impasse [1:<1 Gastroenteritis viral 3 0 Oral candidiasis 3 0 Oropharyngeal candidiasis 3 0 Oropharyngeal pain 3 0 The incidence of adverse reactions associated with Arnuity Ellipta 200 mcg is shown in Table 2 and is based on one 24-week trial (Trial 3) in adolescent and adult subjects with asthma. This trial did not have a placebo arm. Table 2. Adverse Reactions with Arnuity Ellipta 200 mcg with Greater than or Equal to 3% Incidence (Trial 3, Safety Population) Adverse Reaction Arnuity Ellipta 200 mcg n = 119 % Arnuity Ellipta 100 mcg n = 119 % Nasopharyngitis 13 12 Headache 13 10 Bronchitis 7 12 Influenza 7 4 Upper respiratory tract infection 6 2 Sinusitis 4 7 Oropharyngeal pain 4 3 Pharyngitis 3 6 Back pain 3 3 Dysphonia 3 2 Oral candidiasis 3> <1 Procedural pain 3> <1 Rhinitis 3> <1 Throat irritation 3> <1 Abdominal pain 3 0 Cough 3 0 Adverse reactions observed in the other trials were consistent with those described in Tables 1 and 2. Long-Term Safety: Long-term safety data are based on 2 trials in adolescent and adult subjects with asthma. In one 52-week trial, subjects received fluticasone furoate 100 mcg (n = 201) or fluticasone furoate 200 mcg (n = 202) in combination with a LABA. Subjects had a mean age of 39 years (adolescents made up 16% of the population), 63% were female, and 67% were Caucasian. In addition to the events shown in Table 1 and Table 2, adverse events occurring in greater than or equal to 3% of the subjects treated with fluticasone furoate 100 mcg or fluticasone furoate 200 mcg, in combination with a LABA, included pyrexia, extrasystoles, upper abdominal pain, respiratory tract infection, diarrhea, and allergic rhinitis. In a second 24- to 76-week trial, subjects received fluticasone furoate 100 mcg (n = 1,010). Subjects participating in this trial had a history of one or more asthma exacerbations that required treatment with oral/systemic corticosteroids or emergency department visit or in-patient hospitalization for the treatment of asthma within the previous 12 months. Subjects had a mean age of 42 years (adolescents made up 14% of the population), 67% were female, and 73% were Caucasian. In addition to the events shown in Table 1 and Table 2, adverse events occurring in greater than or equal to 3% of subjects treated with fluticasone furoate 100 mcg for up to 76 weeks included allergic rhinitis, nasal congestion, and arthralgia. Drug Interactions Inhibitors of Cytochrome P450 3A4 Fluticasone furoate is a substrate of CYP3A4. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate. Caution should be exercised when considering the coadministration of Arnuity Ellipta 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 (5.6), Clinical Pharmacology (12.3)] . USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled trials with Arnuity Ellipta in pregnant women. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal reproduction studies are not always predictive of human response, Arnuity Ellipta 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 Arnuity Ellipta. There were no teratogenic effects in rats and rabbits at approximately 4 times and equal to, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mcg/m 2 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 equal to the MRHDID in adults (on a mcg/m 2 basis at maternal doses up to 27 mcg/kg/day). Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored. Labor and Delivery There are no adequate and well-controlled human trials that have investigated the effects of Arnuity Ellipta during labor and delivery. Nursing Mothers It is not known whether fluticasone furoate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Since there are no data from controlled trials on the use of Arnuity Ellipta by nursing mothers, caution should be exercised when it is administered to a nursing woman. Pediatric Use The safety and efficacy in pediatric patients younger than 12 years have not been established. Effects on Growth: Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents. A reduction of growth velocity in children and adolescents may occur as a result of poorly controlled asthma or from use of corticosteroids, including inhaled corticosteroids. The effects of long-term treatment of children and adolescents with inhaled corticosteroids, including fluticasone furoate, on final adult height are not known. Controlled clinical trials have shown that inhaled corticosteroids 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 children and adolescents receiving orally inhaled corticosteroids, including Arnuity 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 Arnuity 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 110 mcg of fluticasone furoate in the nasal spray formulation on growth velocity assessed by stadiometry. The systemic exposure of fluticasone furoate in this trial is lower than that of Arnuity Ellipta. The subjects were 474 prepubescent children (girls aged 5 to 7.5 years and boys aged 5 to 8.5 years). Mean growth velocity over the 52-week treatment