonide and formoterol fumarate dihydrate inhalation aerosol in asthma patients 12 years of age and older have been established in studies up to 12 months. In the two 12-week, double-blind, placebo-controlled US pivotal studies 25 patients 12 to 17 years of age were treated with budesonide and formoterol fumarate dihydrate inhalation aerosol twice daily [see Clinical Studies (14.1)]. Efficacy results in this age group were similar to those observed in patients 18 years and older. There were no obvious differences in the type or frequency of adverse events reported in this age group compared with patients 18 years of age and older. The safety and effectiveness of budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg in asthma patients 6 to less than 12 years of age have been established in studies of up to 12-week duration [see Clinical Studies (14.1)]. The safety profile in these patients was consistent to that observed in patients 12 years of age and older who also received budesonide and formoterol fumarate dihydrate inhalation aerosol [see Adverse Reactions (6.1)]. The safety and effectiveness of budesonide and formoterol fumarate dihydrate inhalation aerosol in asthma patients less than 6 years of age have not been established. Controlled clinical studies have shown that orally inhaled corticosteroids including budesonide, a component of BREYNA, may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of HPA-axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effect of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final height are unknown. The potential for catch-up growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. In a study of asthmatic children 5 to 12 years of age, those treated with budesonide DPI 200 mcg twice daily (n = 311) had a 1.1 centimeter reduction in growth compared with those receiving placebo (n = 418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment. By the end of 4 years, children treated with budesonide DPI and children treated with placebo had similar growth velocities. Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study. The growth of pediatric patients receiving orally inhaled corticosteroids, including BREYNA, should be monitored. If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained. To minimize the systemic effects of orally inhaled corticosteroids, including BREYNA, each patient should be titrated to the lowest strength that effectively controls his/her asthma [see Dosage and Administration (2)].
Of the total number of asthma patients treated with budesonide and formoterol fumarate dihydrate inhalation aerosol twice daily in two 12-week studies and a 26-week postmarketing study, 791 were 65 years of age or older, of whom 141 were 75 years of age or older. In the COPD studies of 6 to 12 months duration, 810 patients treated with budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg, two inhalations twice daily were 65 years old and above and of those, 177 patients were 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. As with other products containing beta2-agonists, special caution should be observed when using BREYNA in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta2-agonists. Based on available data for budesonide and formoterol fumarate dihydrate inhalation aerosol or its active components, no adjustment of dosage of BREYNA in geriatric patients is warranted.
Formal pharmacokinetic studies using budesonide and formoterol fumarate dihydrate inhalation aerosol have not been conducted in patients with hepatic impairment. However, since both 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 hepatic disease should be closely monitored.
Formal pharmacokinetic studies using budesonide and formoterol fumarate dihydrate inhalation aerosol have not been conducted in patients with renal impairment.
BREYNA BREYNA contains both budesonide and formoterol fumarate dihydrate; therefore, the risks associated with overdosage for the individual components described below apply to BREYNA. In pharmacokinetic studies, single doses of 960/54 mcg (12 actuations of budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg) and 1280/36 mcg (8 actuations of 160 mcg/4.5 mcg), were administered to patients with COPD. A total of 1920/54 mcg (12 actuations of budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg) was administered as a single dose to both healthy subjects and patients with asthma. In a long-term active-controlled safety study in adolescent and adult asthma patients 12 years of age and older, budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg was administered for up to 12 months at doses up to twice the highest recommended daily dose. There were no clinically significant adverse reactions observed in any of these studies. Budesonide The potential for acute toxic effects following overdose of budesonide is low. If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur [see Warnings and Precautions (5)]. Budesonide at five times the highest recommended dose (3200 mcg daily) administered to humans for 6 weeks caused a significant reduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%). The corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma cortisol response to ACTH. Formoterol An overdose of formoterol would likely lead to an exaggeration of effects that are typical for beta2 agonists: seizures, angina, hypertension, hypotension, tachycardia, atrial and ventricular tachyarrhythmias, nervousness, headache, tremor, palpitations, muscle cramps, nausea, dizziness, sleep disturbances, metabolic acidosis, hyperglycemia, hypokalemia. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of formoterol. No clinically significant adverse reactions were seen when formoterol was delivered to adult patients with acute bronchoconstriction at a dose of 90 mcg/day over 3 hours or to stable asthmatics 3 times a day at a total dose of 54 mcg/day for 3 days. Treatment of formoterol overdosage consists of discontinuation of the medication together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of formoterol. Cardiac monitoring is recommended in cases of overdosage.
