新复方药物BREO ELLIPTA，作为每日一次的吸入性疗法，用于慢性阻塞性肺病（COPD）患者的长期维持治疗，包括慢性支气管炎和/或肺气肿
2013年5月10日，美国食品药品管理局（FDA）批准Breo Ellipta用于包括慢性支气管炎和/或肺气肿在内的慢性阻塞性肺病（COPD）患者气流阻塞的长期维持治疗，该药物为糠酸氟替卡松和维兰特罗的吸入型复方药物粉末，可每日吸入一次。Breo Ellipta还被批准用于减少患者的慢性阻塞性肺病发作。
慢性阻塞性肺病是一种严重的肺疾病，可随时间的推移而恶化。症状有胸闷、久咳和过度痰液。根据美国国家心脏、肺和血液研究所提供的信息，吸烟是慢性阻塞性肺病的主要因素，而慢性阻塞性肺病在美国是第三大主要死亡原因。Breo Ellipta可通过减轻慢性阻塞性肺病患者肺部的炎症，以及松弛肺气道周围的肌肉来增加气流及减少疾病的发作。
FDA药品评价与研究中心药物评价II办公室的主任Curtis Rosebraugh医学博士说：“慢性阻塞性肺病是一种造成呼吸困难的严重疾病，新型的长期维持药物的应用为美国数百万遭受该病困扰的患者提供了一种新的治疗选择。”
Breo Ellipta中的糠酸氟替卡松是一种吸入型糖皮质激素，维兰特罗是一种长效β2肾上腺素受体激动剂(LABA)。该药物的安全性和有效性通过一项7700名慢性阻塞性肺病患者参与的临床试验进行了评价。用药组患者相比安慰剂组患者其肺部功能得到了改善，疾病发作次数减少。
Breo Ellipta在获批时其标签内容中有一项黑框警告，提示长效β2肾上腺素受体激动剂能增加哮喘有关的死亡风险。这款药物对哮喘患者的安全性和有效性还没得到确认，所以没被批准用于哮喘的治疗。
FDA在批准Breo Ellipta时附带一患者用药指南，内容包含该药物的使用说明和用药后的潜在风险信息。Breo Ellipta不能作为一种急救措施用于治疗突然的呼吸困难（急性支气管痉挛），也不建议用于18岁以下患者。
Breo Ellipta可能会引起严重的副作用，包括肺炎和骨折的风险增加。Breo Ellipta用药患者报道的最常见副作用有鼻腔炎症（鼻咽炎）、上呼吸道感染、头痛及口腔念珠菌病(鹅口疮)。
Breo Ellipta由葛兰素史克与总部位于旧金山的治疗先锋公司联合开发。
APPROVED USES
BREO ELLIPTA is approved for adults with chronic obstructive pulmonary disease (COPD), including chronic bronchitis, emphysema, or both. BREO ELLIPTA is a prescription medicine that is used long term as 1 inhalation 1 time each day to improve symptoms of COPD for better breathing and to reduce the number of flare-ups (the worsening of your COPD symptoms for several days). BREO is not for use to treat sudden symptoms of COPD and won't replace a rescue inhaler. BREO is not for the treatment of asthma.
TALK TO YOUR DOCTOR TO SEE IF BREO CAN IMPROVE YOUR SYMPTOMS OF COPD FOR BETTER BREATHING.
Whether you're coordinating a food drive or planning a family outing, you believe in making things happen. And you don't want your breathing problems to get in the way. BREO ELLIPTA may be able to help you breathe better.
BREO is a combination of two medicines—an inhaled corticosteroid (ICS) medicine called fluticasone furoate, and a long-acting beta2-adrenergic agonist (LABA) medicine called vilanterol—creating the first and only once-daily ICS/LABA that helps improve lung function for a full 24 hours. Your results may vary.

Fluticasone Furoate and Vilanterol Inhalation Powder
WARNING: ASTHMA-RELATED DEATH
Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including vilanterol, an active ingredient in fluticasone furoate/vilanterol trifenatate inhaler [see Warnings and Precautions (5.1)].
