ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Systemic and local corticosteroid use may result in the following:oCandida albicans infection [see Warnings and Precautions (5.1)] oImmunosuppression [see Warnings and Precautions (5.3)]oHypercorticism and adrenal suppression [see Warnings and Precautions (5.5)]oReduction in BMD [see Warnings and Precautions (5.9)]oGrowth effects in pediatrics [see Warnings and Precautions (5.10)]oGlaucoma and cataracts [see Warnings and Precautions (5.11)]. oCandida albicans infection [see Warnings and Precautions (5.1)] oImmunosuppression [see Warnings and Precautions (5.3)]. oHypercorticism and adrenal suppression [see Warnings and Precautions (5.5)]. oReduction in BMD [see Warnings and Precautions (5.9)]. oGrowth effects in pediatrics [see Warnings and Precautions (5.10)]. oGlaucoma and cataracts [see Warnings and Precautions (5.11)]. Most common adverse reactions reported in >=5% of adult and adolescent subjects are nasopharyngitis, bronchitis, upper respiratory tract infection, and headache. (6.1)Most common adverse reactions reported in >=3% of pediatric subjects aged to 11 years are pharyngitis, bronchitis, and viral infection. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.Adult and Adolescent Subjects Aged 12 Years and OlderThe safety of ARNUITY ELLIPTA was evaluated in 10 double-blind, parallel-group, controlled trials (7 with placebo) of to 76 weeks duration that enrolled 6,219 subjects with asthma. Doses of fluticasone furoate studied ranged from 25 to 800 mcg.ARNUITY ELLIPTA 100 mcg was studied in 1,663 subjects, and ARNUITY ELLIPTA 200 mcg was studied in 608 subjects. Subject ages ranged from 12 to 84 years, 65% were female, and 75% were Caucasian.In these trials, the proportion of subjects who discontinued study treatment early due to adverse reactions was 2% for subjects treated with both ARNUITY ELLIPTA 100 mcg and ARNUITY ELLIPTA 200 mcg and <=1% for placebo-treated subjects. Serious adverse events, whether considered drug-related or not by the investigators, that occurred in more than subject and in greater percentage of subjects treated with ARNUITY ELLIPTA than placebo included hypertension, abscess, breast cancer, traumatic limb amputation, subarachnoid hemorrhage, and intervertebral disc protrusion; all events occurred at rates <=1%.The incidence of adverse reactions associated with ARNUITY ELLIPTA 100 mcg is shown in Table and is based on one 24-week trial (Trial 1) in adult and adolescent subjects with asthma.Table 1. Adverse Reactions with ARNUITY ELLIPTA 100 mcg with >=3% Incidence and More Common than Placebo (Trial 1, Intent-to-Treat Population)Adverse ReactionARNUITY ELLIPTA 100 mcg(n 114)%Placebo(n 115)%Nasopharyngitis85Bronchitis76Upper respiratory tract infection65Headache64Pharyngitis43Sinusitis4<1Toothache3<1Gastroenteritis viral30Oral candidiasis30Oropharyngeal candidiasis30Oropharyngeal pain30The incidence of adverse reactions associated with ARNUITY ELLIPTA 200 mcg is shown in Table and is based on one 24-week trial (Trial 3) in adult and adolescent subjects with asthma. This trial did not have placebo arm.Table 2. Adverse Reactions with ARNUITY ELLIPTA 200 mcg with >=3% Incidence (Trial 3, Safety Population)Adverse ReactionARNUITY ELLIPTA200 mcg(n 119)%ARNUITY ELLIPTA100 mcg(n 119)%Nasopharyngitis1312Headache1310Bronchitis712Influenza74Upper respiratory tract infection62Sinusitis47Oropharyngeal pain43Pharyngitis36Back pain33Dysphonia32Oral candidiasis3<1Procedural pain3<1Rhinitis3<1Throat irritation3<1Abdominal pain30Cough30Adverse reactions observed in the other trials were consistent with those described in Tables and 2.Long-term SafetyLong-term safety data are based on trials in adult and adolescent 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 LABA. Subjects had 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 and Table 2, adverse events occurring in >=3% of the subjects treated with fluticasone furoate 100 mcg or fluticasone furoate 200 mcg, in combination with LABA, included pyrexia, extrasystoles, upper abdominal pain, respiratory tract infection, diarrhea, and allergic rhinitis.In second 24- to 76-week trial, subjects received fluticasone furoate 100 mcg (n 1,010). Subjects participating in this trial had history of 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 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 and Table 2, adverse events occurring in >=3% of subjects treated with fluticasone furoate 100 mcg for up to 76 weeks included allergic rhinitis, nasal congestion, and arthralgia.Pediatric Subjects Aged to 11 YearsThe safety data for pediatric subjects is based upon one 12-week clinical trial that enrolled 593 subjects with asthma aged to 11 years. Dosages of fluticasone furoate studied were 25, 50, or 100 mcg administered once daily. ARNUITY ELLIPTA 50 mcg was studied in 120 subjects (46 females and 74 males) [see Clinical Studies (14.2)]. Adverse reactions (>=3% and greater than placebo) seen in pediatric subjects were similar to those reported in adult and adolescent subjects. Adverse reactions occurring in >=3% of subjects treated with ARNUITY ELLIPTA 50 mcg and greater than placebo were pharyngitis, bronchitis, and viral infection.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 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 and 19 mcg/kg/day, respectively (less than the MRHDID on mcg/m2 basis).Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in 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 and times, respectively, the MRHDID in adults on mcg/m2 basis).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Fluticasone furoate is synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone furoate has been shown in vitro to exhibit binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown.The precise mechanism through which fluticasone furoate affects asthma symptoms is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy.Though effective for the treatment of asthma, corticosteroids may not affect symptoms immediately. Individual patients will experience variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for to 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 favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone furoate. This is explained by combination of relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (approximately 1.3%), and the minimal pharmacological activity of the metabolites detected in man.. 12.2 Pharmacodynamics. The pharmacodynamics of fluticasone furoate was characterized in trials of fluticasone furoate given as single component and also in trials of fluticasone furoate given in combination with vilanterol.Hypothalamic-Pituitary-Adrenal Axis EffectsHealthy 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: randomized, double-blind, parallel-group trial in 104 pediatric subjects with asthma (aged to 11 years) showed no difference between once-daily treatment with ARNUITY ELLIPTA 50 mcg compared with placebo on serum cortisol weighted mean (0 to 24 hours) and serum cortisol AUC(0-24) following weeks of treatment.A randomized, double-blind, parallel-group trial in 185 subjects with asthma aged 12 to 65 years 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 weeks of treatment, whereas prednisolone 10 mg given once daily for days resulted in significant cortisol suppression.Cardiac ElectrophysiologyA QT/QTc trial did not demonstrate an effect of fluticasone furoate administration on the QTc interval. The effect of 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 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 treatment difference of 0.788 msec (90% CI: -1.802, 3.378). In contrast, moxifloxacin given as 400-mg tablet resulted in prolongation of the QTcF maximal mean change from baseline compared with placebo with treatment difference of 9.929 msec (90% CI: 7.339, 12.520).. 