BREYNA

1 INDICATIONS AND USAGE BREYNA is a combination product containing a corticosteroid and a long-acting beta 2 -adrenergic agonist indicated for: • Treatment of asthma in patients 6 years of age and older. ( 1.1 ) • Maintenance treatment of airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and/or emphysema. ( 1.2 ) Important limitations: • Not indicated for the relief of acute bronchospasm. ( 1.1 , 1.2 ) 1.1 Treatment of Asthma BREYNA is indicated for the treatment of asthma in patients 6 years of age and older. BREYNA should be used for patients not adequately controlled on a long-term asthma-control medication such as an inhaled corticosteroid (ICS) or whose disease warrants initiation of treatment with both an inhaled corticosteroid and long-acting beta 2 -adrenergic agonist (LABA). Important Limitations of Use: • BREYNA is NOT indicated for the relief of acute bronchospasm. 1.2 Maintenance Treatment of Chronic Obstructive Pulmonary Disease BREYNA 160 mcg/4.5 mcg is indicated for the maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and/or emphysema. BREYNA 160 mcg/4.5 mcg is also indicated to reduce exacerbations of COPD. BREYNA 160 mcg/4.5 mcg is the only strength indicated for the treatment of COPD. Important Limitations of Use: • BREYNA is NOT indicated for the relief of acute bronchospasm.

2 DOSAGE AND ADMINISTRATION 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 ) 2.1 Administration Information 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) ] . 2.2 Asthma If asthma symptoms arise in the period between doses, an inhaled, short-acting beta 2 -agonist should be taken for immediate relief. Adult and Adolescent Patients 12 Years of Age and Older For patients 12 years of age and older, the dosage is 2 inhalations of BREYNA 80 mcg/4.5 mcg or BREYNA 160 mcg/4.5 mcg twice daily. The recommended starting dosages for BREYNA for patients 12 years of age and older are based upon patients’ asthma severity or level of control of asthma symptoms, and risk of exacerbations on current inhaled corticosteroids. The maximum recommended dosage in adult and adolescent patients 12 years and older is BREYNA 160 mcg/4.5 mcg, two inhalations twice daily. Improvement in asthma control following inhaled administration of BREYNA can occur within 15 minutes of beginning treatment, although maximum benefit may not be achieved for 2 weeks or longer after beginning treatment. Individual patients will experience a variable time to onset and degree of symptom relief. For patients who do not respond adequately to the starting dose after 1-2 weeks of therapy with BREYNA 80 mcg/4.5 mcg, replacement with BREYNA 160 mcg/4.5 mcg may provide additional asthma control. If a previously effective dosage regimen of BREYNA fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, (e.g., replacing the lower strength of BREYNA with the higher strength, adding additional inhaled corticosteroid, or initiating oral corticosteroids) should be considered. Pediatric Patients Aged 6 to Less than 12 Years For patients 6 to less than 12 years of age, the dosage is 2 inhalations of BREYNA 80 mcg/4.5 mcg twice daily. 2.3 Chronic Obstructive Pulmonary Disease 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 beta 2 -agonist should be taken for immediate relief.