period was lower in the subjects receiving fluticasone furoate nasal spray (5.19 cm/year) compared with placebo (5.46 cm/year). The mean reduction in growth velocity was 0.27 cm/year (95% CI: 0.06, 0.48) [see Warnings and Precautions (5.10)] . Geriatric Use For the 4 confirmatory trials, 71 subjects were aged 65 and older (56 of which were treated with Arnuity Ellipta) and 5 were aged 75 and older (1 of which was treated with Arnuity Ellipta) [see Clinical Studies (14.2)] . Based on available data, no adjustment of the dosage of Arnuity Ellipta in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of Arnuity Ellipta did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Hepatic Impairment Fluticasone furoate systemic exposure increased by up to 3-fold in subjects with hepatic impairment compared with healthy subjects. Use Arnuity Ellipta with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects [see Clinical Pharmacology (12.3)] . Renal Impairment There were no significant increases in fluticasone furoate exposure in subjects with severe renal impairment (CrCl less than 30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)] . Overdosage No human overdosage data have been reported for Arnuity Ellipta. The potential for acute toxic corticosteroid effects following overdosage with Arnuity Ellipta is low. Because of low systemic bioavailability (13.9%) 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 (5.5)] . 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. Arnuity Ellipta Description The active component of Arnuity Ellipta is fluticasone furoate, 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: Fluticasone furoate is a white powder with a molecular weight of 538.6, and the empirical formula is C 27 H 29 F 3 O 6 S. It is practically insoluble in water. Arnuity Ellipta is a light grey and orange plastic inhaler containing a foil blister strip. Each blister on the strip contains a white powder mix of micronized fluticasone furoate (100 or 200 mcg) and lactose monohydrate (12.4 or 12.3 mg) for a total powder mix of 12.5 mg per blister. The lactose monohydrate contains milk proteins. After the inhaler is activated, the powder within the blister is exposed and ready for dispersion into the airstream created by the patient inhaling through the mouthpiece. Under standardized in vitro test conditions, Arnuity Ellipta 100 mcg and Arnuity Ellipta 200 mcg deliver 90 and 182 mcg, respectively, of fluticasone furoate per blister when tested at a flow rate of 60 L/min for 4 seconds. In adult subjects with asthma and a mean FEV 1 of 2.55 L/sec (range: 1.63 to 3.97 L/sec), mean peak inspiratory flow through the ELLIPTA inhaler was 103.2 L/min (range: 71.2 to 133.1 L/min). The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile. Arnuity Ellipta - Clinical Pharmacology Mechanism of Action 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 of corticosteroid action on asthma is not known. Inflammation is an important component in the pathogenesis of 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. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma. Though effective for the treatment of asthma, corticosteroids may not affect symptoms immediately. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer. Trials in subjects with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone furoate. This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (approximately 1.3%), and the minimal pharmacological activity of the metabolites detected in man. Pharmacodynamics The pharmacodynamics of fluticasone furoate were characterized in trials of fluticasone furoate given as a single component and also in trials of fluticasone furoate given in combination with vilanterol. 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. Subjects with Asthma: A randomized, double-blind, parallel-group trial in 185 subjects with asthma showed no difference between once-daily treatment with fluticasone furoate/vilanterol 100 mcg/25 mcg or fluticasone furoate/vilanterol 200 mcg/25 mcg compared with placebo on serum cortisol weighted mean (0 to 24 hours), serum cortisol AUC (0-24) , and 24-hour urinary cortisol after 6 weeks of treatment, whereas prednisolone 10 mg given once daily for 7 days resulted in significant cortisol suppression. Cardiac Effects: A QT/QTc trial did not demonstrate an effect of fluticasone furoate administration on the QTc interval. The effect of a single dose of 4,000 mcg of orally inhaled fluticasone furoate on the QTc interval was evaluated over 24 hours in 40 healthy male and female subjects in a placebo- and positive-controlled (a single dose of 400 mg oral moxifloxacin) cross-over trial. The QTcF maximal mean change from baseline following fluticasone furoate was similar to that observed with placebo with a treatment difference of 0.788 msec (90% CI: -1.802, 3.378). In contrast, moxifloxacin given as a 400-mg tablet resulted in prolongation of the QTcF maximal mean change from baseline compared with placebo with a