BREYNA 80 mcg/4.5 mcg and BREYNA 160 mcg/4.5 mcg each contain micronized budesonide and micronized formoterol fumarate dihydrate for oral inhalation only. Each BREYNA 80 mcg/4.5 mcg and BREYNA 160 mcg/4.5 mcg canister is formulated as a hydrofluoroalkane (HFA 227; 1,1,1,2,3,3,3-heptafluoropropane)-propelled pressurized metered dose inhaler containing 120 actuations [see Dosage Forms and Strengths (3) and How Supplied/Storage and Handling (16)]. After priming, each actuation meters either 91/5.1 mcg or 181/5.1 mcg from the valve and delivers either 80/4.5 mcg, or 160/4.5 mcg (budesonide micronized/formoterol fumarate dihydrate micronized) from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between actuation of the device and inspiration through the delivery system. BREYNA also contains povidone K25 USP as a suspending agent and polyethylene glycol 1000 NF as a lubricant. BREYNA should be primed before using for the first time by releasing two test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well for 5 seconds before each spray and releasing two test sprays into the air away from the face. One active component of BREYNA is budesonide, a corticosteroid designated chemically as (RS) 11 , 16 , 17,21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C25H34O6 and its molecular weight is 430.5. Its structural formula is: Budesonide is a white to off-white, tasteless, odorless powder which is practically insoluble in water and in heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 7.4 is 1.6 x 103. The other active component of BREYNA is formoterol fumarate dihydrate, a selective beta2-agonist designated chemically as (R*,R*)-( )-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide, (E)-2-butendioate(2:1), dihydrate. The empirical formula of formoterol is C42H56N4O14 and its molecular weight is 840.9. Its structural formula is: Formoterol fumarate dihydrate is a powder which is slightly soluble in water. Its octanol-water partition coefficient at pH 7.4 is 2.6. The pKa of formoterol fumarate dihydrate at 25 C is 7.9 for the phenolic group and 9.2 for the amino group.
In two COPD lung function studies, 6 months and 12 months in duration including 3668 COPD patients, no clinically important differences were seen in pulse rate, blood pressure, potassium, and glucose between budesonide and formoterol fumarate dihydrate inhalation aerosol, the individual components of budesonide and formoterol fumarate dihydrate inhalation aerosol, and placebo [see Clinical Studies (14.2)]. ECGs recorded at multiple clinic visits on treatment in both studies showed no clinically important differences for heart rate, PR interval, QRS duration, heart rate, signs of cardiac ischemia or arrhythmias between budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg, the monoproducts and placebo, all administered as 2 inhalations twice daily. Based on ECGs, 6 patients treated with budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg, 6 patients treated with formoterol 4.5 mcg, and 6 patients in the placebo group experienced atrial fibrillation or flutter that was not present at baseline. There were no cases of nonsustained ventricular tachycardia in the budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg, formoterol 4.5 mcg, or placebo groups. In the 12-month study, 520 patients had evaluable continuous 24-hour ECG (Holter) monitoring prior to the first dose and after approximately 1 and 4 months on treatment. No clinically important differences in ventricular or supraventricular arrhythmias, ventricular or supraventricular ectopic beats, or heart rate were observed among the groups treated with budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg, formoterol or placebo taken as 2 inhalations twice daily. Based on ECG (Holter) monitoring, one patient on budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg, no patients on formoterol 4.5 mcg, and three patients in the placebo group experienced atrial fibrillation or flutter that was not present at baseline.