12.3 Pharmacokinetics. The pharmacokinetics of fluticasone furoate was characterized in trials of fluticasone furoate given as single component and in trials of fluticasone furoate given in combination with vilanterol. Linear pharmacokinetics was observed for fluticasone furoate (200 to 800 mcg). On repeated once-daily inhalation administration, steady state of fluticasone furoate plasma concentration was achieved after days, and the accumulation was up to 2.6-fold as compared with single dose.AbsorptionFluticasone furoate plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 0.5 to 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.DistributionFollowing 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%).MetabolismFluticasone 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.EliminationFluticasone 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.Specific PopulationsThe 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) Age, gender, and ethnicity comparison for ARNUITY ELLIPTA in adult and adolescent subjects with asthma. 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.Pediatric Patients: population pharmacokinetics analysis to assess impact of age on fluticasone furoate systemic exposure was conducted using combined data from clinical trials in pediatric subjects aged to 11 years (n 306). There was no relevant effect of age on the apparent clearance of fluticasone furoate. The rate and extent of fluticasone furoate systemic exposure at steady state in children aged to 11 years were comparable to that observed in adult and adolescent subjects following dosing with fluticasone furoate 100 mcg monotherapy.Racial or Ethnic Groups: 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). 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.Patients with Hepatic Impairment: Following repeat dosing of fluticasone furoate/vilanterol 200 mcg/25 mcg (100 mcg/12.5 mcg in the severe impairment group) for 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 (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.Patients with Renal Impairment: Fluticasone furoate systemic exposure was not increased in subjects with severe renal impairment compared with healthy subjects (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 Interaction StudiesThe 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 (Figure 2). The increase in fluticasone furoate exposure was associated with 27% reduction in weighted mean serum cortisol (0 to 24 hours).Figure 2. Impact of Coadministered Ketoconazolea on the Pharmacokinetics (PK) of Fluticasone Furoate Compared with placebo group.. Age, gender, and ethnicity comparison for ARNUITY ELLIPTA in adult and adolescent subjects with asthma.. 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.. Compared with placebo group.. Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF). Figure 2. Impact of Coadministered Ketoconazolea on the Pharmacokinetics (PK) of Fluticasone Furoate.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of ARNUITY ELLIPTA were evaluated in 3,611 adult and adolescent subjects with asthma. The development program included confirmatory trials of and months duration and dose-ranging trials of weeks duration. The efficacy of ARNUITY ELLIPTA is based primarily on the dose-ranging trials and the confirmatory trials described below. One additional trial evaluated the safety and efficacy of ARNUITY ELLIPTA in 593 subjects aged to 11 years.. 14.1 Dose-Ranging Trials. Eight doses of fluticasone furoate ranging from 25 to 800 mcg once daily were evaluated in randomized, double-blind, placebo-controlled, 8-week trials in adult and adolescent subjects with asthma. Across the trials, subjects were uncontrolled at baseline on treatments of short-acting beta2-agonist and/or non-corticosteroid controller medications (Trial 687), low-dose ICS (Trial 685), or medium doses of ICS (Trial 684). The trials in Figure 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. dose-related increase in trough FEV1 at Week 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, 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 TrialsFF Fluticasone furoate, FP Fluticasone propionate, OD Once daily, BD Twice daily.. Figure 3. Dose-Ranging Trials. 14.2 Confirmatory Trials. Adult and Adolescent Subjects Aged 12 Years and OlderThe clinical development program for ARNUITY ELLIPTA included confirmatory trials in adult and adolescent subjects with asthma aged 12 years and older. 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 ICS, or combination therapy consisting of an ICS plus LABA. Study treatments were delivered as inhalation powders. The primary endpoint in all trials was change from baseline in evening trough FEV1 measured approximately 24 hours after the final dose of study medication. Trough FEV1 (assessed at approximately 24 hours after the previous dose) was also assessed at clinic visits throughout the trials. Trials and had co-primary endpoint of change from baseline in weighted mean serial FEV1 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 was 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 4-week run-in period during which the subjects were symptomatic while taking their usual low- to mid-dose ICS therapy (i.e., fluticasone propionate 100 to 500 mcg daily or equivalent). Mean baseline percent predicted FEV1 was approximately 73% overall and was similar across the 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 FEV1 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 FEV1 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 FEV1 (mL) at Week 24 Trial 1FEV1 forced expiratory volume in second, SE standard error, CI confidence interval.Trough FEV1 (Week 24)Placebo(n 113)ARNUITY ELLIPTA100 mcg(n 111)Fluticasone Propionate250 mcgTwice Daily(n 107)Least squares mean2,3722,5192,517Least squares mean change (SE)15 (39.4)161 (39.8)159 (40.6)Column vs. placebo Difference--146145 95% CI--36, 25733, 257 value--0.0090.011Trial was 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 treatment arm. Of the 609 subjects, 58% were female and 84% were Caucasian. The mean age was 40 years. The trial included 4-week run-in period during which the subjects were symptomatic while taking their usual low- to mid-dose ICS (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 FEV1 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 were change from baseline in trough FEV1 at Week 12 and weighted mean FEV1 (0-24 hours) at the end of the 12-week treatment period. Trough FEV1 was assessed at clinic visits throughout the trial. Weighted mean FEV1 (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 subset of subjects (n 201).ARNUITY ELLIPTA 100 mcg once daily had greater mean changes from baseline in trough FEV1 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 FEV1 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 (Figure 4). Compared with placebo, at Week 12 the change from baseline in weighted mean FEV1 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 FEV1 (mL) Assessments after 12 Weeks of Treatment Trial 2Subjects in both Trials and receiving ARNUITY ELLIPTA 100 mcg once daily had greater improvement from baseline in percentage of 24-hour periods without need of beta2-agonist rescue medication use than subjects receiving placebo.Clinical Trial with ARNUITY ELLIPTA 200 mcg: Trial was 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 4-week run-in period during which the subjects were symptomatic while taking their usual mid- to high-dose ICS 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 FEV1 was approximately 68% overall and similar in the 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 FEV1 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 (Figure 5). At Week 24 or the last available on-treatment visit prior to Week 24, the mean change from baseline in trough FEV1 was 208 mL for ARNUITY ELLIPTA 100 mcg, as compared with 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 FEV1 (mL) over Time Trial 3Trial was 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 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 4-week run-in period during which the subjects were symptomatic while taking their usual mid- to high-dose ICS (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 FEV1 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 FEV1 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 (Figure 6). At Week 24, the change from baseline in weighted mean FEV1 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 FEV1 (mL) Assessments after 24 Weeks of Treatment Trial 4Pediatric Subjects Aged to 11 YearsA 12-week trial evaluated the efficacy of fluticasone furoate (25, 50, or 100 mcg) administered once daily in the evening compared with placebo in 593 pediatric subjects with asthma aged to 11 years. Inhaled fluticasone propionate 100 mcg twice daily was included as an active control. At trial entry