Fluticasone Furoate and Vilanterol Trifenatate

BREO ELLIPTA is a combination of fluticasone furoate, a corticosteroid, and vilanterol, a long-acting beta 2 -adrenergic agonist (LABA), indicated for:

• the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). ( 1.1 )
• the maintenance treatment of asthma in patients aged 5 years and older. ( 1.2 ) Limitations of Use: Not indicated for relief of acute bronchospasm. ( 1.3 , 5.2 )

1.1 Maintenance Treatment of Chronic Obstructive Pulmonary Disease BREO ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

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

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

Inhalation powder:

• 50 mcg fluticasone furoate and 25 mcg vilanterol (50/25 mcg) per actuation
• 100 mcg fluticasone furoate and 25 mcg vilanterol (100/25 mcg) per actuation
• 200 mcg fluticasone furoate and 25 mcg vilanterol (200/25 mcg) per actuation Inhalation powder:
• 50 mcg fluticasone furoate and 25 mcg vilanterol (50/25 mcg) per actuation ( 3 )
• 100 mcg fluticasone furoate and 25 mcg vilanterol (100/25 mcg) per actuation ( 3 )
• 200 mcg fluticasone furoate and 25 mcg vilanterol (200/25 mcg) per actuation ( 3 )

BREO ELLIPTA is contraindicated in the following conditions:

• Primary treatment of status asthmaticus or other acute episodes of COPD or asthma where intensive measures are required [see Warnings and Precautions ( 5.2 )] .
• Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone furoate, vilanterol, or any of the excipients [see Warnings and Precautions ( 5.11 ), Description ( 11 )] .
• Primary treatment of status asthmaticus or acute episodes of COPD or asthma requiring intensive measures. ( 4 )
• Severe hypersensitivity to milk proteins or any ingredients. ( 4 )

• LABA monotherapy increases the risk of serious asthma-related events. ( 5.1 )
• Do not initiate in acutely deteriorating COPD or asthma. Do not use to treat acute symptoms. ( 5.2 )
• Do not use in combination with additional therapy containing a LABA because of risk of overdose. ( 5.3 )
• Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 )
• Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. ( 5.5 )
• Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; 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 )
• Risk of impaired adrenal function when transferring from systemic corticosteroids. Wean patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. ( 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 BREO ELLIPTA slowly. ( 5.8 )
• If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy. ( 5.10 )
• Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.12 )
• Assess for decrease in bone mineral density (BMD) initially and periodically thereafter. ( 5.13 )
• Monitor growth of pediatric patients ( 5.14 )
• Glaucoma and cataracts may occur with long-term use of Inhaled Corticosteroid (ICS). Consider referral to an ophthalmologist in patients who develop ocular symptoms or use BREO ELLIPTA long term. ( 5.15 )
• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.16 )
• Increased blood glucose levels have been reported. Also, be alert to hypokalemia. ( 5.17 )

5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death Use of Long-acting Beta 2 -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 Beta 2 -Adrenergic Agonists) . Serious Asthma-Related Events with Inhaled Corticosteroid/Long-Acting Beta 2 -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 ( 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. a Randomized patients who had taken at least 1 dose of study drug. Planned treatment used for analysis. b Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials. c 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. ICS/LABA (n = 17,537) a ICS (n = 17,552) a ICS/LABA vs. ICS Hazard Ratio (95% CI) b Serious asthma-related event c 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 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.

5.2 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, beta 2 -agonist becomes less effective; or the patient needs more short-acting beta 2 -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 beta 2 -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. […]

The following clinically significant adverse reactions are described elsewhere in labeling:

