Fluticasone Furoate Drug Information

• For oral inhalation only. ( 2.3 )
• Maintenance treatment of COPD: 1 actuation of Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg once daily administered by oral inhalation. ( 2.1 )
• Maintenance treatment of asthma in adult patients aged 18 years and older: 1 actuation of Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg or Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg once daily administered by oral inhalation. ( 2.2 )
• Maintenance treatment of asthma in pediatric patients aged 12 to 17 years: 1 actuation of Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg once daily administered by oral inhalation. ( 2.2 )
• Maintenance treatment of asthma in pediatric patients aged 5 to 11 years: 1 actuation of fluticasone furoate/vilanterol ELLIPTA 50/25 mcg once daily administered by oral inhalation. ( 2.2 ) 2.1 Recommended Dosage for Maintenance Treatment of Chronic Obstructive Pulmonary Disease The recommended dosage of Fluticasone Furoate/Vilanterol 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 beta 2 -agonist (rescue medicine, e.g., albuterol) should be used for immediate relief. 2.2 Recommended Dosage for Maintenance Treatment of Asthma Adult Patients Aged 18 Years and Older The recommended dosage of Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation or Fluticasone Furoate/Vilanterol 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 Fluticasone Furoate/Vilanterol 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 (FEV 1 ), 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 Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg once daily, increasing the dose to Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg once daily may provide additional improvement in asthma control. For patients who do not respond adequately to Fluticasone Furoate/Vilanterol 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 Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg once daily.
• If asthma symptoms arise in the period between doses, an inhaled, short-acting beta 2 -agonist (rescue medicine, e.g., albuterol) should be used for immediate relief. Pediatric Patients Aged 12 to 17 Years The recommended dosage of Fluticasone Furoate/Vilanterol 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 ( 5.14 )] . Pediatric Patients Aged 5 to 11 Years The recommended dosage of Fluticasone Furoate/Vilanterol 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 ( 5.14 )] . 2.3 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 )] .
• Fluticasone Furoate/Vilanterol ELLIPTA should be used at the same time every day. Do not use Fluticasone Furoate/Vilanterol 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 Fluticasone Furoate/Vilanterol ELLIPTA is not recommended as some patients are more likely to experience adverse effects with higher doses.