subjects were symptomatic, had at least 6-month history of asthma, and had been receiving stable asthma therapy for at least weeks prior to screening. Subjects had to have pre-bronchodilator PEF of >=60% to <=90% of their best post-bronchodilator value and, in subjects able to perform the maneuver, demonstrate >=12% reversibility of FEV1 within approximately 10 to 40 minutes following to inhalations of albuterol inhalation aerosol. The primary endpoint of this trial was the mean change from baseline in daily pre-dose AM PEF from the patient electronic daily diary averaged over the 12-week treatment period. secondary endpoint was the change from baseline in the percentage of rescue-free 24-hour periods during the 12-week treatment period. Of the 593 subjects, the mean age was years, 62% were male, and 42% were Caucasian. Lung function improvements based on the primary endpoint of mean change from baseline in AM PEF are presented in Table 4.Table 4. Least Squares Mean Change from Baseline in Pre-Dose AM PEF over the 12-Week Treatment Period (Intent-to-Treat Population)AM PEF Morning Peak Expiratory Flow, LS Least squares, SE standard error, CI confidence interval. Average over Weeks to 12.Primary EndpointPlacebo(n 119)Fluticasone Furoate25 mcg(n 118)Fluticasone Furoate50 mcg(n 120)Fluticasone Furoate100 mcg(n 118)Fluticasone Propionate100 mcg(n 118)AM PEF (L/min)a = 119n 117n 118n 118n 117 LS mean change (SE)3.3 (2.63)21.9 (2.66)22.8 (2.65)15.8 (2.64)17.3 (2.64) Difference vs placebo18.619.512.514.0 (95% CI)(11.3, 26.0)(12.1, 26.9)(5.1, 19.8)(6.7, 21.4)Pediatric subjects receiving ARNUITY ELLIPTA 50 mcg had greater improvement from baseline in percentage of 24-hour periods without need of beta2-agonist rescue medication use than subjects receiving placebo.Given the demonstration of efficacy of ARNUITY ELLIPTA 100 mcg and ARNUITY ELLIPTA 200 mcg in the adult and adolescent population, the results support the efficacy of ARNUITY ELLIPTA 50 mcg once daily in pediatric subjects with asthma aged to 11 years.. Difference. 95% CI. value. LS mean change (SE). Difference vs placebo. (95% CI). Figure 4. Mean Change from Baseline in Individual Serial FEV1 (mL) Assessments after 12 Weeks of Treatment Trial 2. Figure 5. Mean Change from Baseline in Trough FEV1 (mL) over Time Trial 3. Figure 6. Mean Change from Baseline in Individual Serial FEV1 (mL) Assessments after 24 Weeks of Treatment Trial 4.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. The use of ARNUITY ELLIPTA is contraindicated in the following conditions:oPrimary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required [see Warnings and Precautions (5.2)].oSevere hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone furoate or any of the excipients [see Warnings and Precautions (5.8), Description (11)].. oPrimary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required [see Warnings and Precautions (5.2)].. oSevere hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone furoate or any of the excipients [see Warnings and Precautions (5.8), Description (11)].. oPrimary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures. (4.1)oSevere hypersensitivity to milk proteins or any ingredients. (4.2). oPrimary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures. (4.1). oSevere hypersensitivity to milk proteins or any ingredients. (4.2).

DESCRIPTION SECTION.

11 DESCRIPTION. ARNUITY ELLIPTA is an inhalation powder drug product for delivery of fluticasone furoate (an ICS) to patients by oral inhalation.Fluticasone furoate, synthetic trifluorinated corticosteroid, has the chemical name (6,11,16,17)-6,9-difluoro-17-[(fluoro-methyl)thioi]carbonyl-11-hydroxy-16-methyl-3-oxoandrosta-1,4-dien-17-yl 2-furancarboxylate and the following chemical structure:Fluticasone furoate is white powder with molecular weight of 538.6, and the empirical formula is C27H29F3O6S. It is practically insoluble in water.ARNUITY ELLIPTA is light grey and orange plastic inhaler containing foil blister strip. Each blister on the strip contains white powder mix of micronized fluticasone furoate (50, 100, or 200 mcg) and lactose monohydrate (12.45, 12.40, or 12.30 mg, respectively) for 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 50 mcg, ARNUITY ELLIPTA 100 mcg, and ARNUITY ELLIPTA 200 mcg deliver 46, 90, and 182 mcg, respectively, of fluticasone furoate per blister when tested at flow rate of 60 L/min for seconds.In adult subjects with asthma and mean FEV1 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). In pediatric subjects with asthma aged to 11 years and mean peak expiratory flow rate of 242 L/min (range: 130 to 420 L/min), mean peak inspiratory flow through the ELLIPTA inhaler was 51.8 L/min (range: 26.8 to 89.9 L/min). Therefore, the ELLIPTA inhaler is able to deliver the dose of fluticasone furoate in patients with asthma.The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.. fluticasone furoate chemical structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oFor oral inhalation only. (2.1)oTreatment of asthma in patients aged 12 years and older: The starting dosage, inhalation of ARNUITY ELLIPTA 100 mcg or ARNUITY ELLIPTA 200 mcg once daily, is based on prior asthma therapy and disease severity. (2.2)oTreatment of asthma in patients aged to 11 years: inhalation of ARNUITY ELLIPTA 50 mcg once daily. (2.2). oFor oral inhalation only. (2.1). oTreatment of asthma in patients aged 12 years and older: The starting dosage, inhalation of ARNUITY ELLIPTA 100 mcg or ARNUITY ELLIPTA 200 mcg once daily, is based on prior asthma therapy and disease severity. (2.2). oTreatment of asthma in patients aged to 11 years: inhalation of ARNUITY ELLIPTA 50 mcg once daily. (2.2). 2.1 General. ARNUITY ELLIPTA should be administered only by the orally inhaled route [see Instructions for Use leaflet]. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.If symptoms arise between doses, an inhaled, short-acting beta2-agonist should be used for immediate relief.The maximum benefit may not be achieved for up to weeks or longer after starting treatment. Individual patients may experience variable time to onset and degree of symptom relief.. 2.2 Dosing. ARNUITY ELLIPTA should be administered as inhalation once daily by the orally inhaled route. ARNUITY ELLIPTA should be used at the same time every day. Do not use ARNUITY ELLIPTA more than time every 24 hours.Adults and Adolescents Aged 12 Years and OlderThe starting dosage for ARNUITY ELLIPTA should be based upon patients asthma severity. The usual recommended starting dose for adults and adolescents aged 12 years and older not on an inhaled corticosteroid (ICS) is 100 mcg. For other adults and adolescents aged 12 years and older, the starting dose should be based on previous asthma drug therapy and disease severity. For adults and adolescents aged 12 years and older who do not respond to ARNUITY ELLIPTA 100 mcg after weeks of therapy, replacement with ARNUITY ELLIPTA 200 mcg may provide additional asthma control.If dosage regimen of ARNUITY ELLIPTA fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, e.g., replacing the current strength of ARNUITY ELLIPTA with higher strength, initiating an ICS and long-acting beta2-agonist (LABA) combination product, or initiating oral corticosteroids, should be considered.The highest recommended daily dose in adults and adolescents aged 12 years and older is 200 mcg.After asthma stability has been achieved, it is desirable to titrate to the lowest effective dosage to help reduce the possibility of side effects.Pediatric Patients Aged to 11 YearsThe recommended dosage for children aged to 11 years is 50 mcg administered once daily [see Warnings and Precautions (5.10)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Inhalation powder: Disposable light grey and orange plastic inhaler containing foil blister strip of powder intended for oral inhalation only. Each blister contains fluticasone furoate 50, 100, or 200 mcg.. Inhalation powder: Inhaler containing foil blister strip of powder formulation for oral inhalation. Each blister contains 50, 100, or 200 mcg of fluticasone furoate. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. May cause systemic corticosteroid effects. (7.1). 7.1 Inhibitors of Cytochrome P450 3A4. Fluticasone furoate is 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 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)].