treatment difference of 9.929 msec (90% CI: 7.339, 12.520). Pharmacokinetics The pharmacokinetics of fluticasone furoate were characterized in trials of fluticasone furoate given as a single component and also in trials of fluticasone furoate given in combination with vilanterol. Linear pharmacokinetics were observed for fluticasone furoate (200 to 800 mcg). On repeated once-daily inhalation administration, steady state of fluticasone furoate plasma concentration was achieved after 6 days, and the accumulation was up to 2.6-fold as compared with single dose. Absorption: 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 13.9%, 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 asthma was 26% lower than observed in healthy subjects. Distribution: 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%). Metabolism: 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. Elimination: Fluticasone furoate and its metabolites are eliminated primarily in the feces, accounting for approximately 101% and 90% of the orally and intravenously administered doses, 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. Special Populations: The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of fluticasone furoate is shown in Figure 1. Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF) a Age, gender, and ethnicity comparison for Arnuity Ellipta in subjects with asthma. 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 asthma (Figure 1). 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. Hepatic Impairment: Following repeat dosing of fluticasone furoate/vilanterol 200 mcg/25 mcg (100 mcg/12.5 mcg in the severe impairment group) for 7 days, fluticasone furoate systemic exposure (AUC) increased 34%, 83%, and 75% 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% (90% 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% (90% CI: -16%, 55%) compared with healthy subjects. Patients with moderate to severe hepatic disease should be closely monitored. Renal Impairment: Fluticasone furoate systemic exposure was not increased in subjects with severe renal impairment compared with healthy subjects (see Figure 1). There was no evidence of greater corticosteroid class-related systemic effects (assessed by serum cortisol) in subjects with severe renal impairment compared with healthy subjects. Drug Interactions: The potential for fluticasone furoate to inhibit or induce metabolic enzymes and transporter systems is negligible at low inhalation doses. Inhibitors of Cytochrome P450 3A4: The exposure (AUC) of fluticasone furoate was 36% higher after single and repeated doses when coadministered with ketoconazole 400 mg compared with placebo (see Figure 2). The increase in fluticasone furoate exposure was associated with a 27% reduction in weighted mean serum cortisol (0 to 24 hours). Figure 2. Impact of Coadministered Ketoconazole a on the Pharmacokinetics (PK) of Fluticasone Furoate a Compared with placebo group. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 9 and 19 mcg/kg/day, respectively (less than the MRHDID in adults on a mcg/m 2 basis). Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro . There was also no evidence of genotoxicity in the in vivo micronucleus test in rats. No evidence of impairment of fertility was observed in male and female rats at inhaled fluticasone furoate doses up to 29 and 91 mcg/kg/day, respectively (approximately equal to and 4 times, respectively, the MRHDID in adults on a mcg/m 2 basis). Clinical Studies The safety and efficacy of Arnuity Ellipta were evaluated in 3,611 subjects with asthma. The development program included 4 confirmatory trials of 3 and 6 months duration and 3 dose-ranging trials of 8 weeks duration. The efficacy of Arnuity Ellipta is based primarily on the dose-ranging trials and the confirmatory trials described below. Dose-Ranging Trials Eight doses of fluticasone furoate ranging from 25 to 800 mcg once daily were evaluated in 3 randomized, double-blind, placebo-controlled, 8-week trials in subjects with asthma. Across the 3 trials, subjects were uncontrolled at baseline on treatments of short-acting beta 2 -agonist and/or non-corticosteroid controller medications (Trial 687), low-dose inhaled corticosteroid (Trial 685), or medium doses of inhaled corticosteroid (Trial 684). The trials in Figure 3 were dose-ranging trials of Arnuity Ellipta not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority/inferiority to fluticasone propionate. A dose-related increase in trough FEV 1 at Week 8 was seen for doses from 25 to 200 mcg with no consistent additional benefit for doses above 200 mcg as seen in Figure 3. To evaluate dosing frequency, a separate trial compared fluticasone furoate 200 mcg once daily, fluticasone furoate 100 mcg twice daily, fluticasone propionate 100 mcg twice daily, and fluticasone propionate 200 mcg once daily. The results supported the selection of the once-daily dosing frequency. Figure 3. Dose-Ranging Trials FF = Fluticasone furoate. FP = Fluticasone propionate. OD = Once daily. BD = Twice daily. Confirmatory Trials The clinical development program for Arnuity Ellipta included 4 confirmatory trials in adolescent and adult subjects aged 12 years and older with asthma. The trials were designed to evaluate the safety and efficacy of Arnuity Ellipta given once daily in the evening on lung function in subjects who were not controlled on their current treatments of inhaled corticosteroids, or combination therapy consisting of an inhaled corticosteroid plus a LABA. Study treatments were delivered as inhalation powders. The primary endpoint in all trials was change from baseline in evening trough FEV 1 measured approximately 24 hours after the final dose of study medication. Trough FEV 1 (assessed at approximately 24 hours after the previous dose) was also assessed at clinic visits throughout the trials. Trials 2 and 4 had a co-primary endpoint of change from baseline in weighted mean serial FEV 1 measured after the final dose of study medication at 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours post-dose. Clinical Trials with Arnuity Ellipta 100 mcg: Trial 1 was a 24-week trial that evaluated the efficacy of Arnuity Ellipta 100 mcg compared with placebo on lung function in subjects with asthma. Inhaled fluticasone propionate 250 mcg twice daily was included as an active control. Of the 343 subjects, 59% were female and 79% were Caucasian. The mean age was 41 years. The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual low- to mid-dose inhaled corticosteroid therapy (i.e., fluticasone propionate 100 to 500 mcg daily or equivalent). Mean baseline percent predicted FEV 1 was approximately 73% overall and was similar across the 3 treatment groups. Thirty-five percent of subjects on placebo and 19% of subjects on Arnuity Ellipta 100 mcg failed to complete the 24-week trial. The change in trough FEV 1 from baseline to Week 24, or the last available on-treatment visit prior to Week 24, was assessed to evaluate the efficacy of Arnuity Ellipta 100 mcg. The mean change from baseline in trough FEV 1 was greater among subjects receiving Arnuity Ellipta 100 mcg than among those receiving placebo (mean treatment difference from placebo 146 mL; 95% CI: 36, 257) as shown in Table 3. Table 3. Change from Baseline in Trough FEV 1 (mL) at Week 24 Trial 1 Trough FEV 1 (Week 24) Placebo (n = 113) Arnuity Ellipta 100 mcg (n = 111) Fluticasone Propionate 250 mcg Twice Daily (n = 107) Least squares mean 2,372 2,519 2,517 Least squares mean change (SE) 15 (39.4) 161 (39.8) 159 (40.6) Column vs. placebo Difference 146 145 95% CI 36, 257 33, 257 P value 0.009 0.011 Trial 2 was a 12-week trial that evaluated the efficacy of Arnuity Ellipta 100 mcg on lung function in subjects with asthma compared with placebo. The combination of fluticasone furoate 100 mcg and vilanterol 25 mcg was also included as a treatment arm. Of the 609 subjects, 58% were female and 84% were Caucasian. The mean age was 40 years. The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual low- to mid-dose inhaled corticosteroid (fluticasone propionate 200 to 500 mcg/day or equivalent). If LABA were used prior to screening, their use was discontinued during the run-in. Mean baseline percent predicted FEV 1 was approximately 70% in both treatment groups. Twenty-six percent of subjects on placebo and 10% of subjects on Arnuity Ellipta 100 mcg failed to complete the 12-week trial. The co-primary efficacy endpoints in Trial 2 were change from baseline in trough FEV 1 at Week 12 and weighted mean FEV 1 (0-24 hours) at the end of the 12-week treatment period. Trough FEV 1 was assessed at clinic visits throughout the trial. Weighted mean FEV 1 (0-24 hours) was recorded at baseline and after the final study dose with serial measurements taken at frequent intervals (at 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours post-dose) in a subset of subjects (n = 201). Arnuity Ellipta 100 mcg once daily had greater mean changes from baseline in trough FEV 1 than placebo throughout the trial. At Week 12 or the last available on-treatment visit prior to Week 12, the mean change from baseline in trough FEV 1 was greater among subjects receiving Arnuity Ellipta 100 mcg once daily than among those receiving placebo (mean treatment difference 136 mL; 95% CI: 51, 222). Lung function improvements were sustained over the 24-hour period following the final dose of Arnuity Ellipta 100 mcg (see Figure 4). Compared with placebo, at Week 12 the change from baseline in weighted mean FEV 1 was significantly greater for Arnuity Ellipta 100 mcg (mean treatment difference 186 mL; 95% CI: 62, 310). Figure 4. Mean Change from Baseline in Individual Serial FEV 1 (mL) Assessments after 12 Weeks of Treatment Trial 2 Subjects in both Trials 1 and 2 receiving Arnuity Ellipta 100 mcg once daily had a greater improvement from baseline in percentage of 24-hour periods without need of beta 2 -agonist rescue medication use than subjects receiving placebo. Clinical Trial with Arnuity