Breo Ellipta

Maintenance Treatment of Chronic Obstructive Pulmonary Disease

BREO ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

Maintenance Treatment of Asthma

BREO ELLIPTA is indicated for the maintenance treatment of asthma in patients aged 5 years and older.

Limitations of Use

BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm.

Recommended Dosage for Maintenance Treatment of Chronic Obstructive Pulmonary Disease

The recommended dosage of BREO ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation.

If shortness of breath occurs in the period between doses, an inhaled, short-acting beta2-agonist (rescue medicine, e.g., albuterol) should be used for immediate relief.

Recommended Dosage for Maintenance Treatment of Asthma

Adult Patients Aged 18 Years and Older

The recommended dosage of BREO ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation or BREO ELLIPTA 200/25 mcg (containing fluticasone furoate 200 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation.

•

When choosing the starting dosage strength of BREO ELLIPTA, consider the patients’ disease severity, their previous asthma therapy, including the inhaled corticosteroid (ICS) dosage, as well as the patients’ current control of asthma symptoms and risk of future exacerbation.

•

The median time to onset, defined as a 100-mL increase from baseline in mean forced expiratory volume in 1 second (FEV1), was approximately 15 minutes 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 BREO ELLIPTA 100/25 mcg once daily, increasing the dose to BREO ELLIPTA 200/25 mcg once daily may provide additional improvement in asthma control. For patients who do not respond adequately to BREO ELLIPTA 200/25 mcg once daily, re-evaluate and consider other therapeutic regimens and additional therapeutic options.

•

The maximum recommended dosage is 1 inhalation of BREO ELLIPTA 200/25 mcg once daily.

•

If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist (rescue medicine, e.g., albuterol) should be used for immediate relief.

Pediatric Patients Aged 12 to 17 Years

The recommended dosage of BREO ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation [see Warnings and Precautions ].

Pediatric Patients Aged 5 to 11 Years

The recommended dosage of BREO ELLIPTA 50/25 mcg (containing fluticasone furoate 50 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation [see Warnings and Precautions ].

Administration Information

•

After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis [see Warnings and Precautions ( 5.4)]5.4)].

•

BREO ELLIPTA should be used at the same time every day. Do not use BREO ELLIPTA more than 1 time every 24 hours.

•

More frequent administration or a greater number of inhalations (more than 1 inhalation daily) of the prescribed strength of BREO ELLIPTA is not recommended as some patients are more likely to experience adverse effects with higher doses.

Pregnancy

Risk Summary

There are insufficient data on the use of BREO ELLIPTA or its individual components, fluticasone furoate and vilanterol, in pregnant women to inform a drug-associated risk. (See Clinical Considerations.) In an animal reproduction study, fluticasone furoate and vilanterol administered by inhalation alone or in combination to pregnant rats during the period of organogenesis produced no fetal structural abnormalities. The highest fluticasone furoate and vilanterol doses in this study were approximately 5 and 40 times the maximum recommended human daily inhalation doses (MRHDID) of 200 and 25 mcg, respectively. (See Data.)

The estimated risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated 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 Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored, and medication adjusted as necessary to maintain optimal control of asthma.

Labor or Delivery: BREO ELLIPTA should be used during late gestation and labor only if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility.

Data

Animal Data: Fluticasone Furoate and Vilanterol: In an embryofetal developmental study, pregnant rats received fluticasone furoate and vilanterol during the period of organogenesis at doses up to approximately 5 and 40 times the MRHDID of 200 and 25 mcg, respectively, alone or in combination (on a mcg/m2 basis at inhalation doses up to approximately 95 mcg/kg/day). No evidence of structural abnormalities was observed.

            Fluticasone Furoate: In 2 separate embryofetal developmental studies, pregnant rats and rabbits received fluticasone furoate during the period of organogenesis at doses up to approximately 4 and 1 times, respectively, the MRHDID of 200 mcg (on a mcg/m2 basis at maternal inhalation doses up to 91 and 8 mcg/kg/day, respectively). No evidence of structural abnormalities in fetuses was observed in either species. In a perinatal and postnatal developmental study in rats, dams received fluticasone furoate during late gestation and lactation periods at doses up to approximately 1 time the MRHDID of 200 mcg (on a mcg/m2 basis at maternal inhalation doses up to 27 mcg/kg/day). No evidence of effects on offspring development was observed.