4 CONTRAINDICATIONS 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 )

5 WARNINGS AND PRECAUTIONS • Serious asthma-related events: Long-acting beta 2 -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 beta 2 -agonist: Do not use in combination because of risk of overdose. ( 5.3 ) • Localized infections: Candida albicans infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 ) • Pneumonia: Increased risk in patients with COPD. Monitor patients for signs and symptoms of pneumonia and other potential lung infections. ( 5.5 ) • Immunosuppression: Potential worsening of infections (e.g., existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. ( 5.6 ) • Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to BREYNA. ( 5.7 ) • Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue BREYNA slowly. ( 5.8 ) • Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased systemic corticosteroid effects. Exercise caution when used with BREYNA. ( 5.9 ) • Paradoxical bronchospasm: Discontinue BREYNA and institute alternative therapy if paradoxical bronchospasm occurs. ( 5.10 ) • Patients with cardiovascular or central nervous system disorders: Use with caution because of beta-adrenergic stimulation. ( 5.12 ) • Decreases in bone mineral density: Assess bone mineral density initially and periodically thereafter. ( 5.13 ) • Effects on growth: Monitor growth of pediatric patients. ( 5.14 ) • Glaucoma and cataracts: Close monitoring is warranted. ( 5.15 ) • Metabolic effects: Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. ( 5.16 , 5.18 ) • Coexisting conditions: Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.17 ) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations and Death Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART) ]. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to ICS alone (see Serious Asthma-Related Events with ICS/LABA ). Serious Asthma-Related Events with ICS/LABA Four large, 26-week, randomized, blinded, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared to ICS alone in patients with asthma. Three trials included adult and adolescent patients aged ≥ 12 years: one trial compared budesonide/formoterol (budesonide and formoterol fumarate dihydrate inhalation aerosol) to budesonide [see Clinical Studies (14.1) ] ; one trial compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder; and one trial compared mometasone furoate/formoterol to mometasone furoate. The fourth trial included pediatric patients 4 to 11 years of age and compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder. The primary safety endpoint for all four trials was serious asthma-related events (hospitalizations, intubations and death). A blinded adjudication committee determined whether events were asthma-related. The three adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk of 2.7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the three adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS. Table 1. Meta-analysis of Serious Asthma-Related Events in Patients with Asthma Aged 12 Years and Older ICS = Inhaled Corticosteroid, LABA = Long-acting Beta 2 -adrenergic Agonist ICS/LABA (N = 17,537) Randomized patients who had taken at least 1 dose of study drug. Planned treatment used for analysis. ICS (N = 17,552) ICS/LABA vs ICS Hazard Ratio (95% CI) Estimated using a Cox proportional hazards model of time to first event with baseline hazards stratified by each of the 3 trials. Serious asthma-related event Number of patients with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Patients can have one or more events, but only the first event was counted for analysis. A single, blinded, independent adjudication committee determined whether events were asthma-related. 116 105 1.10 (0.85, 1.44) Asthma-related death 2 0 Asthma-related intubation (endotracheal) 1 2 Asthma-related hospitalization (≥24-hour stay) 115 105 The pediatric safety trial included 6208 pediatric patients 4 to 11 years of age who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3107 (0.9%) patients randomized to ICS/LABA and 21/3101 (0.7%) patients randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared to ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27). Salmeterol Multicenter Asthma Research Trial (SMART) A 28-week, placebo-controlled U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; relative risk: 4.37 [95% CI 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy. Formoterol Monotherapy Studies Clinical studies with formoterol used as monotherapy suggested a higher incidence of serious asthma exacerbation in patients who received formoterol than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the difference in serious asthma exacerbations between treatment groups. 5.2 Deterioration of Disease and Acute Episodes BREYNA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. BREYNA has not been studied in patients with acutely deteriorating asthma or COPD. The initiation of BREYNA in this setting is not appropriate. Increasing use of inhaled, short-acting beta 2 -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 beta 2 -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 beta 2 -agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs. 5.3 Excessive Use of BREYNA and Use with Other Long-Acting Beta 2 -Agonists As with other inhaled drugs containing beta 2 -adrenergic agents, BREYNA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREYNA should not use an additional LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced bronchospasm (EIB) or the treatment of asthma or COPD. 5.4 Local Effects In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with budesonide and formoterol fumarate dihydrate inhalation aerosol. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while treatment with BREYNA continues, but at times therapy with BREYNA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. 5.5 Pneumonia and Other Lower Respiratory Tract Infections Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap. Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids. In a 6-month lung function study of 1704 patients with COPD, there was a higher incidence of lung infections other than pneumonia (e.g., bronchitis, viral lower respiratory tract infections, etc.) in patients receiving budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg (7.6%) than in those receiving budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg (3.2%), formoterol 4.5 mcg (4.6%) or placebo (3.3%). Pneumonia did not occur with greater incidence in the budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg group (1.1 %) compared with placebo (1.3%). In a 12-month lung function study of 1964 patients with COPD, there was also a higher incidence of lung infections other than pneumonia in patients receiving budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg (8.1%) than in those receiving budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg (6.9%), formoterol 4.5 mcg (7.1%) or placebo (6.2%). Similar to the 6-month study, pneumonia did not occur with greater incidence in the budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg group (4.0%) compared with placebo (5.0%). 