Ellipta 200 mcg: Trial 3 was a 24-week trial that evaluated the relative efficacy of Arnuity Ellipta 100 mcg and Arnuity Ellipta 200 mcg on lung function in subjects with asthma. Of the 219 subjects, 68% were female and 87% were Caucasian. The mean age was 46 years. The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual mid- to high-dose inhaled corticosteroid therapy (i.e., fluticasone propionate greater than 250 to 1,000 mcg/day or equivalent). If LABA were used prior to screening, their use was discontinued during the run-in. Mean baseline percent predicted FEV 1 was approximately 68% overall and similar in the 2 treatment groups. Sixteen percent of subjects on Arnuity Ellipta 100 mcg and 13% of subjects on Arnuity Ellipta 200 mcg failed to complete the 24-week trial. The primary efficacy endpoint was mean change from baseline in trough FEV 1 at Week 24. There were trends toward greater mean changes from baseline in the group receiving Arnuity Ellipta 200 mcg than the group receiving Arnuity Ellipta 100 mcg throughout the trial (see Figure 5). At Week 24 or the last available on-treatment visit prior to Week 24, the mean change from baseline in trough FEV 1 was 208 mL for Arnuity Ellipta 100 mcg, as compared to 284 mL for Arnuity Ellipta 200 mcg (difference of 77 mL; 95% CI: -39, 192) as seen in Figure 5. Figure 5. Mean Change from Baseline in Trough FEV 1 (mL) over Time Trial 3 Trial 4 was a 24-week trial that evaluated the efficacy of Arnuity Ellipta 200 mcg once daily and fluticasone propionate 500 mcg twice daily on lung function in subjects with asthma. The combination of fluticasone furoate 200 mcg and vilanterol 25 mcg was also included as a treatment arm (data not shown). Of the 586 subjects, 59% were female and 84% were Caucasian. The mean age was 46 years. The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual mid- to high-dose inhaled corticosteroid (fluticasone propionate 500 to 1,000 mcg/day or equivalent). If LABA were used prior to screening, their use was discontinued during the run-in. Mean baseline percent predicted FEV 1 was approximately 67% in both treatment groups. Both Arnuity Ellipta 200 mcg once daily and fluticasone propionate 500 mcg twice daily produced improvement from baseline in lung function. At Week 24 the mean change from baseline in trough FEV 1 was 201 mL for Arnuity Ellipta 200 mcg once daily and 183 mL for fluticasone propionate 500 mcg twice daily (treatment difference of 18 mL, 95% CI: -66, 102). Lung function improvements were sustained over the 24-hour period following the final dose of Arnuity Ellipta 200 mcg (see Figure 6). At Week 24, the change from baseline in weighted mean FEV 1 was 328 mL for Arnuity Ellipta 200 mcg once daily and 258 mL for fluticasone propionate 500 twice daily (difference of 70 mL; 95% CI: -67, 208). Figure 6. Mean Change from Baseline in Individual Serial FEV 1 (mL) Assessments after 24 Weeks of Treatment Trial 4 How Supplied/Storage and Handling Arnuity Ellipta 100 mcg is supplied as a disposable light grey and orange plastic inhaler containing a foil strip with 30 blisters (NDC 0173-0874-10) or 14 blisters (institutional pack) (NDC 0173-0874-14). Arnuity Ellipta 200 mcg is supplied as a disposable light grey and orange plastic inhaler containing a foil strip with 30 blisters (NDC 0173-0876-10) or 14 blisters (institutional pack) (NDC 0173-0876-14). The inhaler is packaged in a moisture-protective foil tray with a desiccant and a peelable lid. Store at room temperature between 68 F and 77 F (20 C and 25 C); excursions permitted from 59 F to 86 F (15 C 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. Arnuity Ellipta should be stored inside the unopened moisture-protective foil tray and only removed from the tray immediately before initial use. Discard Arnuity 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. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Not for Acute Symptoms: Inform patients that Arnuity Ellipta is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose. Arnuity Ellipta is not a bronchodilator and should not be used to treat status asthmaticus or to relieve acute asthma symptoms. Advise patients to treat acute symptoms with an inhaled, short-acting beta 2 -agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used . Instruct patients to seek medical attention immediately if they experience any of the following: Symptoms get worse Significant decrease in lung function as outlined by the physician Need for more inhalations than usual of inhaled, short-acting beta 2 -agonists Advise patients not to increase the dose or frequency of Arnuity Ellipta. The daily dosage of Arnuity Ellipta should not exceed 1 inhalation. If they miss a dose, instruct patients to take their next dose at the same time they normally do. Tell patients they should not stop or reduce therapy with Arnuity Ellipta without physician/provider guidance since symptoms may recur after discontinuati will give you
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