The safety and efficacy of fluticasone furoate/vilanterol trifenatate inhaler in patients with asthma have not been established. Fluticasone furoate/vilanterol trifenatate inhaler is not indicated for the treatment of asthma.
1. DESCRIPTION 
Fluticasone furoate/vilanterol trifenatate inhaler is a combination of fluticasone furoate (an ICS) and vilanterol (a LABA).
Fluticasone furoate is a synthetic trifluorinated corticosteroid having the chemical name (6α,11β,16α,17α)-6,9-difluoro-17-{[(fluoro-methyl)thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4-dien-17-yl 2-furancarboxylate and the following chemical structure:

Empirical formula: C27H29F3O6S - Molecular weight: 538.6
Fluticasone furoate is a white powder. It is practically insoluble in water.
Vilanterol trifenatate is a LABA with the chemical name triphenylacetic acid-4-{(1R)-2-[(6-{2-[2,6-dicholorobenzyl)oxy]ethoxy} hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol (1:1) and the following chemical structure:

Empirical formula: C24H33Cl2NO5•C20H16O2 - Molecular weight: 774.8
Vilanterol trifenatate is a white powder. It is practically insoluble in water.
Fluticasone furoate/vilanterol trifenatate inhaler is a light grey and pale blue plastic inhaler containing 2 double-foil blister strips. Each blister on one strip contains a white powder mix of micronized fluticasone furoate (100 mcg) and lactose monohydrate (12.4 mg), and each blister on the other strip contains a white powder mix of micronized vilanterol trifenatate (40 mcg equivalent to 25 mcg of vilanterol), magnesium stearate (125 mcg), and lactose monohydrate (12.34 mg). The lactose monohydrate contains milk proteins. After the inhaler is activated, the powder within both blisters is exposed and ready for dispersion into the airstream created by the patient inhaling through the mouthpiece.
Under standardized in vitro test conditions, fluticasone furoate/vilanterol trifenatate inhaler delivers 92 mcg of fluticasone furoate and 22 mcg of vilanterol per blister when tested at a flow rate of 60 L/min for 4 seconds.
In adult subjects with obstructive lung disease and severely compromised lung function (COPD with FEV1/FVC less than 70% and FEV1 less than 30% predicted or FEV1 less than 50% predicted plus chronic respiratory failure), mean peak inspiratory flow through the inhaler was 66.5 L/min (range: 43.5 to 81.0 L/min).
The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.
2. INDICATIONS AND USAGE 
Fluticasone furoate/vilanterol trifenatate inhaler is a combination inhaled corticosteroid/long-acting beta2-adrenergic agonist (ICS/LABA) indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Fluticasone furoate/vilanterol trifenatate inhaler is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations.
Important Limitations of Use: Fluticasone furoate/vilanterol trifenatate inhaler is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.
3. DOSAGE AND ADMINISTRATION 
Fluticasone furoate/vilanterol trifenatate inhaler 100 mcg/25 mcg should be administered as 1 inhalation once daily by the orally inhaled route only. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.
Fluticasone furoate/vilanterol trifenatate inhaler should be taken at the same time every day. Do not use fluticasone furoate/vilanterol trifenatate inhaler more than 1 time every 24 hours.
No dosage adjustment is required for geriatric patients, patients with hepatic impairment, or renally impaired patients.
4. CONTRAINDICATIONS 
The use of fluticasone furoate/vilanterol trifenatate inhaler is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients [see Warnings and Precautions (5.11), Description (1)].
5. WARNINGS AND PRECAUTIONS 
5.1 Asthma-Related Death
• Data from a large placebo-controlled trial in subjects with asthma showed that LABA may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by LABA.
• A 28-week, placebo-controlled, US trial comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABA, including vilanterol, one of the active ingredients in fluticasone furoate/vilanterol trifenatate inhaler.