            Vilanterol: In 2 separate embryofetal developmental studies, pregnant rats and rabbits received vilanterol during the period of organogenesis at doses up to approximately 13,000 and 1,000 times, respectively, the MRHDID (on a mcg/m2 basis at maternal inhalation doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 5,740 mcg/kg/day in rabbits). No evidence of structural abnormalities was observed at any dose in rats or in rabbits up to approximately 160 times the MRHDID (on an AUC basis at maternal doses up to 591 mcg/kg/day). However, fetal skeletal variations were observed in rabbits at approximately 1,000 times the MRHDID (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals. In a perinatal and postnatal developmental study in rats, dams received vilanterol during late gestation and the lactation periods at doses up to approximately 3,900 times the MRHDID (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day). No evidence of effects in offspring development was observed.

Lactation

Risk Summary

There is no information available on the presence of fluticasone furoate or vilanterol in human milk, the effects on the breastfed child, or the effects on milk production. Low concentrations of other ICS have been detected in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BREO ELLIPTA and any potential adverse effects on the breastfed child from fluticasone furoate or vilanterol or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of BREO ELLIPTA for the maintenance treatment of asthma in pediatric patients 5 years of age and older have been established. This indication is based on Trial 14, an adequate and well-controlled trial in pediatric patients aged 5 to 17 years [see Adverse Reactions , Clinical Studies ]. The recommended dosage for pediatric patients is different than the adult dosage [see Dosage and Administration ].

The safety and efficacy of BREO ELLIPTA in pediatric patients aged younger than 5 years have not been established.

In Trial 12, an exacerbation trial [see Clinical Studies ], pediatric patients aged 12 to 17 years (n = 281) were treated with BREO ELLIPTA 100/25 mcg (n = 151) or treated with fluticasone furoate 100 mcg (n = 130). Among these patients, 10% of patients treated with BREO ELLIPTA 100/25 mcg reported an asthma exacerbation compared with 7% for patients treated with fluticasone furoate 100 mcg. Asthma-related hospitalizations occurred in 4 patients (2.6%) treated with BREO ELLIPTA 100/25 mcg compared with 0 patients treated with fluticasone furoate 100 mcg.

Effects on Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in pediatric patients may occur as a result of poorly controlled asthma or from use of corticosteroids, including ICS. The effects of long-term treatment of pediatric patients with ICS, including fluticasone furoate, on final adult height are not known.

Controlled clinical trials have shown that ICS may cause a reduction in growth in children. In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appears to be related to dose and duration of exposure. 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 children than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The growth of pediatric patients receiving orally inhaled corticosteroids, including BREO ELLIPTA, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including BREO ELLIPTA, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

A randomized, double-blind, parallel-group, multicenter, 1-year, placebo-controlled trial evaluated the effect of once-daily treatment with orally inhaled fluticasone furoate 50 mcg on growth velocity assessed by stadiometry. The patients were 457 prepubertal children (girls aged 5 to <8 years and boys aged 5 to <9 years). Mean growth velocity over the 52-week treatment period was lower in the patients receiving orally inhaled fluticasone furoate (5.905 cm/year) compared with placebo (6.065 cm/year). The mean reduction in growth velocity was 0.16 cm/year (95% CI: -0.14, 0.46) [see Warnings and Precautions ].

Geriatric Use

Based on available data, no adjustment of the dosage of BREO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.

Clinical trials of BREO ELLIPTA for COPD included 4,820 subjects aged 65 years and older and 1,118 subjects aged 75 years and older. Clinical trials of BREO ELLIPTA for asthma included 854 subjects aged 65 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Hepatic Impairment

Fluticasone furoate systemic exposure increased by up to 3-fold in adult patients with hepatic impairment compared with healthy subjects. Hepatic impairment had no effect on vilanterol systemic exposure. Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects. The effect of hepatic impairment on fluticasone furoate and vilanterol systemic exposure in patients aged younger than 18 years has not been evaluated [see Clinical Pharmacology ].

Renal Impairment

There were no significant increases in either fluticasone furoate or vilanterol exposure in patients with severe renal impairment (CrCl <30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology ].