GERIATRIC USE SECTION.

8.5 Geriatric Use For the confirmatory trials, 71 subjects were aged 65 years and older (56 of which were treated with ARNUITY ELLIPTA) and were aged 75 years 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 years 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 subjects. 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. ARNUITY ELLIPTA 50 mcg is supplied as disposable light grey and orange plastic inhaler containing foil strip with 30 blisters (NDC 0173-0888-10).ARNUITY ELLIPTA 100 mcg is supplied as disposable light grey and orange plastic inhaler containing 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 disposable light grey and orange plastic inhaler containing foil strip with 30 blisters (NDC 0173-0876-10) or 14 blisters (institutional pack) (NDC 0173-0876-14).The inhaler is packaged in moisture-protective foil tray with desiccant and peelable lid.Store at room temperature between 68F and 77F (20C and 25C); excursions permitted from 59F to 86F (15C to 30C) [See USP Controlled Room Temperature]. Store in 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 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.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ARNUITY ELLIPTA is corticosteroid indicated for once-daily maintenance treatment of asthma as prophylactic therapy in patients aged years and older. (1.1)Important limitation of use: Not indicated for relief of acute bronchospasm. (1.1, 5.2). 1.1 Treatment of Asthma. ARNUITY ELLIPTA is indicated for the once-daily maintenance treatment of asthma as prophylactic therapy in patients aged years and older.Important Limitation of UseARNUITY ELLIPTA is NOT indicated for the relief of acute bronchospasm.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Not for Acute SymptomsInform patients that ARNUITY ELLIPTA is not meant to relieve acute symptoms of asthma and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting beta2-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:oDecreasing effectiveness of inhaled, short-acting beta2-agonistsoNeed for more inhalations than usual of inhaled, short-acting beta2-agonistsoSignificant decrease in lung function as outlined by the physicianAdvise patients not to increase the dose or frequency of ARNUITY ELLIPTA. The daily dosage of ARNUITY ELLIPTA should not exceed inhalation. If they miss dose, instruct patients to take their next dose at the same time they normally do.Tell patients they should not stop therapy with ARNUITY ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation.Local EffectsInform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with ARNUITY ELLIPTA, but at times therapy with ARNUITY ELLIPTA may need to be temporarily interrupted under close medical supervision. Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush.ImmunosuppressionWarn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections or ocular herpes simplex.Hypercorticism and Adrenal SuppressionAdvise patients that ARNUITY ELLIPTA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to ARNUITY ELLIPTA.Reduction in Bone Mineral DensityAdvise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk.Reduced Growth VelocityInform patients that orally inhaled corticosteroids, including ARNUITY ELLIPTA, may cause reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route.Glaucoma and CataractsAdvise patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.Hypersensitivity Reactions, Including AnaphylaxisAdvise patients that hypersensitivity reactions (e.g., urticaria, flushing, allergic dermatitis, bronchospasm), including anaphylaxis, may occur after administration of ARNUITY ELLIPTA. Instruct patients to discontinue ARNUITY ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use ARNUITY ELLIPTA.Use Daily for Best EffectAdvise patients to use ARNUITY ELLIPTA at regular intervals, since its effectiveness depends on regular use. Maximum benefit may not be achieved for week or longer after starting treatment. If symptoms do not improve after weeks of therapy or if the condition worsens, instruct patients to contact their physicians.Trademarks are owned by or licensed to the GSK group of companies.GlaxoSmithKlineResearch Triangle Park, NC 27709(C)2020 GSK group of companies or its licensor.ARN:9PI. oDecreasing effectiveness of inhaled, short-acting beta2-agonists. oNeed for more inhalations than usual of inhaled, short-acting beta2-agonists. oSignificant decrease in lung function as outlined by the physician.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USEARNUITY ELLIPTA (ar-NEW-i-te e-LIP-ta)(fluticasone furoate inhalation powder)for oral inhalation useRead this before you start:oIf you open and close the cover without inhaling the medicine, you will lose the dose.oThe lost dose will be securely held inside the inhaler, but it will no longer be available to be inhaled.oIt is not possible to accidentally take double dose or an extra dose in inhalation.Your ARNUITY ELLIPTA inhalerHow to use your inhaleroARNUITY ELLIPTA comes in tray.oPeel back the lid to open the tray. See Figure A.oThe tray contains desiccant to reduce moisture. Do not eat or inhale. Throw it away in the household trash out of reach of children and pets. See Figure B.Figure AFigure BImportant Notes:oYour inhaler contains 30 doses (14 doses if you have 100-mcg or 200-mcg strength sample or institutional pack).oEach time you fully open the cover of the inhaler (you will hear clicking sound), dose is ready to be inhaled. This is shown by decrease in the number on the counter.oIf you open and close the cover without inhaling the medicine, you will lose the dose. The lost dose will be held in the inhaler, but it will no longer be available to be inhaled. It is not possible to accidentally take double dose or an extra dose in inhalation.oDo not open the cover of the inhaler until you are ready to use it. To avoid wasting doses after the inhaler is ready, do not close the cover until after you have inhaled the medicine.oWrite the Tray opened and Discard dates on the inhaler label. The Discard date is weeks from the date you open the tray.Check the counter. See Figure C.Figure CoBefore the inhaler is used for the first time, the counter should show the number 30 (14 if you have 100-mcg or 200-mcg strength sample or institutional pack). This is the number of doses in the inhaler.oEach time you open the cover, you prepare dose of medicine.oThe counter counts down by each time you open the cover.Prepare your dose:Wait to open the cover until you are ready to take your dose.Figure Step 1. Open the cover of the inhaler. See Figure D.oSlide the cover down to expose the mouthpiece. You should hear click. The counter will count down by number. You do not need to shake this kind of inhaler. Your inhaler is now ready to use. oIf the counter does not count down as you hear the click, the inhaler will not deliver the medicine. Call your healthcare provider or pharmacist if this happens.Figure Step 2. Breathe out. See Figure E.oWhile holding the inhaler away from your mouth, breathe out (exhale) fully. Do not breathe out into the mouthpiece.Figure Step 3. Inhale your medicine. See Figure F.oPut the mouthpiece between your lips, and close your lips firmly around it. Your lips should fit over the curved shape of the mouthpiece.oTake long, steady, deep breath in through your mouth. Do not breathe in through your nose.Figure GoDo not block the air vent with your fingers. See Figure G.Figure HoRemove the inhaler from your mouth and hold your breath for about to seconds (or as long as comfortable for you). See Figure H.Figure Step 4. Breathe out slowly and gently. See Figure I.oYou may not taste or feel the medicine, even when you are using the inhaler correctly.oDo not take another dose from the inhaler even if you do not feel or taste the medicine.Figure Step 5. Close the inhaler. See Figure J.oYou can clean the mouthpiece if needed, using dry tissue, before you close the cover. Routine cleaning is not required.oSlide the cover up and over the mouthpiece as far as it will go.Figure Step 6. Rinse your mouth. See Figure K.oRinse your mouth with water after you have used the inhaler and spit the water out. Do not swallow the water.Important Note: When should you get refillFigure LoWhen you have fewer than 10 doses remaining in your inhaler, the left half of the counter shows red as reminder to get refill. See Figure L. oAfter you have inhaled the last dose, the counter will show 0 and will be