5.6 Immunosuppression Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see the respective package inserts for complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents may be considered. The immune responsiveness to varicella vaccine was evaluated in pediatric patients with asthma ages 12 months to 8 years with budesonide inhalation suspension. An open-label, nonrandomized clinical study examined the immune responsiveness to varicella vaccine in 243 asthma patients 12 months to 8 years of age who were treated with budesonide inhalation suspension 0.25 mg to 1 mg daily (n = 151) or noncorticosteroid asthma therapy (n = 92) (i.e., beta 2 -agonists, leukotriene receptor antagonists, cromones). The percentage of patients developing a seroprotective antibody titer of ≥ 5.0 (gpELISA value) in response to the vaccination was similar in patients treated with budesonide inhalation suspension (85%), compared to patients treated with noncorticosteroid asthma therapy (90%). No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.7 Transferring Patients From Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although BREYNA may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress, a severe asthma attack or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe asthma attack, or a severe COPD exacerbation. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREYNA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREYNA. Lung function (mean forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [PEF]), beta-agonist use, and asthma or COPD symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to inhaled corticosteroids or BREYNA may unmask conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function. 5.8 Hypercorticism and Adrenal Suppression Budesonide, a component of BREYNA, will often help control asthma and COPD symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since budesonide is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of BREYNA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with BREYNA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when budesonide is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of BREYNA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms. 5.9 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of BREYNA with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. 5.10 Paradoxical Bronchospasm and Upper Airway Symptoms As with other inhaled medications, BREYNA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREYNA, it should be treated immediately with an inhaled, short-acting bronchodilator, BREYNA should be discontinued immediately, and alternative therapy should be instituted. 5.11 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of BREYNA, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm. 5.12 Cardiovascular and Central Nervous System Effects Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see Overdosage (10) ] . Therefore, BREYNA, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Formoterol, a component of BREYNA, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of formoterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. 5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREYNA and periodically thereafter. If significant reductions in BMD are seen and BREYNA is still considered medically important for that patient’s COPD therapy, use of medication to treat or prevent osteoporosis should be strongly considered. Effects of treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg, budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg, formoterol 4.5 mcg, or placebo on BMD was evaluated in a subset of 326 patients (females and males 41 to 88 years of age) with COPD in the 12-month lung function study. BMD evaluations of the hip and lumbar spine regions were conducted at baseline and 52 weeks using dual energy x-ray absorptiometry (DEXA) scans. Mean changes in BMD from baseline to end of treatment were small (mean changes ranged from -0.01 - 0.01 g/cm 2 ). ANCOVA results for total spine and total hip BMD based on the end of treatment time point showed that all geometric LS Mean ratios for the pairwise treatment group comparisons were close to 1, indicating that overall, BMD for total hip and total spine regions for the 12‑month time point were stable over the entire treatment period. 5.14 Effect on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving BREYNA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including BREYNA, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2.2) and Use in Specific Populations (8.4) ] . 5.15 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long-term administration of inhaled corticosteroids, including budesonide, a component of BREYNA. Therefore, close monitoring is warranted in patients with a change in vision or with history of increased intraocular pressure, glaucoma, and/or cataracts. Effects of treatment with budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg, budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg, formoterol 4.5 mcg, or placebo on development of cataracts or glaucoma were evaluated in a subset of 461 patients with COPD in the 12-month lung function study. Ophthalmic examinations were conducted at baseline, 24 weeks, and 52 weeks. There were 26 subjects (6%) with an increase in posterior subcapsular score from baseline to maximum value (> 0.7) during the randomized treatment period. Changes in posterior subcapsular scores of > 0.7 from baseline to treatment maximum occurred in 11 patients (9.0%) in the budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg group, 4 patients (3.8%) in the budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg group, 5 patients (4.2%) in the formoterol group, and 6 patients (5.2%) in the placebo group. 5.16 Eosinophilic Conditions and Churg-Strauss Syndrome In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between budesonide and these underlying conditions has not been established. 5.17 Coexisting Conditions BREYNA, like all medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta 2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.18 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology (12.2) ] . The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with budesonide and formoterol fumarate dihydrate inhalation aerosol at recommended doses.