The effects of inhaled budesonide administered via a dry powder inhaler on the HPA-axis were studied in 905 adults and 404 pediatric patients with asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by cosyntropin (ACTH) stimulation test, remained intact with budesonide treatment at recommended doses. For adult patients treated with 100, 200, 400, or 800 mcg twice daily for 12 weeks, 4%, 2%, 6%, and 13%, respectively, had an abnormal stimulated cortisol response (peak cortisol < 14.5 mcg/dL assessed by liquid chromatography following short-cosyntropin test) as compared to 8% of patients treated with placebo. Similar results were obtained in pediatric patients. In another study in adults, doses of 400, 800, and 1600 mcg of inhaled budesonide twice daily for 6 weeks were examined; 1600 mcg twice daily (twice the maximum recommended dose) resulted in a 27% reduction in stimulated cortisol (6-hour ACTH infusion) while 10-mg prednisone resulted in a 35% reduction. In this study, no patient on budesonide at doses of 400 and 800 mcg twice daily met the criterion for an abnormal stimulated-cortisol response (peak cortisol < 14.5 mcg/dL assessed by liquid chromatography) following ACTH infusion. An open-label, long-term follow-up of 1133 patients for up to 52 weeks confirmed the minimal effect on the HPA-axis (both basal- and stimulated- plasma cortisol) of budesonide when administered at recommended doses. In patients who had previously been oral-steroid-dependent, use of budesonide in recommended doses was associated with higher stimulated-cortisol response compared to baseline following 1 year of therapy.
The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum concentration of budesonide for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after dosing. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide levels in plasma samples obtained from five infants at about 90 minutes after breastfeeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (< 0.02 nmol/L in four infants and < 0.04 nmol/L in one infant) [see Use in Specific Populations (8.2)].
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.
BREYNA (budesonide and formoterol fumarate dihydrate) Inhalation Aerosol is available in two strengths and is supplied in the following package sizes: Dosage Forms and Strengths Package Size NDC BREYNA Inhalations 80 mcg/4.5 mcg 120 0378-7502-32 BREYNA Inhalations 160 mcg/4.5 mcg 120 0378-7503-32 Each strength 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. Each 120 inhalation canister has a net fill weight of 10.3 grams. Each canister is packaged in a foil overwrap pouch with desiccant sachet and placed into a carton. Each carton contains one canister and a Patient Information leaflet. The BREYNA canister should only be used with the BREYNA actuator, and the BREYNA actuator should not be used with any other inhalation drug product. The correct amount of medication in each inhalation cannot be ensured after the labeled number of inhalations from the canister have been used, even though the inhaler may not feel completely empty and may continue to operate. The inhaler should be discarded when the labeled number of inhalations have been used or within 3 months after removal from the foil pouch. Never immerse the canister into water to determine the amount remaining in the canister ( float test ). Store at 20 to 25 C (68 to 77 F) [See USP Controlled Room Temperature]. Store the inhaler with the mouthpiece down. For best results, the canister should be at room temperature before use. Shake well for 5 seconds before using. Keep out of the reach of children. Avoid spraying in eyes. CONTENTS UNDER PRESSURE. Do not puncture or incinerate. Do not store near heat or open flame. Exposure to temperatures over 120 F may cause bursting. Never throw container into fire or incinerator.