• No study adequate to determine whether the rate of asthma-related death is increased in subjects treated with fluticasone furoate/vilanterol trifenatate inhaler has been conducted. The safety and efficacy of fluticasone furoate/vilanterol trifenatate inhaler in patients with asthma have not been established. Fluticasone furoate/vilanterol trifenatate inhaler is not indicated for the treatment of asthma.
5.2 Deterioration of Disease and Acute Episodes
Fluticasone furoate/vilanterol trifenatate inhaler should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. Fluticasone furoate/vilanterol trifenatate inhaler has not been studied in patients with acutely deteriorating COPD. The initiation of fluticasone furoate/vilanterol trifenatate inhaler in this setting is not appropriate.
Fluticasone furoate/vilanterol trifenatate inhaler should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Fluticasone furoate/vilanterol trifenatate inhaler 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 fluticasone furoate/vilanterol trifenatate inhaler, 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 fluticasone furoate/vilanterol trifenatate inhaler, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used. Increasing inhaled, short-acting beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.
COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If fluticasone furoate/vilanterol trifenatate inhaler 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 a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of fluticasone furoate/vilanterol trifenatate inhaler beyond the recommended dose is not appropriate in this situation.
5.3 Excessive Use of Fluticasone Furoate/Vilanterol Trifenatate Inhaler and Use With Other Long-Acting Beta2-Agonists
Fluticasone furoate/vilanterol trifenatate inhaler should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines 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 fluticasone furoate/vilanterol trifenatate inhaler should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.
5.4 Local Effects of Inhaled Corticosteroids
In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with fluticasone furoate/vilanterol trifenatate inhaler. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with fluticasone furoate/vilanterol trifenatate inhaler continues, but at times therapy with fluticasone furoate/vilanterol trifenatate inhaler may need to be interrupted. Advise the patient to rinse his/her mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.
5.5 Pneumonia
An increase in the incidence of pneumonia has been observed in subjects with COPD receiving the fluticasone furoate/vilanterol combination, including fluticasone furoate/vilanterol trifenatate inhaler 100 mcg/25 mcg, in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.
In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 6% [48 of 820 subjects];100 mcg/25 mcg: 6% [51 of 806 subjects]; or 200 mcg/25 mcg: 7% [55 of 811 subjects]) than in subjects receiving vilanterol 25 mcg (3% [27 of 818 subjects]). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg. There was fatal pneumonia in 1 subject receiving fluticasone furoate/vilanterol 100 mcg/25 mcg and in 7 subjects receiving fluticasone furoate/vilanterol 200 mcg/25 mcg (less than 1% for each treatment group).
5.6 Immunosuppression
Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration 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 package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.
Inhaled corticosteroids 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.
5.7 Transferring Patients From Systemic Corticosteroid Therapy
Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.
Patients who have been previously maintained on 20 mg or more 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 fluticasone furoate/vilanterol trifenatate inhaler may control COPD symptoms during these episodes, in recommended doses it supplies less than normal physiological amount of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.
During periods of stress or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe COPD exacerbation.
Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to fluticasone furoate/vilanterol trifenatate inhaler. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with fluticasone furoate/vilanterol trifenatate inhaler. Lung function (mean forced expiratory volume in 1 second [FEV1]), beta-agonist use, and COPD symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.
Transfer of patients from systemic corticosteroid therapy to fluticasone furoate/vilanterol trifenatate inhaler may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).
During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, and depression) despite maintenance or even improvement of respiratory function.
5.8 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 dose of fluticasone furoate/vilanterol trifenatate inhaler. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)].
Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with fluticasone furoate/vilanterol trifenatate inhaler 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, fluticasone furoate/vilanterol trifenatate inhaler should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD symptoms should be considered.
5.9 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors
Caution should be exercised when considering the coadministration of fluticasone furoate/vilanterol trifenatate inhaler with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., 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 (7.1)].