• Serious Asthma-Related Events – Hospitalizations, Intubations, Death [see Warnings and Precautions ( 5.1 )]
• Oropharyngeal Candidiasis [see Warnings and Precautions ( 5.4 )]
• Pneumonia [see Warnings and Precautions ( 5.5 )]
• Immunosuppression and Risk of Infections [see Warnings and Precautions ( 5.6 )]
• Hypercorticism and Adrenal Suppression [see Warnings and Precautions ( 5.8 )]
• Paradoxical Bronchospasm [see Warnings and Precautions ( 5.10 )]
• Cardiovascular Effects [see Warnings and Precautions ( 5.12 )]
• Reduction in Bone Mineral Density [see Warnings and Precautions ( 5.13 )]
• Growth Effects [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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• COPD: Most common adverse reactions (incidence ≥3%) are nasopharyngitis, upper respiratory tract infection, headache, oral candidiasis, back pain, pneumonia, bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, and pyrexia. ( 6.1 )
• Asthma: Most common adverse reactions (incidence ≥2%) are nasopharyngitis, oral candidiasis, headache, influenza, upper respiratory tract infection, bronchitis, sinusitis, oropharyngeal pain, dysphonia, and cough. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease The safety data described below are based on two 6-month and two 12-month trials and one long-term mortality trial. In these studies, 5,356 patients with COPD received at least 1 dose of BREO ELLIPTA 100/25 mcg. Adverse reactions observed in other studies of BREO ELLIPTA in COPD patients were similar to those observed in these 5 trials. 6-Month Trials The incidence of adverse reactions associated with BREO ELLIPTA 100/25 mcg in Table 2 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 patients, 70% were male and 84% were White. They had a mean age of 62 years and an average smoking history of 44 pack years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 14% to 87%), the mean postbronchodilator FEV 1 /forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%). Patients received 1 inhalation once daily of the following: BREO ELLIPTA 100/25 mcg, BREO ELLIPTA 200/25 mcg, fluticasone furoate/vilanterol 50/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo. Table 2. Adverse Reactions with BREO ELLIPTA 100/25 mcg with ≥3% Incidence and More Common than Placebo in Patients with Chronic Obstructive Pulmonary Disease a Includes oral candidiasis, oropharyngeal candidiasis, candidiasis, and fungal oropharyngitis. Adverse Reaction BREO ELLIPTA 100/25 mcg (n = 410) % Vilanterol 25 mcg (n = 408) % Fluticasone Furoate 100 mcg (n = 410) % Placebo (n = 412) % Infections and infestations Nasopharyngitis 9 10 8 8 Upper respiratory tract infection 7 5 4 3 Oropharyngeal candidiasis a 5 2 3 2 Nervous system disorders Headache 7 9 7 5 12-Month Trials Long-term safety data are based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 patients, of which 57% were male and 85% were White. They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV 1 was 45% (range: 12% to 91%), and the mean postbronchodilator FEV 1 /FVC ratio was 46% (range: 17% to 81%), indicating that the patient population had moderate to very severely impaired airflow obstruction. Patients received 1 inhalation once daily of the following: BREO ELLIPTA 100/25 mcg, BREO ELLIPTA 200/25 mcg, fluticasone furoate/vilanterol 50/25 mcg, or vilanterol 25 mcg. In addition to the reactions shown in Table 2 , adverse reactions occurring in ≥3% of the patients treated with BREO ELLIPTA 100/25 mcg (n = 806) for 12 months included back pain, pneumonia [see Warnings and Precautions ( 5.5 )] , bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, influenza, pharyngitis, and pyrexia. Mortality Trial Safety data are available from a mortality trial in patients with moderate COPD (moderate airflow limitation [≥50% and ≤70% predicted FEV 1 ]) who either had a history of, or were at risk of, cardiovascular disease and were treated for up to 4 years (median treatment duration of 1.5 years). The trial included 16,568 patients, 4,140 of whom received BREO ELLIPTA 100/25 mcg. In addition to the events in COPD trials shown in Table 2 , adverse reactions occurring in ≥3% of the patients treated with BREO ELLIPTA 100/25 mcg and more common than placebo included pneumonia, back pain, hypertension, and influenza.