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Serious Asthma-Related Events: Inform patients with asthma that LABA when used alone increases the risk of asthma-related hospitalization or asthma-related death. Available data show that when ICS and LABA are used together, such as with BREYNA, there is not a significant increase in risk of these events. Not for Acute Symptoms: Inform patients that BREYNA is not meant to relieve acute symptoms of asthma or 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 the patient 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 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, it should be treated with appropriate local or systemic (i.e., 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. Rinsing the mouth with water without swallowing after inhalation is advised to reduce the risk of thrush. Pneumonia: Patients with COPD have a higher risk of pneumonia; instruct them to contact their healthcare provider if they develop symptoms of pneumonia. Immunosuppression: Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chicken pox or measles and, if exposed, to consult their physician 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: Inform patients that orally inhaled corticosteroids, a component of BREYNA, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route. Ocular Effects: Long-term use of inhaled corticosteroids 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. BREYNA is a trademark of Mylan Pharmaceuticals Inc. 2020 Mylan Inc. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Manufactured by: Kindeva Drug Delivery L.P. Northridge CA 91324 U.S.A. Product of U.S.A. Revised: 9/2020KD:BUFOIA:R1
BREYNA (brehy-nah) (budesonide 80 mcg and formoterol fumarate dihydrate 4.5 mcg)Inhalation Aerosol BREYNA (brehy-nah) (budesonide 160 mcg and formoterol fumarate dihydrate 4.5 mcg)Inhalation Aerosol What is BREYNA? BREYNA combines an inhaled corticosteroid medicine (ICS), budesonide and a long-acting beta2-adrenergic agonist (LABA) medicine, formoterol. Inhaled corticosteroids help to decrease inflammation in the lungs. Inflammation in the lungs can lead to breathing problems. LABA medicines are used in people with chronic obstructive pulmonary disease (COPD) and asthma. LABA medicines help the muscles around the airways in your lungs stay relaxed to prevent symptoms such as wheezing, cough, chest tightness, and shortness of breath. These symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe. In severe cases, wheezing can stop your breathing and may lead to death if not treated right away. BREYNA is not used to relieve sudden breathing problems and will not replace a rescue inhaler. BREYNA is used for asthma and COPD as follows: Asthma: BREYNA is used to control symptoms of asthma, and prevent symptoms such as wheezing in adults and children ages 6 and older.BREYNA contains formoterol. LABA medicines such as formoterol when used alone increase the risk of death and hospitalizations from asthma problems. BREYNA contains an ICS and a LABA. When an ICS and LABA are used together, there is not a significant increased risk in hospitalizations and death from asthma problems. BREYNA is not for adults and children with asthma who are well controlled with an asthma-control medicine, such as a low to medium dose of an ICS. BREYNA is for adults and children with asthma who need both an ICS and LABA medicine.It is not known if BREYNA is safe and effective in children less than 6 years of age with asthma. COPD: COPD is a long-term (chronic) lung disease that includes chronic bronchitis, emphysema, or both. BREYNA 160 mcg/4.5 mcg is used long-term, as 2 inhalations 2 times each day, to improve symptoms of COPD for better breathing and to reduce the number of flare-ups (the worsening of your COPD symptoms for several days). Do not use BREYNA: to treat sudden severe symptoms of asthma or COPD. if you are allergic to any of the ingredients in BREYNA. See the end of this leaflet for a list of ingredients in BREYNA. Before you use BREYNA, tell your healthcare provider about all of your medical conditions, including if you: have heart problems. have high blood pressure. have seizures. have thyroid problems. have diabetes. have liver problems. have osteoporosis. have an immune system problem. have eye problems such as increased pressure in the eye, glaucoma, or cataracts. are allergic to any medicines. have any type of viral, bacterial, fungal, or parasitic infection. are exposed to chicken pox or measles. are pregnant or plan to become pregnant. It is not known if BREYNA may harm your unborn baby. are breastfeeding. Budesonide, one of the active ingredients in BREYNA, passes into breast milk. You and your healthcare provider should decide if you will take BREYNA while breastfeeding. Tell your healthcare provider about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements. BREYNA and certain