5.10 Paradoxical Bronchospasm
As with other inhaled medicines, fluticasone furoate/vilanterol trifenatate inhaler can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with fluticasone furoate/vilanterol trifenatate inhaler, it should be treated immediately with an inhaled, short-acting bronchodilator; fluticasone furoate/vilanterol trifenatate inhaler should be discontinued immediately; and alternative therapy should be instituted.
5.11 Hypersensitivity Reactions
Hypersensitivity reactions may occur after administration of fluticasone furoate/vilanterol trifenatate inhaler. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not take fluticasone furoate/vilanterol trifenatate inhaler [see Contraindications (4)].
5.12 Cardiovascular Effects
Vilanterol, like other 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. If such effects occur, fluticasone furoate/vilanterol trifenatate inhaler 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. In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12-fold higher systemic exposure than seen in patients with COPD) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, fluticasone furoate/vilanterol trifenatate inhaler, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
5.13 Reduction in Bone Mineral Density
Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating fluticasone furoate/vilanterol trifenatate inhaler and periodically thereafter. If significant reductions in BMD are seen and fluticasone furoate/vilanterol trifenatate inhaler is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered.
In replicate 12-month trials in 3,255 subjects with COPD, bone fractures were reported by 2% of subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 2% [14 of 820 subjects]; 100 mcg/25 mcg: 2% [19 of 806 subjects]; or 200 mcg/25 mcg: 2% [14 of 811 subjects]) than in subjects receiving vilanterol 25 mcg alone (less than 1% [8 of 818 subjects]).
5.14 Glaucoma and Cataracts
Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.
In replicate 12-month trials in 3,255 subjects with COPD, similar incidences of ocular effects (including glaucoma and cataracts) were reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: less than 1% [7 of 820 subjects]; 100 mcg/25 mcg: 1% [12 of 806 subjects]; 200 mcg/25 mcg: less than 1% [7 of 811 subjects]) as those receiving vilanterol 25 mcg alone (1% [9 of 818 subjects]).
5.15 Coexisting Conditions
Fluticasone furoate/vilanterol trifenatate inhaler, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
5.16 Hypokalemia and Hyperglycemia
Beta-adrenergic agonist medicines 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. Beta-agonist medications may produce transient hyperglycemia in some patients. In 4 clinical trials of 6- and 12-month duration evaluating fluticasone furoate/vilanterol trifenatate inhaler in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.
6. ADVERSE REACTIONS 
LABA, such as vilanterol, one of the active ingredients in fluticasone furoate/vilanterol trifenatate inhaler, increase the risk of asthma-related death. Fluticasone furoate/vilanterol trifenatate inhaler is not indicated for the treatment of asthma. [See Boxed Warnings and Warnings and Precautions (5.1).]
Systemic and local corticosteroid use may result in the following:
• Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5)]
• Increased risk for decrease in bone mineral density [see Warnings and Precautions (5.13)]
6.1 Clinical Trials Experience
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.
The clinical program for fluticasone furoate/vilanterol trifenatate inhaler included 7,700 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, and 6 other trials of shorter duration. A total of 2,034 subjects have received at least 1 dose of fluticasone furoate/vilanterol trifenatate inhaler 100 mcg/25 mcg, and 1,087 subjects have received higher doses of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6-month and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials.
6-Month Trials: The incidence of adverse reactions associated with fluticasone furoate/vilanterol trifenatate inhaler in Table 1 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 subjects, 70% were male and 84% were Caucasian. 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 FEV1 was 48% (range: 14% to 87%), the mean postbronchodilator FEV1/forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%).
Subjects received 1 inhalation once daily of the following: Fluticasone furoate/vilanterol trifenatate inhaler 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/vilanterol 200 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo.
Table 1. Adverse Reactions With ≥3% Incidence and More Common Than Placebo With Fluticasone Furoate/Vilanterol Trifenatate Inhaler in Subjects With Chronic Obstructive Pulmonary Disease

a Includes terms oral candidiasis, oropharyngeal candidiasis, candidiasis, and oropharyngitis fungal.