• 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 Prasco Laboratories at 1-866-525-0688 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 fluticasone furoate/vilanterol ELLIPTA 100/25 mcg. Adverse reactions observed in other studies of fluticasone furoate/vilanterol ELLIPTA in COPD patients were similar to those observed in these 5 trials. 6-Month Trials The incidence of adverse reactions associated with fluticasone furoate/vilanterol 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: fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol 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 Fluticasone Furoate/Vilanterol 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 Fluticasone Furoate/ Vilanterol 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: fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol 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 are based on trials that evaluated fluticasone furoate/vilanterol ELLIPTA 100/25 mcg in 1,757 patients and fluticasone furoate/vilanterol ELLIPTA 200/25 mcg in 745 patients. While patients aged 12 to 17 years were included in these trials, fluticasone furoate/vilanterol 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, fluticasone furoate/vilanterol ELLIPTA 100/25 mcg was studied in 117 patients aged 12 to 17 years and fluticasone furoate/vilanterol ELLIPTA 50/25 mcg was studied in 337 patients aged 5 to 11 years. Adult Patients The safety of fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol ELLIPTA 100/25 mcg in patients with asthma compared with fluticasone furoate 100 mcg and placebo. The incidence of adverse reactions associated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg is shown in Table 3 . Table 3. Adverse Reactions with Fluticasone Furoate/Vilanterol 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 Fluticasone Furoate/Vilanterol 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 fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol ELLIPTA 100/25 mcg and fluticasone furoate/vilanterol ELLIPTA 200/25 mcg is shown in Table 4 . Table 4. Adverse Reactions with Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg and Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg with ≥2% Incidence in Patients with Asthma (Trial 9) Adverse Reaction Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg (n = 346) % Fluticasone Furoate/Vilanterol 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 fluticasone furoate/vilanterol ELLIPTA 200/25 mcg once daily, fluticasone furoate 200 mcg once daily, and fluticasone propionate 500 mcg twice daily in patients with asthma. This trial did not have a placebo arm. In addition to the reactions shown in Tables 3 and 4, adverse reactions occurring in ≥2% of patients treated with fluticasone furoate/vilanterol ELLIPTA 200/25 mcg included viral respiratory tract infection, pharyngitis, pyrexia, and arthralgia. 12-Month Trial Long-term safety data are based on a 12-month trial that evaluated the safety of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg once daily (n = 201), fluticasone furoate/vilanterol ELLIPTA 200/25 mcg once daily (n = 202), and fluticasone propionate 500 mcg twice daily (n = 100) in patients with asthma (Trial 11). In addition to the reactions shown in Tables 3 and 4, adverse reactions occurring in ≥2% of the patients treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg or fluticasone furoate/vilanterol ELLIPTA 200/25 mcg for 12 months included pyrexia, back pain, extrasystoles, upper abdominal pain, respiratory tract infection, allergic rhinitis, pharyngitis, rhinitis, arthralgia, supraventricular extrasystoles, ventricular extrasystoles, acute sinusitis, and pneumonia. Adult and Pediatric Patients Aged 12 to 17 Years Exacerbation Trial Trial 12 included both adult and pediatric patients 12 years of age and older. Although this trial did not support efficacy of fluticasone furoate/vilanterol ELLIPTA for maintenance treatment of asthma in pediatric patients 12 to 17 years of age, it was used to evaluate safety in both adult and pediatric patients 12 to 17 years of age. Patients received fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 1,009) or fluticasone furoate 100 mcg (n = 1,010). Patients participating in this trial had a history of 1 or more asthma exacerbations that required treatment with oral/systemic corticosteroids or emergency department visit or in-patient hospitalization for the treatment of asthma in the year prior to trial entry. Asthma-related hospitalizations occurred in 10 patients (1%) treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with 7 patients (0.7%) treated with fluticasone furoate 100 mcg. Among patients aged 12 to 17 years, asthma-related hospitalizations occurred in 4 patients (2.6%) treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 151) compared with 0 patients treated with fluticasone furoate 100 mcg (n = 130). There were no asthma-related deaths or asthma-related intubations observed in this trial. Pediatric Patients Aged 5 to 17 Years The safety of fluticasone furoate/vilanterol ELLIPTA for the maintenance treatment of asthma in pediatric patients 5 years and older was based on the data from Trial 14, a 24-week clinical trial that enrolled 902 patients with asthma aged 5 to 17 years (aged 5 to 11 years [n = 673]; aged 12 to 17 years [n = 229]). Pediatric patients aged 12 to 17 years were randomized to fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 117) or fluticasone furoate 100 mcg (n = 112). Pediatric patients aged 5 to 11 years were randomized to fluticasone furoate/vilanterol ELLIPTA 50/25 mcg (n = 337) or fluticasone furoate 50 mcg (n = 336) [see Clinical Studies ( 14.2 )] . Adverse reactions reported in ≥3% of pediatric patients treated with fluticasone furoate/vilanterol ELLIPTA is shown in Table 5 . Table 5. Adverse Reactions with Fluticasone Furoate/Vilanterol ELLIPTA with ≥3% Incidence in Pediatric Patients with Asthma (Trial 14) a The dose of fluticasone furoate/vilanterol ELLIPTA was 100/25 mcg once daily for pediatric patients aged 12 to 17 years and 50/25 mcg once daily for pediatric patients aged 5 to 11 years. b The dose of fluticasone furoate was 100 mcg once daily for pediatric patients aged 12 to 17 years and 50 mcg once daily for pediatric patients aged 5 to 11 years. Adverse Reaction Fluticasone Furoate/Vilanterol ELLIPTA a (n = 454) % Fluticasone Furoate b (n = 448) % Infections and infestations Nasopharyngitis 10 8 Upper respiratory tract infection 7 6 Rhinitis 3 1 Viral upper respiratory tract infection 3 <1 Respiratory, thoracic, and mediastinal disorders Rhinitis allergic 4 1 Nervous system disorders Headache 3 2 6.3 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post approval use of fluticasone furoate/vilanterol ELLIPTA. 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. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone furoate/vilanterol ELLIPTA or a combination of these factors. Cardiac Disorders Palpitations, tachycardia. Immune System Disorders Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria. Metabolism and Nutrition Disorders Hyperglycemia. Musculoskeletal and Connective Tissue Disorders Muscle spasms. Nervous System Disorders Tremor. Psychiatric Disorders Nervousness. Respiratory, Thoracic, and Mediastinal Disorders Paradoxical bronchospasm.

• 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 Fluticasone Furoate/Vilanterol 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.

Pregnancy Risk Summary There are insufficient data on the use of fluticasone furoate/vilanterol 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: Fluticasone Furoate/Vilanterol 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.

Pediatric Use The safety and effectiveness of Fluticasone Furoate/Vilanterol 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 . The recommended dosage for pediatric patients is different than the adult dosage . The safety and efficacy of Fluticasone Furoate/Vilanterol ELLIPTA in pediatric patients aged younger than 5 years have not been established. In Trial 12, an exacerbation trial , pediatric patients aged 12 to 17 years (n = 281) were treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 151) or treated with fluticasone furoate 100 mcg (n = 130). Among these patients, 10% of patients treated with fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol 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 Fluticasone Furoate/Vilanterol 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 Fluticasone Furoate/Vilanterol 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) .

• Fluticasone Furoate/Vilanterol 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 )

Fluticasone Furoate/Vilanterol ELLIPTA contains both fluticasone furoate and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to Fluticasone Furoate/Vilanterol ELLIPTA. Treatment of overdosage consists of discontinuation of Fluticasone Furoate/Vilanterol ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta‑receptor blocker may be considered, bearing in mind that such medicine can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage.

Fluticasone Furoate Because of low systemic bioavailability (15.2%) and an absence of acute drug-related systemic findings in clinical trials, overdosage of fluticasone furoate is unlikely to require any treatment other than observation. If used at excessive doses for prolonged periods, systemic effects such as hypercorticism may occur . Vilanterol The expected signs and symptoms with overdosage of vilanterol are those of excessive beta‑adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of vilanterol.