empty.oThrow the empty inhaler away in your household trash out of reach of children and pets.For more information about ARNUITY ELLIPTA or how to use your inhaler, call 1-888-825-5249 or visit our website at www.ARNUITY.com.Trademarks are owned by or licensed to the GSK group of companies.GlaxoSmithKline, Research Triangle Park, NC 27709(C)2018 GSK group of companies or its licensor.ARN:1IFUThis Instructions for Use has been approved by the U.S. Food and Drug Administration Revised: May 2018. oIf you open and close the cover without inhaling the medicine, you will lose the dose.. oThe lost dose will be securely held inside the inhaler, but it will no longer be available to be inhaled.. oIt is not possible to accidentally take double dose or an extra dose in inhalation.. oARNUITY ELLIPTA comes in tray.. oPeel back the lid to open the tray. See Figure A.. oThe tray contains desiccant to reduce moisture. Do not eat or inhale. Throw it away in the household trash out of reach of children and pets. See Figure B.. oYour inhaler contains 30 doses (14 doses if you have 100-mcg or 200-mcg strength sample or institutional pack).. oEach time you fully open the cover of the inhaler (you will hear clicking sound), dose is ready to be inhaled. This is shown by decrease in the number on the counter.. oIf you open and close the cover without inhaling the medicine, you will lose the dose. The lost dose will be held in the inhaler, but it will no longer be available to be inhaled. It is not possible to accidentally take double dose or an extra dose in inhalation.. oDo not open the cover of the inhaler until you are ready to use it. To avoid wasting doses after the inhaler is ready, do not close the cover until after you have inhaled the medicine.. oWrite the Tray opened and Discard dates on the inhaler label. The Discard date is weeks from the date you open the tray.. oBefore the inhaler is used for the first time, the counter should show the number 30 (14 if you have 100-mcg or 200-mcg strength sample or institutional pack). This is the number of doses in the inhaler.. oEach time you open the cover, you prepare dose of medicine.. oThe counter counts down by each time you open the cover.. Step 1. Open the cover of the inhaler. See Figure D.. oSlide the cover down to expose the mouthpiece. You should hear click. The counter will count down by number. You do not need to shake this kind of inhaler. Your inhaler is now ready to use. oIf the counter does not count down as you hear the click, the inhaler will not deliver the medicine. Call your healthcare provider or pharmacist if this happens.. Step 2. Breathe out. See Figure E.. oWhile holding the inhaler away from your mouth, breathe out (exhale) fully. Do not breathe out into the mouthpiece.. Step 3. Inhale your medicine. See Figure F.. oPut the mouthpiece between your lips, and close your lips firmly around it. Your lips should fit over the curved shape of the mouthpiece.. oTake long, steady, deep breath in through your mouth. Do not breathe in through your nose.. oDo not block the air vent with your fingers. See Figure G.. oRemove the inhaler from your mouth and hold your breath for about to seconds (or as long as comfortable for you). See Figure H.. Step 4. Breathe out slowly and gently. See Figure I.. oYou may not taste or feel the medicine, even when you are using the inhaler correctly.. oDo not take another dose from the inhaler even if you do not feel or taste the medicine.. Step 5. Close the inhaler. See Figure J.. oYou can clean the mouthpiece if needed, using dry tissue, before you close the cover. Routine cleaning is not required.. oSlide the cover up and over the mouthpiece as far as it will go.. Step 6. Rinse your mouth. See Figure K.. oRinse your mouth with water after you have used the inhaler and spit the water out. Do not swallow the water.. oWhen you have fewer than 10 doses remaining in your inhaler, the left half of the counter shows red as reminder to get refill. See Figure L. oAfter you have inhaled the last dose, the counter will show 0 and will be empty.. oThrow the empty inhaler away in your household trash out of reach of children and pets.. ELLIPTA figure--parts. Fig A. ELLIPTA figure--Figure B. Fig C. Fig D. Fig D. Fig F. Fig G. Fig H. Fig I. Fig J. Fig K. Fig L.

LACTATION SECTION.

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

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Fluticasone furoate is synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone furoate has been shown in vitro to exhibit binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown.The precise mechanism through which fluticasone furoate affects asthma symptoms is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy.Though effective for the treatment of asthma, corticosteroids may not affect symptoms immediately. Individual patients will experience variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for to 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 favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone furoate. This is explained by combination of relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (approximately 1.3%), and the minimal pharmacological activity of the metabolites detected in man.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 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 and 19 mcg/kg/day, respectively (less than the MRHDID on mcg/m2 basis).Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in 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 and times, respectively, the MRHDID in adults on mcg/m2 basis).

OVERDOSAGE SECTION.

10 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANELNDC 0173-0888-10ARNUITY ELLIPTA\ (fluticasone furoate inhalation powder)50 mcgRx OnlyFOR ORAL INHALATION ONLYEach blister contains 50 mcg of fluticasone furoate and lactose monohydrate.1 Ellipta Inhaler containing Foil Strip of 30 BlistersMade in Singapore(C)2018 GSK group of companies or its licensor. 10000000148298Rev. 4/18 10000000148298Rev. 4/18. Arnuity Ellipta 50mcg 30 count carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety and efficacy of ARNUITY ELLIPTA in pediatric patients with asthma aged to 11 years have been established in clinical trials. In those trials, 234 subjects were administered ARNUITY ELLIPTA 50 mcg once daily. Subjects aged to 11 years demonstrated safety and efficacy results similar to those observed in subjects aged 12 years and older. The safety and efficacy of ARNUITY ELLIPTA have not been established in pediatric patients aged younger than years. [See Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.2), Clinical Studies (14.2).] Effects on GrowthOrally inhaled corticosteroids may cause reduction in growth velocity when administered to children and adolescents. reduction of growth velocity in children and adolescents may occur as result of poorly controlled asthma or from use of corticosteroids, including ICS. The effects of long-term treatment of children and adolescents with ICS, including fluticasone furoate, on final adult height are not known.Controlled clinical trials have shown that ICS may cause reduction in growth in children. In these trials, the mean reduction in growth velocity was approximately 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 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 50 mcg. The subjects were 474 prepubescent children (girls aged to 7.5 years and boys aged 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)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The pharmacodynamics of fluticasone furoate was characterized in trials of fluticasone furoate given as single component and also in trials of fluticasone furoate given in combination with vilanterol.Hypothalamic-Pituitary-Adrenal Axis EffectsHealthy 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: randomized, double-blind, parallel-group trial in 104 pediatric subjects with asthma (aged to 11 years) showed no difference between once-daily treatment with ARNUITY ELLIPTA 50 mcg compared with placebo on serum cortisol weighted mean (0 to 24 hours) and serum cortisol AUC(0-24) following weeks of treatment.A randomized, double-blind, parallel-group trial in 185 subjects with asthma aged 12 to 65 years 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 weeks of treatment, whereas prednisolone 10 mg given once daily for days resulted in significant cortisol suppression.Cardiac ElectrophysiologyA QT/QTc trial did not demonstrate an effect of fluticasone furoate administration on the QTc interval. The effect of 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 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 treatment difference of 0.788 msec (90% CI: -1.802, 3.378). In contrast, moxifloxacin given as 400-mg tablet resulted in prolongation of the QTcF maximal mean change from baseline compared with placebo with treatment difference of 9.929 msec (90% CI: 7.339, 12.520).