7 DRUG INTERACTIONS In clinical studies, concurrent administration of budesonide and formoterol fumarate dihydrate inhalation aerosol and other drugs, such as short-acting beta 2 -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 ) 7.1 Inhibitors of Cytochrome P4503A4 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) ] . 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants 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. 7.3 Beta-Adrenergic Receptor Blocking Agents 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. 7.4 Diuretics 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.

6 ADVERSE REACTIONS 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 Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience in Asthma Adult and Adolescent Patients 12 Years of Age and Older The overall safety data in adults and adolescents are based upon 10 active- and placebo-controlled clinical trials in which 3393 patients ages 12 years and older (2052 females and 1341 males) with asthma of varying severity were treated with budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg or 160 mcg/4.5 mcg taken 2 inhalations once or twice daily for 12 to 52 weeks. In these trials, the patients on budesonide and formoterol fumarate dihydrate inhalation aerosol had a mean age of 38 years and were predominantly Caucasian (82%). The incidence of common adverse events in Table 2 below is based upon pooled data from three 12‑week, double-blind, placebo-controlled clinical studies in which 401 adult and adolescent patients (148 males and 253 females) age 12 years and older were treated with 2 inhalations of budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg or budesonide and formoterol fumarate dihydrate inhalation aerosol 160 mcg/4.5 mcg twice daily. The budesonide and formoterol fumarate dihydrate inhalation aerosol group was composed of mostly Caucasian (84%) patients with a mean age of 38 years, and a mean percent predicted FEV 1 at baseline of 76 and 68 for the 80 mcg/4.5 mcg and 160 mcg/4.5 mcg treatment groups, respectively. Control arms for comparison included 2 inhalations of budesonide HFA metered dose inhaler (MDI) 80 mcg or 160 mcg, formoterol dry powder inhaler (DPI) 4.5 mcg, or placebo (MDI and DPI) twice daily. Table 2 includes all adverse events that occurred at an incidence of ≥ 3% in any one budesonide and formoterol fumarate dihydrate inhalation aerosol group and more commonly than in the placebo group with twice-daily dosing. In considering these data, the increased average duration of patient exposure for budesonide and formoterol fumarate dihydrate inhalation aerosol patients should be taken into account, as incidences are not adjusted for an imbalance of treatment duration. Table 2. Adverse Reactions Occurring at an Incidence of ≥ 3% and More Commonly Than Placebo in the Budesonide and Formoterol Fumarate Dihydrate Inhalation Aerosol Groups: Pooled Data from Three 12-week, Double-blind, Placebo-controlled Clinical Asthma Trials in Patients 12 Years and Older Treatment All treatments were administered as 2 inhalations twice daily. Budesonide and Formoterol Fumarate Dihydrate Inhalation Aerosol Budesonide Formoterol Placebo Adverse Event 80 mcg/4.5 mcg N = 277 % 160 mcg/4.5 mcg N = 124 % 80 mcg N = 121 % 160 mcg N = 109 % 4.5 mcg N = 237 % N = 400 % Nasopharyngitis 10.5 9.7 14.0 11.0 10.1 9.0 Headache 6.5 11.3 11.6 12.8 8.9 6.5 Upper respiratory tract infection 7.6 10.5 8.3 9.2 7.6 7.8 Pharyngolaryngeal pain 6.1 8.9 5.0 7.3 3.0 4.8 Sinusitis 5.8 4.8 5.8 2.8 6.3 4.8 Influenza 3.2 2.4 6.6 0.9 3.0 1.3 Back pain 3.2 1.6 2.5 5.5 2.1 0.8 Nasal congestion 2.5 3.2 2.5 3.7 1.3 1.0 Stomach discomfort 1.1 6.5 2.5 4.6 1.3 1.8 Vomiting 1.4 3.2 0.8 2.8 1.7 1.0 Oral Candidiasis 1.4 3.2 0 0 0 0.8 Average Duration of Exposure (days) 77.7 73.8 77.0 71.4 62.4 55.9 Long-term Safety - Asthma Clinical Trials in Patients 12 Years and Older Long-term safety studies in adolescent and adult patients 12 years of age and older, treated for up to 1 year at doses up to 1280/36 mcg/day (640/18 mcg twice daily), revealed neither clinically important changes in the incidence nor new types of adverse events emerging after longer periods of treatment. Similarly, no significant or unexpected patterns of abnormalities were observed for up to 1 year in safety measures including chemistry, hematology, ECG, Holter monitor, and