Serious Asthma-Related Events – Hospitalizations, Intubations, Death

Use of Long-acting Beta2-adrenergic Agonist (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 patients. These findings are considered a class effect of LABA monotherapy. 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 with ICS alone (see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-Acting Beta2-Adrenergic Agonists).

Serious Asthma-Related Events with Inhaled Corticosteroid/Long-Acting Beta2-Adrenergic Agonists

Four (4) large, 26-week, randomized, double-blind, 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 with ICS alone in patients with asthma. Three (3) trials included adult and pediatric patients aged 12 years and older: 1 trial compared budesonide/formoterol with budesonide, 1 trial compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder, and 1 trial compared mometasone furoate/formoterol with mometasone furoate. The fourth trial included pediatric patients aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder. The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A blinded adjudication committee determined whether events were asthma related.

The 3 adult and pediatric trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk margin 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 3 adult and pediatric 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 . These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS.

The pediatric safety trial included 6,208 pediatric patients aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3,107 (0.9%) patients randomized to ICS/LABA and 21/3,101 (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 with 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.

Deterioration of Disease and Acute Episodes

BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD or asthma. BREO ELLIPTA has not been studied in patients with acutely deteriorating COPD or asthma. The initiation of BREO ELLIPTA in this setting is not appropriate.

In COPD, if BREO ELLIPTA 100/25 mcg no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting, re-evaluate the patient and the COPD treatment regimen at once. For COPD, the daily dose of BREO ELLIPTA 100/25 mcg should not be increased.

Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the need for additional therapeutic options. Patients should not use more than 1 inhalation once daily of BREO ELLIPTA.

BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

When beginning treatment with BREO ELLIPTA, 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 and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used.

Risk Associated with Excessive Use of Long-Acting Beta2-Agonists, including BREO ELLIPTA

BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended [see Dosage and Administration ], or in conjunction with other therapies 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 BREO ELLIPTA should not use another therapy containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

Oropharyngeal Candidiasis

BREO ELLIPTA contains fluticasone furoate, an ICS. Localized infections of the mouth and pharynx with Candida albicans have occurred in patients treated with orally inhaled drug products containing fluticasone furoate. Monitor patients periodically. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues. In some cases, therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following administration of BREO ELLIPTA to help reduce the risk of oropharyngeal candidiasis.

Pneumonia

An increase in the incidence of pneumonia has been observed in patients with COPD receiving BREO ELLIPTA 100/25 mcg in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal. Healthcare providers should remain vigilant for the possible development of pneumonia in patients with COPD as clinical features of pneumonia and exacerbations frequently overlap.

In replicate 12-month trials in 3,255 patients with moderate to severe COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in patients receiving fluticasone furoate/vilanterol 50/25 mcg: 6% (48 of 820 patients); BREO ELLIPTA 100/25 mcg: 6% (51 of 806 patients); or BREO ELLIPTA 200/25 mcg: 7% (55 of 811 patients) than in patients receiving vilanterol 25 mcg: 3% (27 of 818 patients). There was no fatal pneumonia in patients receiving vilanterol or fluticasone furoate/vilanterol 50/25 mcg. There was fatal pneumonia in 1 patient receiving BREO ELLIPTA 100/25 mcg and in 7 patients receiving BREO ELLIPTA 200/25 mcg (<1% for each treatment group).

In a mortality trial with a median treatment duration of 1.5 years in 16,568 patients with moderate COPD and cardiovascular disease, the annualized incidence rate of pneumonia was 3.4 per 100 patient-years for BREO ELLIPTA 100/25 mcg, 3.2 for placebo, 3.3 for fluticasone furoate 100 mcg, and 2.3 for vilanterol 25 mcg. Adjudicated, on-treatment deaths due to pneumonia occurred in 13 patients receiving BREO ELLIPTA 100/25 mcg, 9 patients receiving placebo, 10 patients receiving fluticasone furoate 100 mcg, and 6 patients receiving vilanterol 25 mcg (<0.2 per 100 patient-years for each treatment group).

Immunosuppression and Risk of Infections

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chickenpox and measles can have a more serious or even fatal course in susceptible patients using corticosteroids. In such patients 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 affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective Prescribing Information for VZIG and IG) If chickenpox develops, treatment with antiviral agents may be considered.

ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Transferring Patients from Systemic Corticosteroid Therapy

Hypothalamic-Pituitary-Adrenal Suppression/Adrenal Insufficiency

Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients during and after transfer from systemic corticosteroids to less systemically available ICS. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more 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 BREO ELLIPTA may control COPD or asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress, a severe COPD exacerbation, or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their healthcare practitioner for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack.

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

Unmasking of Allergic Conditions Previously Suppressed by Systemic Corticosteroids

Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

Corticosteroid Withdrawal Symptoms

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

Hypercorticism and Adrenal Suppression

Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic doses of fluticasone furoate in BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions , Drug Interactions ].

Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, reduce the dose of BREO ELLIPTA slowly, consistent with accepted procedures for reducing systemic corticosteroids, and consider other treatments for management of COPD or asthma symptoms.

Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

Caution should be exercised when considering the coadministration of BREO ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors (including, but not limited to, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions , Clinical Pharmacology ].

Paradoxical Bronchospasm

BREO ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted [see Adverse Reactions ].

Hypersensitivity Reactions, including Anaphylaxis

Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of BREO ELLIPTA. Discontinue BREO ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use BREO ELLIPTA [see Contraindications , Adverse Reactions ].

Cardiovascular Effects

BREO ELLIPTA, like other drugs containing beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles [see Adverse Reactions ]. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown [see Clinical Pharmacology ]. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12- or 10-fold higher systemic exposure than seen in patients with COPD or asthma, respectively) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

In a mortality trial with a median treatment duration of 1.5 years in 16,568 patients with moderate COPD and cardiovascular disease, the annualized incidence rate of adjudicated cardiovascular events (composite of myocardial infarction, stroke, unstable angina, transient ischemic attack, or on-treatment death due to cardiovascular events) was 2.5 per 100 patient-years for BREO ELLIPTA 100/25 mcg, 2.7 for placebo, 2.4 for fluticasone furoate 100 mcg, and 2.6 for vilanterol 25 mcg. Adjudicated, on-treatment deaths due to cardiovascular events occurred in 82 patients receiving BREO ELLIPTA 100/25 mcg, 86 patients receiving placebo, 80 patients receiving fluticasone furoate 100 mcg, and 90 patients receiving vilanterol 25 mcg (annualized incidence rate ranged from 1.2 to 1.3 per 100 patient-years for the treatment groups).

Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient’s COPD therapy, use of therapy to treat or prevent osteoporosis should be strongly considered.

In replicate 12-month trials in 3,255 patients with moderate to severe COPD, bone fractures were reported by 2% of patients receiving the fluticasone furoate/vilanterol combination (50/25 mcg: 2% [14 of 820 patients]; 100/25 mcg: 2% [19 of 806 patients]; or 200/25 mcg: 2% [14 of 811 patients]) compared with <1% of patients receiving vilanterol 25 mcg alone (8 of 818 patients).

Similar findings were seen in a mortality trial with a median treatment duration of 1.5 years in 16,568 patients with moderate COPD and cardiovascular disease.

Effect on Growth

Orally inhaled corticosteroids, , including fluticasone furoate, a component in BREO ELLIPTA may cause a reduction in growth velocity when administered to pediatric patients. The safety and effectiveness of BREO ELLIPTA have not been established in pediatric patients less than 5 years of age. Monitor the growth of pediatric patients receiving BREO ELLIPTA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including BREO ELLIPTA, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration , Use in Specific Populations ].

Glaucoma and Cataracts

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of ICS, including fluticasone furoate, a component in BREO ELLIPTA. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use BREO ELLIPTA long term.

Risk of Using Sympathomimetic Amines in Certain Coexisting Conditions

BREO ELLIPTA, like all therapies containing sympathomimetic amines, should be used with caution in patients with convulsive disorders, thyrotoxicosis, or diabetes mellitus 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.

Hyperglycemia and Hypokalemia

There have been reports of increases in blood glucose levels with BREO ELLIPTA. This should be considered in patients with a history of, or with risk factors for, diabetes mellitus [see Adverse Reactions ].

Beta-adrenergic agonist therapies may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In clinical trials evaluating BREO ELLIPTA in patients with COPD or asthma, there was no evidence of a treatment effect on serum potassium.