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of fluticasone furoate was characterized in trials of fluticasone furoate given as single component and in trials of fluticasone furoate given in combination with vilanterol. Linear pharmacokinetics was observed for fluticasone furoate (200 to 800 mcg). On repeated once-daily inhalation administration, steady state of fluticasone furoate plasma concentration was achieved after days, and the accumulation was up to 2.6-fold as compared with single dose.AbsorptionFluticasone furoate plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 0.5 to 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.DistributionFollowing 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%).MetabolismFluticasone 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.EliminationFluticasone 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.Specific PopulationsThe 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) Age, gender, and ethnicity comparison for ARNUITY ELLIPTA in adult and adolescent subjects with asthma. 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.Pediatric Patients: population pharmacokinetics analysis to assess impact of age on fluticasone furoate systemic exposure was conducted using combined data from clinical trials in pediatric subjects aged to 11 years (n 306). There was no relevant effect of age on the apparent clearance of fluticasone furoate. The rate and extent of fluticasone furoate systemic exposure at steady state in children aged to 11 years were comparable to that observed in adult and adolescent subjects following dosing with fluticasone furoate 100 mcg monotherapy.Racial or Ethnic Groups: 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). 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.Patients with Hepatic Impairment: Following repeat dosing of fluticasone furoate/vilanterol 200 mcg/25 mcg (100 mcg/12.5 mcg in the severe impairment group) for 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 (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.Patients with Renal Impairment: Fluticasone furoate systemic exposure was not increased in subjects with severe renal impairment compared with healthy subjects (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 Interaction StudiesThe 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 (Figure 2). The increase in fluticasone furoate exposure was associated with 27% reduction in weighted mean serum cortisol (0 to 24 hours).Figure 2. Impact of Coadministered Ketoconazolea on the Pharmacokinetics (PK) of Fluticasone Furoate Compared with placebo group.. Age, gender, and ethnicity comparison for ARNUITY ELLIPTA in adult and adolescent subjects with asthma.. 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.. Compared with placebo group.. Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF). Figure 2. Impact of Coadministered Ketoconazolea on the Pharmacokinetics (PK) of Fluticasone Furoate.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryThere are insufficient data on the use of ARNUITY ELLIPTA in pregnant women. There are clinical considerations with use of ARNUITY ELLIPTA in pregnant women to inform drug-associated risk. (See Clinical Considerations.) In animal reproduction studies, fluticasone furoate administered by inhalation to rats and rabbits during the period of organogenesis produced no fetal structural abnormalities. The highest fluticasone furoate doses in the rat and rabbit studies were times and times the maximum recommended human daily inhalation dose (MRHDID), 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 ConsiderationsDisease-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.DataAnimal Data: Fluticasone Furoate: In separate embryofetal developmental studies, pregnant rats and rabbits received fluticasone furoate during the period of organogenesis at doses up to approximately and times the MRHDID, respectively (on mcg/m2 basis at maternal inhalation doses up to 91 and mcg/kg/day). No evidence of structural abnormalities in fetuses was observed in either species. In perinatal and postnatal developmental study in rats, dams received fluticasone furoate during late gestation and lactation periods at doses up to approximately time the MRHDID (on mcg/m2 basis at maternal inhalation doses up to 27 mcg/kg/day). No evidence of effects on offspring development was observed.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationARNUITY ELLIPTA (ar-NEW-i-te e-LIP-ta)(fluticasone furoate inhalation powder)for oral inhalation useWhat is ARNUITY ELLIPTA oARNUITY ELLIPTA is an inhaled corticosteroid (ICS) medicine used for the control and prevention of asthma in adults and children aged years and older.oARNUITY ELLIPTA helps to prevent and control symptoms of asthma.oARNUITY ELLIPTA is not used to relieve sudden breathing problems and will not replace rescue inhaler. Always have rescue inhaler (an inhaled, short-acting bronchodilator) with you to treat sudden breathing problems. If you do not have rescue inhaler, contact your healthcare provider to have one prescribed for you.oIt is not known if ARNUITY ELLIPTA is safe and effective in children younger than years.Do not use ARNUITY ELLIPTA:oto treat sudden symptoms of asthma. oif you have severe allergy to milk proteins. Ask your healthcare provider if you are not sure.oif you are allergic to fluticasone furoate or any of the ingredients in ARNUITY ELLIPTA. See the end of this Patient Information for complete list of ingredients in ARNUITY ELLIPTA.Before using ARNUITY ELLIPTA, tell your healthcare provider about all of your medical conditions, including if you:ohave liver problems.ohave weak bones (osteoporosis).ohave an immune system problem.ohave eye problems such as glaucoma, increased pressure in your eye, cataracts, or other changes in vision.oare allergic to milk proteins.ohave any type of viral, bacterial, fungal, or parasitic infection.oare exposed to chickenpox or measles.oare pregnant or plan to become pregnant. It is not known if ARNUITY ELLIPTA may harm your unborn baby.oare breastfeeding. It is not known if the medicine in ARNUITY ELLIPTA passes into your breast milk and if it can harm your baby.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ARNUITY ELLIPTA and certain other medicines may interact with each other. This may cause serious side effects. Especially, tell your healthcare provider if you take antifungal, anti-HIV, or any other corticosteroid medicines. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should use ARNUITY ELLIPTARead the step-by-step instructions for using ARNUITY ELLIPTA at the end of this Patient Information.oDo not use ARNUITY ELLIPTA unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly.oARNUITY ELLIPTA comes in different strengths. Your healthcare provider prescribed the strength that is best for you.oUse ARNUITY ELLIPTA exactly as your healthcare provider tells you to use it. Do not use ARNUITY ELLIPTA more often than prescribed.oChildren and adolescents may need help to use ARNUITY ELLIPTA.oUse inhalation of ARNUITY ELLIPTA time each day. Use ARNUITY ELLIPTA at the same time each day.oIf you miss dose of ARNUITY ELLIPTA, take it as soon as you remember. Do not take more than inhalation each day. Take your next dose at your usual time. Do not take doses at time.oDo not stop using ARNUITY ELLIPTA unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider will change your medicines as needed.oARNUITY ELLIPTA does not relieve sudden symptoms of asthma and you should not take extra doses of ARNUITY ELLIPTA to relieve these sudden symptoms. Always have rescue inhaler with you to treat sudden symptoms. If you do not have rescue inhaler, call your healthcare provider to have one prescribed for you.oCall your healthcare provider or get medical care right away if:oyour breathing problems get worse.oyou need to use your rescue inhaler more often than usual.oyour rescue inhaler does not work as well to relieve your symptoms.oyour peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you.What