12-Month Trials: Long-term safety data is 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 subjects, of which 57% were male and 85% were Caucasian. 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 FEV1 was 45% (range: 12% to 91%), and the mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: Fluticasone furoate/vilanterol trifenatate inhaler 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/vilanterol 200 mcg/25 mcg, or vilanterol 25 mcg. In addition to the events shown in Table 1, adverse reactions occurring in greater than or equal to 3% of the subjects treated with fluticasone furoate/vilanterol trifenatate inhaler (N = 806) for 12 months included COPD, back pain, pneumonia [see Warnings and Precautions (5.5)], bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, diarrhea, peripheral edema, and pyrexia.
7. DRUG INTERACTIONS 
7.1 Inhibitors of Cytochrome P450 3A4
Fluticasone furoate and vilanterol, the individual components of fluticasone furoate/vilanterol trifenatate inhaler, are both substrates of CYP3A4. Concomitant administration of the potent CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of fluticasone furoate/vilanterol trifenatate inhaler with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) [see Warnings and Precautions (5.9)].
7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants
Vilanterol, like other beta2-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, a component of fluticasone furoate/vilanterol trifenatate inhaler, but may produce severe bronchospasm in patients with reversible obstructive airways disease. Therefore, patients with COPD 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.
8. USE IN SPECIFIC POPULATIONS 
8.1 Usage in Pregnancy
Teratogenic Effects - Pregnancy Category C
There are no adequate and well-controlled trials with fluticasone furoate/vilanterol trifenatate inhaler in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal studies are not always predictive of human response, fluticasone furoate/vilanterol trifenatate inhaler should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking fluticasone furoate/vilanterol trifenatate inhaler.
Fluticasone Furoate and Vilanterol: There was no evidence of teratogenic interactions between fluticasone furoate and vilanterol in rats at approximately 9 and 40 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mcg/m2 basis at maternal inhaled doses of fluticasone furoate and vilanterol, alone or in combination, up to approximately 95 mcg/kg/day).
Fluticasone Furoate: There were no teratogenic effects in rats and rabbits at approximately 9 and 2 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 91 and 8 mcg/kg/day in rats and rabbits, respectively). There were no effects on perinatal and postnatal development in rats at approximately 3 times the MRHDID in adults (on a mcg/m2 basis at maternal doses up to 27 mcg/kg/day).
Vilanterol: There were no teratogenic effects in rats and rabbits at approximately 13,000 and 160 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 1,000 times the MRHDID in adults (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. There were no effects on perinatal and postnatal development in rats at approximately 3,900 times the MRHDID in adults (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day).
Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.
8.2 Labor and Delivery
There are no adequate and well-controlled human trials that have investigated the effects of fluticasone furoate/vilanterol trifenatate inhaler during labor and delivery.
Because beta-agonists may potentially interfere with uterine contractility, fluticasone furoate/vilanterol trifenatate inhaler should be used during labor only if the potential benefit justifies the potential risk.
8.3 Nursing Mothers
It is not known whether fluticasone furoate or vilanterol are excreted in human breast milk. However, other corticosteroids and beta2-agonists have been detected in human milk. Since there are no data from controlled trials on the use of fluticasone furoate/vilanterol trifenatate inhaler by nursing mothers, caution should be exercised when it is administered to a nursing woman.
8.4 Pediatric Use
Fluticasone furoate/vilanterol trifenatate inhaler is not indicated for use in children. The safety and efficacy in pediatric patients have not been established.
8.5 Geriatric Use
Based on available data, no adjustment of the dosage of fluticasone furoate/vilanterol trifenatate inhaler in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.
Clinical trials of fluticasone furoate/vilanterol trifenatate inhaler for COPD included 2,508 subjects aged 65 and older and 564 subjects aged 75 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 subjects.
8.6 Hepatic Impairment
Fluticasone furoate systemic exposure increased by up to 3-fold in subjects with hepatic impairment compared with healthy subjects. Hepatic impairment had no effect on vilanterol systemic exposure. Use fluticasone furoate/vilanterol trifenatate inhaler with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects.