6.2 Clinical Trials Experience in Asthma The safety data described below were based on trials that evaluated BREO ELLIPTA 100/25 mcg in 1,757 patients and BREO ELLIPTA 200/25 mcg in 745 patients. While patients aged 12 to 17 years were included in these trials, BREO ELLIPTA 200/25 mcg is not approved for use in this age group [see Dosage and Administration ( 2.2 )] . One additional 24-week trial enrolled 902 pediatric patients with asthma. In this trial, BREO ELLIPTA 100/25 mcg was studied in 117 patients aged 12 to 17 years and BREO ELLIPTA 50/25 mcg was studied in 337 patients aged 5 to 11 years. Adult Patients The safety of BREO ELLIPTA for the maintenance treatment of asthma in adult patients was based on the data from Trials 8, 9, 10, 11, and 12 [see Clinical Studies ( 14.2 )] . Trial 8 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25 mcg in patients with asthma compared with fluticasone furoate 100 mcg and placebo. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 mcg is shown in Table 3 . Table 3. Adverse Reactions with BREO ELLIPTA 100/25 mcg with ≥2% Incidence and More Common than Placebo in Patients with Asthma (Trial 8) a Includes oral candidiasis and oropharyngeal candidiasis. Adverse Reaction BREO ELLIPTA 100/25 mcg (n = 201) % Fluticasone Furoate 100 mcg (n = 205) % Placebo (n = 203) % Infections and infestations Nasopharyngitis 10 7 7 Oral candidiasis a 2 2 0 Nervous system disorders Headache 5 4 4 Respiratory, thoracic, and mediastinal disorders Oropharyngeal pain 2 2 1 Dysphonia 2 1 0 Trial 9 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25 mcg, BREO ELLIPTA 200/25 mcg, and fluticasone furoate 100 mcg in patients with asthma. This trial did not have a placebo arm. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 mcg and BREO ELLIPTA 200/25 mcg is shown in Table 4 . Table 4. Adverse Reactions with BREO ELLIPTA 100/25 mcg and BREO ELLIPTA 200/25 mcg with ≥2% Incidence in Patients with Asthma (Trial 9) Adverse Reaction BREO ELLIPTA 200/25 mcg (n = 346) % BREO ELLIPTA 100/25 mcg (n = 346) % Fluticasone Furoate 100 mcg (n = 347) % Nervous system disorders Headache 8 8 9 Infections and infestations Nasopharyngitis 7 6 7 Influenza 3 3 1 Upper respiratory tract infection 2 2 3 Sinusitis 2 1 <1 Bronchitis 2 <1 2 Respiratory, thoracic, and mediastinal disorders Oropharyngeal pain 2 2 1 Cough 1 2 1 24-Week Trial Trial 10 was a 24-week trial that evaluated the efficacy of BREO ELLIPTA 200/25 mcg once daily, fluticasone furoate 200 mcg once daily, and fluticasone propionate 500 mcg twice daily in patients with asthma. […]

• Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. May cause systemic corticosteroid and cardiovascular effects. ( 7.1 )
• Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of vilanterol on cardiovascular 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 P450 3A4 Fluticasone furoate and vilanterol are both substrates of CYP3A4. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of BREO ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors [see Warnings and Precautions ( 5.9 ), Clinical Pharmacology ( 12.3 )] .

7.2 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, and QTc Prolonging Drugs Vilanterol, like other beta 2 -agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.

7.3 Beta-Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as vilanterol, but may also produce severe bronchospasm in patients with COPD or asthma. Therefore, patients with COPD or 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 for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

7.4 Non–Potassium-Sparing Diuretics The electrocardiographic 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 beta-agonists with non–potassium-sparing diuretics.

Hepatic impairment: Fluticasone furoate systemic exposure may increase in patients with moderate or severe impairment. Monitor for systemic corticosteroid effects. ( 8.6 , 12.3 )

8.1 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 basis at maternal oral doses up to 10,000 mcg/kg/day). No evidence of effects in offspring development was observed.

8.2 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.

8.4 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 ( 6.2 ), Clinical Studies ( 14.2 )] . The recommended dosage for pediatric patients is different than the adult dosage [see Dosage and Administration ( 2.2 )] . 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 ( 14.2 )] , 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). […]

BREO ELLIPTA BREO ELLIPTA contains both fluticasone furoate and vilanterol. The mechanisms of action described below for the individual components apply to BREO ELLIPTA. These drugs represent 2 different classes of medications (an ICS and a LABA), each having different effects on clinical and physiological indices. Fluticasone Furoate Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown. The precise mechanism through which fluticasone furoate affects COPD and asthma symptoms is not known. Inflammation is an important component in the pathogenesis of COPD and asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy. Vilanterol Vilanterol is a LABA. In vitro tests have shown the functional selectivity of vilanterol was similar to salmeterol. The clinical relevance of this in vitro finding is unknown. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -adrenergic agonist drugs, including vilanterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.