other medicines may interact with each other. This may cause serious side effects. Especially tell your healthcare provider if you take antifungal or anti-HIV medicines. Know all the medicines you take. Keep a list and show it to your healthcare provider and pharmacist each time you get a new medicine. How should I use BREYNA? See the step-by-step instructions for using BREYNA at the end of this Patient Information leaflet. Do not use BREYNA unless your healthcare provider has taught you and you understand everything. Ask your healthcare provider or pharmacist if you have any questions. Use BREYNA exactly as prescribed. Do not use BREYNA more often than prescribed. BREYNA comes in 2 strengths. Your healthcare provider has prescribed the strength that is best for you. Note the differences between BREYNA and your other inhaled medications, including the differences in prescribed use and physical appearance. Children should use BREYNA with an adult s help, as instructed by the child s healthcare provider. BREYNA should be taken every day as 2 puffs in the morning and 2 puffs in the evening about 12 hours apart. If you miss a dose of BREYNA, you should take your next dose at the same time you normally do. Rinse your mouth with water and spit the water out after each dose (2 puffs) of BREYNA. Do not swallow the water. This will help to lessen the chance of getting a fungus infection (thrush) in the mouth and throat. If you take too much BREYNA, call your healthcare provider or go to the nearest hospital emergency room right away if you have any unusual symptoms, such as worsening shortness of breath, chest pain, increased heart rate, or shakiness. Do not spray BREYNA in your eyes. If you accidentally get BREYNA in your eyes, rinse your eyes with water, and if redness or irritation persists, consult your healthcare provider. Do not change or stop any medicines used to control or treat your breathing problems. Your healthcare provider will change your medicines as needed. While you are using BREYNA 2 times each day, do not use other medicines that contain a LABA for any reason. Ask your healthcare provider or pharmacist if any of your other medicines are LABA medicines. BREYNA does not relieve sudden symptoms. Always have a rescue inhaler medicine with you to treat sudden symptoms. If you do not have a rescue inhaler, call your healthcare provider to have one prescribed for you. Call your healthcare provider or get medical care right away if: oyour breathing problems worsen with BREYNA. oyou need to use your rescue inhaler medicine more often than usual. oyour rescue inhaler medicine does not work as well for you at relieving symptoms. oyour peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you. oyour symptoms do not improve after using BREYNA regularly for 1 week. What are the possible side effects of BREYNA? BREYNA may cause serious side effects, including: Using too much of a LABA medicine may cause: ochest pain oa fast and irregular heartbeat otremor oincreased blood pressure oheadache onervousness Fungal infection in your mouth or throat (thrush). Rinse your mouth with water without swallowing after using BREYNA to help reduce your chance of getting thrush. Pneumonia and other lower respiratory tract infections. People with COPD have a higher chance of getting pneumonia and other lung infections. Inhaled corticosteroids may increase the chance of getting pneumonia. Call your healthcare provider if you notice any of these symptoms: oincrease in mucus (sputum) production ofever oincreased cough change in mucus color chills increased breathing problems Immune system effects and a higher chance for infections. Tell your healthcare provider about any signs of infection such as: ofever obody aches ofeeling tired ovomiting opain ochills onausea Adrenal insufficiency. Adrenal insufficiency is a condition in which the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines and start inhaled corticosteroid medicine. Increased wheezing right after taking BREYNA. Always have a rescue inhaler with you to treat sudden wheezing. Serious allergic reactions including rash, hives, swelling of the face, mouth, and tongue, and breathing problems. Call your healthcare provider or get emergency medical care if you get any symptoms of a serious allergic reaction. Lower bone mineral density. This can happen in people who have a high chance for low bone mineral density (osteoporosis). Your healthcare provider should check you for this during treatment with BREYNA. Slowed growth in children. A child s growth should be checked regularly while using BREYNA. Eye problems including glaucoma and cataracts. You should have regular eye exams while using BREYNA. Swelling of your blood vessels. This can happen in people with asthma. Tell your healthcare provider right away if you have: oa feeling of pins and needles or numbness of your arms or legs orash oflu like symptoms