8.7 Renal Impairment
There were no significant increases in either fluticasone furoate or vilanterol exposure in subjects with severe renal impairment (CrCl<30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment.
9. OVERDOSAGE 
No human overdosage data has been reported for fluticasone furoate/vilanterol trifenatate inhaler.
Fluticasone furoate/vilanterol trifenatate inhaler contains both fluticasone furoate and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to fluticasone furoate/vilanterol trifenatate inhaler.
9.1 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 [see Warnings and Precautions (5.8)].
Single- and repeat-dose trials of fluticasone furoate at doses of 50 to 4,000 mcg have been studied in human subjects. Decreases in mean serum cortisol were observed at dosages of 500 mcg or higher given once daily for 14 days.
9.2 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., angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, seizures, 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.
Treatment of overdosage consists of discontinuation of fluticasone furoate/vilanterol trifenatate inhaler 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.
10. MECHANISM OF ACTION 
Fluticasone furoate/vilanterol trifenatate inhaler: Since fluticasone furoate/vilanterol trifenatate inhaler contains both fluticasone furoate and vilanterol, the mechanisms of action described below for the individual components apply to fluticasone furoate/vilanterol trifenatate inhaler. These drugs represent 2 different classes of medications (a synthetic corticosteroid and a LABA) that have 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 in vitro findings is unknown. The precise mechanism through which fluticasone furoate affects COPD symptoms is not known. 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.
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 beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-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 beta2-agonists may have cardiac effects.
The pharmacologic effects of beta2-adrenoceptor 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.
11. PHARMACODYNAMICS  
Cardiovascular Effects: Healthy Subjects: QTc interval prolongation was studied in a double-blind, multiple dose, placebo- and positive-controlled crossover study in 85 healthy volunteers. The maximum mean (95% upper confidence bound) difference in QTcF from placebo after baseline-correction was 4.9 (7.5) milliseconds and 9.6 (12.2) milliseconds seen 30 minutes after dosing for fluticasone furoate /vilanterol 200mcg/25 mcg and fluticasone furoate/vilanterol 800 mcg/100 mcg, respectively.
A dose-dependent increase in heart rate was also observed. The maximum mean (95% upper confidence bound) difference in heart rate from placebo after baseline-correction was 7.8 (9.4) beats/min and 17.1 (18.7) beats/min seen 10 minutes after dosing for fluticasone furoate/vilanterol 200 mcg/25 mcg and fluticasone furoate/vilanterol 800 mcg/100 mcg, respectively.
Chronic Obstructive Pulmonary Disease: In 4 clinical trials of 6- and 12-month duration, there was no evidence of a treatment effect on heart rate, QTcF, or blood pressure in subjects with COPD given combination doses of fluticasone furoate (50, 100, or 200 mcg)/vilanterol 25 mcg, the individual components of fluticasone furoate or vilanterol alone, or placebo.
HPA Axis Effects: Healthy Subjects: Inhaled fluticasone furoate at repeat doses up to 400 mcg was not associated with statistically significant decreases in serum or urinary cortisol in healthy subjects. Decreases in serum and urine cortisol levels were observed at fluticasone furoate exposures several-fold higher than exposures observed at the therapeutic dose.
Chronic Obstructive Pulmonary Disease: In a trial with subjects with COPD, treatment with fluticasone furoate/vilanterol (50 mcg/25 mcg, 100 mcg/25 mcg, and 200 mcg/25 mcg), vilanterol 25 mcg, and fluticasone furoate (100 and 200 mcg) for 6 months did not affect 24-hour urinary cortisol excretion. A separate trial with subjects with COPD demonstrated no effects on serum cortisol after 28 days of treatment with fluticasone furoate/vilanterol (50 mcg/25mcg, 100mcg/25 mcg, and 200 mcg/25 mcg).