are the possible side effects of ARNUITY ELLIPTAARNUITY ELLIPTA can cause serious side effects, including: ofungal infection in your mouth or throat (thrush). Rinse your mouth with water without swallowing after using ARNUITY ELLIPTA to help reduce your chance of getting thrush.oweakened immune system and increased chance of getting infections (immunosuppression).oreduced adrenal function (adrenal insufficiency). Adrenal insufficiency is condition where the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking medicine containing an ICS (such as ARNUITY ELLIPTA). During this transition period, when your body is under stress from fever, trauma (such as car accident), infection, surgery, or worse asthma symptoms, adrenal insufficiency can get worse and may cause death.Symptoms of adrenal insufficiency include:ofeeling tiredolack of energyoweaknessonausea and vomitingolow blood pressure (hypotension)osudden breathing problems immediately after inhaling your medicine. If you have sudden breathing problems immediately after inhaling your medicine, stop taking ARNUITY ELLIPTA and call your healthcare provider right away.oserious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following symptoms of serious allergic reaction:orashohivesoswelling of your face, mouth, and tongueobreathing problemsobone thinning or weakness (osteoporosis).oslow growth in children and adolescents. childs or adolescents growth should be checked often.oeye problems including glaucoma, increased pressure in your eye, cataracts, or other changes in vision. You should have regular eye exams while using ARNUITY ELLIPTA.Common side effects of ARNUITY ELLIPTA include:orunny nose and sore throatoheadacheobreathing problems (bronchitis)ofluThese are not all the possible side effects of ARNUITY ELLIPTA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ARNUITY ELLIPTAoStore ARNUITY ELLIPTA at room temperature between 68F and 77F (20C and 25C). Keep in dry place away from heat and sunlight. oStore ARNUITY ELLIPTA in the unopened tray and only open when ready for use.oSafely throw away ARNUITY ELLIPTA in the trash weeks after you open the tray or when the counter reads 0, whichever comes first. Write the date you open the tray on the label on the inhaler.Keep ARNUITY ELLIPTA and all medicines out of the reach of children.General information about the safe and effective use of ARNUITY ELLIPTA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ARNUITY ELLIPTA for condition for which it was not prescribed. Do not give ARNUITY ELLIPTA to other people, even if they have the same symptoms that you have. It may harm them.You can ask your healthcare provider or pharmacist for information about ARNUITY ELLIPTA that is written for health professionals.What are the ingredients in ARNUITY ELLIPTAActive ingredients: fluticasone furoateInactive ingredients: lactose monohydrate (contains milk proteins)For more information about ARNUITY ELLIPTA, call 1-888-825-5249 or visit our website at www.ARNUITY.com.Trademarks are owned by or licensed to the GSK group of companies.GlaxoSmithKline, Research Triangle Park, NC 27709(C)2019 GSK group of companies or its licensor.ARN:4PILThis Patient Information has been approved by the U.S. Food and Drug Administration Revised: January 2019. oARNUITY ELLIPTA is an inhaled corticosteroid (ICS) medicine used for the control and prevention of asthma in adults and children aged years and older.. oARNUITY ELLIPTA helps to prevent and control symptoms of asthma.. oARNUITY ELLIPTA is not used to relieve sudden breathing problems and will not replace rescue inhaler. Always have rescue inhaler (an inhaled, short-acting bronchodilator) with you to treat sudden breathing problems. If you do not have rescue inhaler, contact your healthcare provider to have one prescribed for you.. oIt is not known if ARNUITY ELLIPTA is safe and effective in children younger than years.. oto treat sudden symptoms of asthma. oif you have severe allergy to milk proteins. Ask your healthcare provider if you are not sure.. oif you are allergic to fluticasone furoate or any of the ingredients in ARNUITY ELLIPTA. See the end of this Patient Information for complete list of ingredients in ARNUITY ELLIPTA.. ohave liver problems.. ohave weak bones (osteoporosis).. ohave an immune system problem.. ohave eye problems such as glaucoma, increased pressure in your eye, cataracts, or other changes in vision.. oare allergic to milk proteins.. ohave any type of viral, bacterial, fungal, or parasitic infection.. oare exposed to chickenpox or measles.. oare pregnant or plan to become pregnant. It is not known if ARNUITY ELLIPTA may harm your unborn baby.. oare breastfeeding. It is not known if the medicine in ARNUITY ELLIPTA passes into your breast milk and if it can harm your baby.. oDo not use ARNUITY ELLIPTA unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly.. oARNUITY ELLIPTA comes in different strengths. Your healthcare provider prescribed the strength that is best for you.. oUse ARNUITY ELLIPTA exactly as your healthcare provider tells you to use it. Do not use ARNUITY ELLIPTA more often than prescribed.. oChildren and adolescents may need help to use ARNUITY ELLIPTA.. oUse inhalation of ARNUITY ELLIPTA time each day. Use ARNUITY ELLIPTA at the same time each day.. oIf you miss dose of ARNUITY ELLIPTA, take it as soon as you remember. Do not take more than inhalation each day. Take your next dose at your usual time. Do not take doses at time.. oDo not stop using ARNUITY ELLIPTA unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider will change your medicines as needed.. oARNUITY ELLIPTA does not relieve sudden symptoms of asthma and you should not take extra doses of ARNUITY ELLIPTA to relieve these sudden symptoms. Always have rescue inhaler with you to treat sudden symptoms. If you do not have rescue inhaler, call your healthcare provider to have one prescribed for you.. oCall your healthcare provider or get medical care right away if:oyour breathing problems get worse.oyou need to use your rescue inhaler more often than usual.oyour rescue inhaler does not work as well to relieve your symptoms.oyour peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you.. oyour breathing problems get worse.. oyou need to use your rescue inhaler more often than usual.. oyour rescue inhaler does not work as well to relieve your symptoms.. oyour peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you.. ofungal infection in your mouth or throat (thrush). Rinse your mouth with water without swallowing after using ARNUITY ELLIPTA to help reduce your chance of getting thrush.. oweakened immune system and increased chance of getting infections (immunosuppression).. oreduced adrenal function (adrenal insufficiency). Adrenal insufficiency is condition where the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking medicine containing an ICS (such as ARNUITY ELLIPTA). During this transition period, when your body is under stress from fever, trauma (such as car accident), infection, surgery, or worse asthma symptoms, adrenal insufficiency can get worse and may cause death.Symptoms of adrenal insufficiency include:. ofeeling tired. olack of energy. oweakness. onausea and vomiting. olow blood pressure (hypotension). osudden breathing problems immediately after inhaling your medicine. If you have sudden breathing problems immediately after inhaling your medicine, stop taking ARNUITY ELLIPTA and call your healthcare provider right away.. oserious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following symptoms of serious allergic reaction:. orash. ohives. oswelling of your face, mouth, and tongue. obreathing problems. obone thinning or weakness (osteoporosis).. oslow growth in children and adolescents. childs or adolescents growth should be checked often.. oeye problems including glaucoma, increased pressure in your eye, cataracts, or other changes in vision. You should have regular eye exams while using ARNUITY ELLIPTA.. orunny nose and sore throat. oheadache. obreathing problems (bronchitis). oflu. oStore ARNUITY ELLIPTA at room temperature between 68F and 77F (20C and 25C). Keep in dry place away from heat and sunlight. oStore ARNUITY ELLIPTA in the unopened tray and only open when ready for use.. oSafely throw away ARNUITY ELLIPTA in the trash weeks after you open the tray or when the counter reads 0, whichever comes first. Write the date you open the tray on the label on the inhaler.

SPL UNCLASSIFIED SECTION.