HPA-axis assessments. Pediatric Patients 6 to Less Than 12 Years of Age The safety data for pediatric patients aged 6 to less than 12 years is based on 1 trial of 12 weeks treatment duration. Patients (79 female and 105 male) receiving inhaled corticosteroid at trial entry were randomized to budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg (n = 92) or budesonide pMDI 80 mcg (n = 92), 2 inhalations twice daily. The overall safety profile of these patients was similar to that observed in patients 12 years of age and older who received budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg twice daily in studies of similar design. Common adverse reactions that occurred in patients treated with budesonide and formoterol fumarate dihydrate inhalation aerosol 80 mcg/4.5 mcg with a frequency of ≥ 3% and more frequently than patients treated only with budesonide pMDI 80 mcg included upper respiratory tract infection, pharyngitis, headache, and rhinitis. 6.2 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease 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 FEV 1 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. 6.3 Postmarketing Experience 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

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of budesonide and formoterol fumarate dihydrate inhalation aerosol or one of its individual components, formoterol fumarate, in pregnant women; however studies are available for the other component budesonide. In animal reproduction studies, budesonide and formoterol fumarate dihydrate, administered by the inhalation route, was teratogenic, embryocidal, and reduced fetal weights in rats at less than the maximum recommended human daily inhalation dose (MRHDID) on a mcg/m 2 basis. Budesonide alone, administered by the subcutaneous route, was teratogenic, embryocidal, and reduced fetal weights in rats and rabbits at less than the MRHDID, but these effects were not seen in rats that received inhaled doses up to 4 times the MRHDID. Studies of pregnant women have not shown that inhaled budesonide alone increases the risk of abnormalities when administered during pregnancy. Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. Formoterol fumarate alone, administered by the oral route, was teratogenic in rats and rabbits at 1600 and 65,000 times the MRHDID, respectively. Formoterol fumarate was also embryocidal, increased pup loss at birth and during lactation, and decreased pup weight in rats at 110 times the MRHDID. These adverse effects generally occurred at large multiples of the MRHDID when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No teratogenic, embryocidal, or developmental effects were seen in rats that received inhalation doses up to 375 times the MRHDID. The estimated background risk of major birth defects and miscarriage of the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Labor or Delivery There are no well-controlled human 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. Data Human Data Studies of pregnant women have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (i.e., Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared to the general population rate (3.8% vs. 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs. 3.3, respectively). These same data were utilized in a second study bringing the total to 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%). Animal Data 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/m 2 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/m 2 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/m 2 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/m 2 basis at a maternal subcutaneous dose of 5 mcg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities at doses less than the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 25 mcg/kg/day). In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-15, budesonide produced similar adverse fetal effects at doses approximately 8 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 500 mcg/kg/day). In another embryo- fetal development study in pregnant rats, no teratogenic or embryocidal effects were seen at doses up to 4 times the MRHDID (on a mcg/m 2 basis at maternal inhalation doses up to 250 mcg/kg/day). 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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.