opain and swelling of the sinuses Decreases in blood potassium levels (hypokalemia). Increases in blood sugar levels (hyperglycemia). The most common side effects of BREYNA include: People with asthma: throat irritation upper respiratory tract infection inflammation of mucous membranes of the sinuses (sinusitis) back pain stomach discomfort thrush in the mouth and throat. Rinse your mouth with water without swallowing after use to help prevent thrush. headache throat pain flu nasal congestion vomiting People with COPD: throat irritation thrush in the mouth and throat. Rinse your mouth with water without swallowing after use to help prevent thrush. infection and inflammation of the mucous membranes of the bronchial tubes (bronchitis) inflammation of mucous membranes in the sinuses (sinusitis) upper respiratory tract infection Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of BREYNA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1 800 FDA-1088. You may also report side effects to Mylan at 1-877-446-3679 (1-877-4-INFO-RX). How should I store BREYNA? Store BREYNA at room temperature between 68 F to 77 F (20 C to 25 C). Store BREYNA with the mouthpiece down. The contents of your BREYNA canister are under pressure. Do not puncture or throw the canister into a fire or incinerator. Do not use or store it near heat or open flame. Storage above 120 F may cause the canister to burst. Throw away BREYNA when the counter reaches zero ( 0 ) or 3 months after you take BREYNA out of its foil pouch, whichever comes first. Keep BREYNA and all medicines out of the reach of children. General Information about the safe and effective use of BREYNA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use BREYNA for a condition for which it was not prescribed. Do not give BREYNA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about BREYNA that is written for health professionals. What are the ingredients in BREYNA? Active ingredients: micronized budesonide and micronized formoterol fumarate dihydrate Inactive ingredients: hydrofluroalkane (HFA 227), povidone K25 USP, and polyethylene glycol 1000 NF Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.Manufactured by: Kindeva Drug Delivery L.P., Northridge CA 91324 U.S.A.Product of U.S.A. For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). Revised: 9/2020KD:PIL:BUFOIA:R1 Instructions for Use BREYNA (brehy-nah) (budesonide 80 mcg and formoterol fumarate dihydrate 4.5 mcg)Inhalation Aerosol BREYNA (brehy-nah) (budesonide 160 mcg and formoterol fumarate dihydrate 4.5 mcg)Inhalation Aerosol Figure 1 Upright Position How to Use BREYNA Follow the instructions below for using BREYNA. You will breathe-in (inhale) the medicine. If you have any questions, ask your doctor or pharmacist. Preparing your BREYNA inhaler for use 1.Take your BREYNA out of the moisture-protective foil pouch before you use it for the first time and throw the foil away. Write the date that you open the foil pouch on the box. 2.The inhaler comes with a counter (see Figure 1). The counter will count down each time you release a puff of BREYNA. The counter will show the number of inhalations (puffs) left in the canister. The counter will stop counting at zero ( 0 ). 3.Use the BREYNA canister only with the blue BREYNA inhaler supplied with the product. Parts of the BREYNA inhaler should not be used with parts from any other inhalation product. 4.Shake your BREYNA inhaler well for 5 seconds right before each use. Remove the mouthpiece cover by squeezing gently at both sides, then pulling out (see Figure 2). Check the mouthpiece for foreign objects before use. Figure 2 5. Priming your BREYNA inhaler Before you use BREYNA for the first time, you will need to prime it. To prime BREYNA, hold it in the upright position (see Figure 1). Shake the BREYNA inhaler well for 5 seconds. Hold your BREYNA inhaler facing away from you and press down firmly and fully on the top of the canister to release a test spray. Then shake it again for 5 seconds and release a second test spray. Your BREYNA inhaler is now primed and ready for use. After you have primed the BREYNA inhaler for the first time, the counter will read 120. If you do not use your BREYNA inhaler for more than 7 days or if you drop it, you will need to prime again. Ways to hold the BREYNA inhaler for use Figure 3 or Figure 4 Using your BREYNA inhaler 6.Shake your BREYNA inhaler well for 5 seconds. Remove the mouthpiece cover. Check the mouthpiece for foreign objects. 7.Breathe out fully (exhale). Hold the BREYNA inhaler up to your mouth. Place the blue mouthpiece fully into your mouth and close your lips around it. Make sure that the BREYNA inhaler is upright and that the opening of the mouthpiece is pointing towards the back of your throat (see Figure 5). Figure 5 8.Breathe in (inhale) deeply and slowly through your mouth. Press down firmly and fully on the top of the canister to release the medicine (see Figures 3 and 4). 