12. PHARMACOKINETICS  
Linear pharmacokinetics was observed for fluticasone furoate (200 to 800 mcg) and vilanterol (25 to 100 mcg). On repeated once-daily inhalation administration, steady state of fluticasone furoate and vilanterol plasma concentrations was achieved after 6 days, and the accumulation was up to 2.6-fold for fluticasone furoate and 2.4-fold for vilanterol as compared with single dose.
Absorption
Fluticasone Furoate: Fluticasone furoate plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 0.5 to 1 hour. Absolute bioavailability of fluticasone furoate when administrated by inhalation was 15.2%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose is low (approximately 1.3%) due to extensive first-pass metabolism. Systemic exposure (AUC) in subjects with COPD was 46% lower than observed in healthy subjects.
Vilanterol: Vilanterol plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 10 minutes following inhalation. Absolute bioavailability of vilanterol when administrated by inhalation was 27.3%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose of vilanterol is low (less than 2%) due to extensive first-pass metabolism. Systemic exposure in subjects with COPD was 24% higher than observed in healthy subjects.
Distribution
Fluticasone Furoate: Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 661 L. Binding of fluticasone furoate to human plasma proteins was high (99.6%).
Vilanterol: Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 165 L. Binding of vilanterol to human plasma proteins was 93.9%.
Metabolism
Fluticasone Furoate: Fluticasone furoate is cleared from systemic circulation principally by hepatic metabolism via CYP3A4 to metabolites with significantly reduced corticosteroid activity. There was no in vivo evidence for cleavage of the furoate moiety resulting in the formation of fluticasone.
Vilanterol: Vilanterol is mainly metabolized, principally via CYP3A4, to a range of metabolites with significantly reduced β1- and β2-agonist activity.
Elimination
Fluticasone Furoate: Fluticasone furoate and its metabolites are eliminated primarily in the feces, accounting for approximately 101% and 90% of the orally and intravenously administered dose, respectively. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered doses, respectively. Following repeat-dose inhaled administration, the plasma elimination phase half-life averaged 24 hours.
Vilanterol: Following oral administration, vilanterol was eliminated mainly by metabolism followed by excretion of metabolites in urine and feces (approximately 70% and 30% of the recovered radioactive dose, respectively). The effective half-life for accumulation of vilanterol, as determined from inhalation administration of multiple doses of vilanterol 25 mcg, is 21.3 hours in subjects with COPD.
Special Populations
The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of fluticasone furoate and vilanterol is shown in Figure 1.
Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate and Vilanterol Following Administration as Fluticasone Furoate/Vilanterol Combination

a Age, gender, and ethnicity comparison for fluticasone furoate/vilanterol trifenatate inhaler (100 mcg/25 mcg) in subjects with COPD.
b Renal groups (fluticasone furoate/vilanterol 200 mcg/25 mcg) and hepatic groups (fluticasone furoate/vilanterol 200 mcg/25 mcg or fluticasone furoate/vilanterol 100 mcg/12.5 mcg) compared with healthy control group.
Race: Systemic exposure (AUC(0-24)) to inhaled fluticasone furoate 200 mcg was 27% to 49% higher in healthy subjects of Japanese, Korean, and Chinese heritage compared with Caucasian subjects. Similar differences were observed for subjects with COPD (Figure 1). However, there is no evidence that this higher exposure to fluticasone furoate results in clinically relevant effects on urinary cortisol excretion or on efficacy in these racial groups.
There was no effect of race on the pharmacokinetics of vilanterol in subjects with COPD.
Hepatic Impairment:
Fluticasone Furoate: Following repeat dosing of fluticasone furoate/vilanterol 200 mcg/25 mcg (100 mcg/12.5 mcg in the severe impairment group) for 7 days, there was an increase of 34%, 83%, and 75% in fluticasone furoate systemic exposure (AUC) in subjects with mild, moderate, and severe hepatic impairment, respectively, compared with healthy subjects (see Figure 1).