1.1 Treatment of Asthma. ARNUITY ELLIPTA is indicated for the once-daily maintenance treatment of asthma as prophylactic therapy in patients aged years and older.Important Limitation of UseARNUITY ELLIPTA is NOT indicated for the relief of acute bronchospasm.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Hepatic impairment: Fluticasone furoate systemic exposure may increase in patients with moderate or severe impairment. Monitor for systemic corticosteroid effects. (8.6, 12.3). 8.1 Pregnancy Risk SummaryThere are insufficient data on the use of ARNUITY ELLIPTA in pregnant women. There are clinical considerations with use of ARNUITY ELLIPTA in pregnant women to inform drug-associated risk. (See Clinical Considerations.) In animal reproduction studies, fluticasone furoate administered by inhalation to rats and rabbits during the period of organogenesis produced no fetal structural abnormalities. The highest fluticasone furoate doses in the rat and rabbit studies were times and times the maximum recommended human daily inhalation dose (MRHDID), 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 ConsiderationsDisease-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.DataAnimal Data: Fluticasone Furoate: In separate embryofetal developmental studies, pregnant rats and rabbits received fluticasone furoate during the period of organogenesis at doses up to approximately and times the MRHDID, respectively (on mcg/m2 basis at maternal inhalation doses up to 91 and mcg/kg/day). No evidence of structural abnormalities in fetuses was observed in either species. In perinatal and postnatal developmental study in rats, dams received fluticasone furoate during late gestation and lactation periods at doses up to approximately time the MRHDID (on mcg/m2 basis at maternal inhalation doses up to 27 mcg/kg/day). No evidence of effects on offspring development was observed.. 8.2 Lactation Risk SummaryThere is no information available on the presence of fluticasone furoate in human milk, the effects on the breastfed child, or the effects on milk production. Low concentrations of other ICS have been detected in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ARNUITY ELLIPTA and any potential adverse effects on the breastfed child from fluticasone furoate or from the underlying maternal condition.. 8.4 Pediatric Use The safety and efficacy of ARNUITY ELLIPTA in pediatric patients with asthma aged to 11 years have been established in clinical trials. In those trials, 234 subjects were administered ARNUITY ELLIPTA 50 mcg once daily. Subjects aged to 11 years demonstrated safety and efficacy results similar to those observed in subjects aged 12 years and older. The safety and efficacy of ARNUITY ELLIPTA have not been established in pediatric patients aged younger than years. [See Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.2), Clinical Studies (14.2).] Effects on GrowthOrally inhaled corticosteroids may cause reduction in growth velocity when administered to children and adolescents. reduction of growth velocity in children and adolescents may occur as result of poorly controlled asthma or from use of corticosteroids, including ICS. The effects of long-term treatment of children and adolescents with ICS, including fluticasone furoate, on final adult height are not known.Controlled clinical trials have shown that ICS may cause reduction in growth in children. In these trials, the mean reduction in growth velocity was approximately 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 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 50 mcg. The subjects were 474 prepubescent children (girls aged to 7.5 years and boys aged 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)].. 8.5 Geriatric Use For the confirmatory trials, 71 subjects were aged 65 years and older (56 of which were treated with ARNUITY ELLIPTA) and were aged 75 years 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 years 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 subjects. 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.. 8.6 Hepatic Impairment Fluticasone furoate systemic exposure increased by up to 3-fold in adult 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. The effect of hepatic impairment on fluticasone furoate systemic exposure in subjects aged younger than 18 years has not been evaluated [see Clinical Pharmacology (12.3)].. 8.7 Renal Impairment There were no significant increases in fluticasone furoate 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 [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oCandida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. (5.1)oDo not use for relief of acute symptoms. Patients require immediate re-evaluation during rapidly deteriorating asthma. (5.2)oPotential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. (5.3)oRisk of impaired adrenal function when transferring from systemic corticosteroids. Wean patients slowly from systemic corticosteroids if transferring to ARNUITY ELLIPTA. (5.4)oHypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, consider appropriate therapy. (5.5)oIf paradoxical bronchospasm occurs, discontinue ARNUITY ELLIPTA and institute alternative therapy. (5.7)oAssess for decrease in bone mineral density initially and periodically thereafter. (5.9)oMonitor growth of children and adolescent patients. (5.10)oGlaucoma and cataracts may occur with long-term use of inhaled corticosteroids. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use ARNUITY ELLIPTA long term. (5.11). oCandida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. (5.1). oDo not use for relief of acute symptoms. Patients require immediate re-evaluation during rapidly deteriorating asthma. (5.2). oPotential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. (5.3). oRisk of impaired adrenal function when transferring from systemic corticosteroids. Wean patients slowly from systemic corticosteroids if transferring to ARNUITY ELLIPTA. (5.4). oHypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, consider appropriate therapy. (5.5). oIf paradoxical bronchospasm occurs, discontinue ARNUITY ELLIPTA and institute alternative therapy. (5.7). oAssess for decrease in bone mineral density initially and periodically thereafter. (5.9). oMonitor growth of children and adolescent patients. (5.10). oGlaucoma and cataracts may occur with long-term use of inhaled corticosteroids. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use ARNUITY ELLIPTA long term. (5.11). 5.1 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 ARNUITY ELLIPTA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with ARNUITY ELLIPTA continues, but at times therapy with ARNUITY ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.. 5.2 Acute Asthma Episodes. ARNUITY ELLIPTA is not indicated for the relief of acute symptoms, i.e., as rescue therapy for treatment of acute episodes of bronchospasm. ARNUITY ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist. Instruct patients to contact their physicians immediately if episodes of asthma not responsive to bronchodilators occur during the course of treatment with ARNUITY ELLIPTA. During such episodes, patients may require therapy with oral corticosteroids.. 5.3 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 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 disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG) may be indicated. If patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG, IVIG, and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.. 5.4 Transferring Patients from Systemic Corticosteroid Therapy. Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available ICS. After withdrawal from systemic corticosteroids, 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 ARNUITY ELLIPTA may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.During periods of stress or severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe asthma attack.Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to ARNUITY ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on weekly basis during therapy with ARNUITY ELLIPTA. Lung function (forced expiratory volume in second [FEV1] or peak expiratory flow [PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.Transfer of patients from systemic corticosteroid therapy to ARNUITY ELLIPTA 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, depression), despite maintenance or even improvement of respiratory function.. 5.5 Hypercorticism and Adrenal Suppression. ARNUITY ELLIPTA will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since ARNUITY ELLIPTA is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of ARNUITY ELLIPTA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with ARNUITY ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in small number of patients, particularly when fluticasone furoate is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of ARNUITY ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.. 5.6 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors. Caution should be exercised when considering the coadministration of ARNUITY ELLIPTA with 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 adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].. 5.7 Paradoxical Bronchospasm. As with other inhaled medicines, ARNUITY ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with ARNUITY ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; ARNUITY ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.. 5.8 Hypersensitivity Reactions, including Anaphylaxis. Hypersensitivity reactions such as urticaria, flushing, allergic dermatitis, and bronchospasm may occur after administration of ARNUITY ELLIPTA. Discontinue ARNUITY ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use ARNUITY ELLIPTA [see Contraindications (4.2)].. 5.9 Reduction in Bone Mineral Density. Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care.. 5.10 Effect on Growth. Orally inhaled corticosteroids, including ARNUITY ELLIPTA, may cause reduction in growth velocity when administered to children and adolescents. Monitor the growth of children and adolescents receiving ARNUITY ELLIPTA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ARNUITY ELLIPTA, titrate each patients dose to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2.2), Use in Specific Populations (8.4)].. 5.11 Glaucoma and Cataracts. Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma following the long-term administration of ICS, including fluticasone furoate. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use ARNUITY ELLIPTA long term.