9.Continue to breathe in (inhale) and hold your breath for about 10 seconds, or for as long as is comfortable. Before you breathe out (exhale), release your finger from the top of the canister. Keep the BREYNA inhaler upright and remove from your mouth. 10.Shake the BREYNA inhaler again for 5 seconds and repeat steps 7 to 9. After using your BREYNA inhaler 11.After use, close the mouthpiece cover by pushing until it clicks in place. 12.After you finish taking BREYNA (2 puffs), rinse your mouth with water. Spit out the water. Do not swallow it. Reading the counter The counter shows the number of inhalations (puffs) left in your inhaler. Counter The counter will count down each time you release a puff of medicine (either when priming your BREYNA inhaler or when taking the medicine). When the counter reads 20, it is time to call your healthcare provider for a refill. It is important that you pay attention to the number of inhalations (puffs) left in your BREYNA inhaler by reading the counter. Throw away BREYNA when the counter shows zero ( 0 ) or 3 months after you take your BREYNA inhaler out of its foil pouch, whichever comes first. Your BREYNA inhaler may not feel empty and it may continue to operate, but you will not get the right amount of medicine if you keep using it. Use a new BREYNA inhaler and follow the instructions for priming (see instruction 5 above). How to clean your BREYNA inhaler Clean the blue mouthpiece of your BREYNA inhaler every 7 days. To clean the mouthpiece: Remove the grey mouthpiece cover Wipe the inside and outside of the blue mouthpiece opening with a clean, dry cloth Replace the mouthpiece cover Do not put the BREYNA inhaler into water Do not try to take apart your BREYNA inhaler Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.Manufactured by: Kindeva Drug Delivery L.P., Northridge CA 91324 U.S.A.Product of U.S.A. This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration. BREYNA is a trademark of Mylan Pharmaceuticals Inc. Foradil Aerolizer is a registered trademark of Novartis AG. 2020 Mylan Inc. Revised: 9/2020KD:IFU:BUFOIA:R1
NDC 0378-7502-32 Rx only STORE UPRIGHT Breyna (budesonide and formoterolfumarate dihydrate)Inhalation Aerosol80 mcg/4.5 mcg FOR ORAL INHALATION ONLY 120 Inhalations Important: Please readaccompanying Patient Informationand Instructions for Use carefullyprior to using. Contents: Each carton containsone canister. Net fill weight 10.3 gproviding 120 inhalations. Eachactuation delivers 80 mcg ofbudesonide and 4.5 mcg offormoterol fumarate dihydrate.Inactive ingredients includepovidone K25, polyethylene glycol1000, and HFA 227. Dosage: Use only as directed byPhysician. Warning: Avoid spraying in eyes. Contents under pressure. Do notpuncture or incinerate. Do not storeat temperatures above 120 F. Keep out of the reach of children.Store at 20 to 25 C (68 to 77 F).[See USP Controlled RoomTemperature.] Store the inhaler with themouthpiece down. Shake inhaler well for 5 secondsbefore using. Discard within three months afterremoving from foil pouch. For oral inhalation with BREYNAinhaler only. Use this device for BREYNA only. Date foil pouch opened:________ Discard the inhaler when the labeled number of inhalations have been used or within 3 months of opening the foil pouch. Don t Forget to Take Daily www.MYLAN.com Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Made in U.S.A. Mylan.com BREYNA is a trademark ofMylan Pharmaceuticals Inc. 2020 Mylan Inc. KD:7502:1C:R1 34-8722-6550-8
NDC 0378-7503-32 Rx only STORE UPRIGHT Breyna (budesonide and formoterolfumarate dihydrate)Inhalation Aerosol160 mcg/4.5 mcg FOR ORAL INHALATION ONLY 120 Inhalations Important: Please readaccompanying Patient Informationand Instructions for Use carefullyprior to using. Contents: Each carton containsone canister. Net fill weight 10.3 gproviding 120 inhalations. Eachactuation delivers 160 mcg ofbudesonide and 4.5 mcg offormoterol fumarate dihydrate.Inactive ingredients includepovidone K25, polyethylene glycol1000, and HFA 227. Dosage: Use only as directed byPhysician. Warning: Avoid spraying in eyes. Contents under pressure. Do notpuncture or incinerate. Do not storeat temperatures above 120 F. Keep out of the reach of children.Store at 20 to 25 C (68 to 77 F).[See USP Controlled RoomTemperature.] Store the inhaler with themouthpiece down. Shake inhaler well for 5 secondsbefore using. Discard within three months afterremoving from foil pouch. For oral inhalation with BREYNAinhaler only. Use this device for BREYNA only. Date foil pouch opened:________ Discard the inhaler when the labeled number of inhalations have been used or within 3 months of opening the foil pouch. Don t Forget to Take Daily www.MYLAN.com Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Made in U.S.A. Mylan.com BREYNA is a trademark ofMylan Pharmaceuticals Inc. 2020 Mylan Inc. KD:7503:1C:R1 34-8722-6552-4