In subjects with moderate hepatic impairment receiving fluticasone furoate/vilanterol 200 mcg/25 mcg, mean serum cortisol (0 to 24 hours) was reduced by 34% (95% CI: 11%, 51%) compared with healthy subjects. In subjects with severe hepatic impairment receiving fluticasone furoate/vilanterol 100 mcg/12.5 mcg, mean serum cortisol (0 to 24 hours) was increased by 14% (95% CI: -16%, 55%) compared with healthy subjects. Patients with moderate to severe hepatic disease should be closely monitored.
Vilanterol: Hepatic impairment had no effect on vilanterol systemic exposure (Cmax and AUC(0-24) on Day 7) following repeat-dose administration of fluticasone furoate/vilanterol 200 mcg/25 mcg (100 mcg/12.5 mcg in the severe impairment group) for 7 days (see Figure 1).
There were no additional clinically relevant effects of the fluticasone furoate/vilanterol combinations on heart rate or serum potassium in subjects with mild or moderate hepatic impairment (vilanterol 25 mcg combination) or with severe hepatic impairment (vilanterol 12.5 mcg combination) compared with healthy subjects.
Renal Impairment:
Fluticasone furoate systemic exposure was not increased and vilanterol systemic exposure (AUC(0-24)) was 56% higher in subjects with severe renal impairment compared with healthy subjects (see Figure 1). There was no evidence of greater corticosteroid or beta-agonist class-related systemic effects (assessed by serum cortisol, heart rate, and serum potassium) in subjects with severe renal impairment compared with healthy subjects.
13. HOW SUPPLIED/STORAGE AND HANDLING 
1) How Available:
a) Brand name: BREO ELLIPTA, by Glaxo GRP LTD.
b) Generic drugs: None.
2) How Supplied:
BREO ELLIPTA is supplied as a disposable light grey and pale blue plastic inhaler containing 2 double-foil strips, each with 30 blisters. The inhaler is packaged within a moisture-protective foil tray with a desiccant and a peelable lid (NDC 0173-0859-10).
BREO ELLIPTA is also supplied in an institutional pack as a disposable light grey and pale blue plastic inhaler containing 2 double-foil strips, each with 14 blisters. It is packaged within a moisture-protective foil tray with a desiccant and a peelable lid (NDC 0173-0859-14).
3) Storage and Handling:
Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59° to 86°F (15° to 30°C) [See USP Controlled Room Temperature]. Store in a dry place away from direct heat or sunlight. Keep out of reach of children.
BREO ELLIPTA should be stored inside the unopened moisture-protective foil tray and only removed from the tray immediately before initial use. Discard BREO ELLIPTA 6 weeks after opening the foil tray or when the counter reads “0” (after all blisters have been used), whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart.
Rx only
Rev 05/13

葛兰素史克向FDA提交复方药Breo Ellipta补充新药申请
2014年7月1日，葛兰素史克（GSK）与Theravance公司宣布，已向FDA提交了新复方药Breo Ellipta（2种剂量，100/25mcg和200/25mcg）的补充新药申请（sNDA），寻求批准作为每日一次的吸入性疗法，用于12岁及以上哮喘（asthma）患者的治疗。该药sNDA的提交，是基于Breo Ellipta用于哮喘治疗的广泛临床开发项目的数据，该项目包括48个临床药理学研究和23个临床研究。
BREO ELLIPTA是新复方药物FF/VI（fluticasone furoate /vilanterol，100/25 mcg）的商品名，该药为每日一次的吸入型糖皮质激素糠酸氟替卡松(FF)和长效β2受体激动剂维兰特罗(VI)的复方药物，开发用于慢性阻塞性肺病（COPD）和哮喘（asthma）的治疗。
BREO ELLIPTA于2013年5月获FDA批准，作为每日一次的吸入性疗法，用于慢性阻塞性肺病（COPD）患者的长期维持治疗，包括慢性支气管炎和/或肺气肿。此外，该药还适用于既往有COPD病情加重(COPD exacerbation)病史患者的COPD病情加重的减少。