Evidence Dossier to support COPD formulary decision making and guideline development

Transcription

1 Evidence Dssier t supprt COPD frmulary decisin making and guideline develpment Prescribing and adverse event reprting infrmatin can be fund n the final page f this dcument. Trelegy and Ellipta Trademarks are wned by r licensed t the GSK Grup f Cmpanies GSK Grup f Cmpanies r its licensr. Trelegy Ellipta was develped in cllabratin with Date f preparatin: March 2018

2 Table f Cntents Clinical study infrmatin... 3 Dsing infrmatin... 3 Licensing infrmatin... 3 Interpreting clinical trial results statistical hierarchy... 3 Feldman et al., 2016 (UMEC vs TIO)... 4 Study design... 4 Patient ppulatin... 4 Endpints... 5 Results... 6 Safety... 8 Vestb et al., 2016 (SLS-COPD)... 9 Study design... 9 Patient ppulatin... 9 Endpints Results Safety Lipsn et al., 2017 (FULFIL) Study design Patient ppulatin Endpints Results Safety Van der Palen et al., 2016 (Critical errrs) Study design Patient ppulatin Endpints Results References Hw t request additinal infrmatin frm GSK Incruse Ellipta (umeclidinium) Prescribing Infrmatin Relvar Ellipta (fluticasne furate/vilanterl) Prescribing Infrmatin Trelegy Ellipta (fluticasne furate/umeclidinium/vilanterl) Prescribing Infrmatin Date f preparatin: March

3 Clinical study infrmatin Dsing infrmatin Please nte that the licensed dse f FF/UMEC/VI is 92/55/22 mcg. Each single inhalatin f Trelegy Ellipta prvides a delivered dse (the dse leaving the muthpiece) f 92 mcg f fluticasne furate, 55 mcg f umeclidinium (equivalent t 65 mcg f umeclidinium brmide) and 22 mcg f vilanterl (as trifenatate). This crrespnds t a pre-dispensed dse f 100 mcg f fluticasne furate, 62.5 mcg f umeclidinium (equivalent t 74.2 mcg f umeclidinium brmide) and 25 mcg f vilanterl (as trifenatate). 1 Licensing infrmatin Trelegy Ellipta is indicated as a maintenance treatment in adult patients with mderate t severe COPD wh are nt adequately treated by a cmbinatin f an inhaled crticsterid and a lng-acting β2-agnist. 1 The cmpnents f Trelegy are available separately as: Incruse Ellipta (umeclidinium 55 mcg), indicated as a maintenance brnchdilatr treatment t relieve symptms in adult patients with COPD 2 Relvar Ellipta (fluticasne furate/vilanterl 92/22 mcg), indicated fr the symptmatic treatment f adults with a FEV1 <70% predicted nrmal (pst-brnchdilatr) with an exacerbatin histry despite regular brnchdilatr therapy 3 Fr further infrmatin please visit We will be discussing the efficacy and safety f Incruse and Relvar in this Evidence Dssier. Interpreting clinical trial results statistical hierarchy When reviewing the utcmes f clinical trials, it is imprtant t understand the relevance f statistical hierarchy and hw that impacts upn the cnclusins that can be derived frm a study. This cncept is explained belw. Statistical hierarchy sequentially tests the significance f a number f endpints in a study prgramme in a predetermined rder. Fr each endpint, a determinatin f significance can nly be made if all prir endpints were als significant. Treatment cmparisns fr the primary endpints are required t be statistically significant in rder t infer significance fr the secndary endpints. Therefre, if the trial des nt meet its primary endpint, the secndary endpints cannt be statistically analysed; thse results are described as descriptive nly. Date f preparatin: March

4 Feldman et al., 2016 (UMEC vs TIO) A randmised, blinded study t evaluate the efficacy and safety f umeclidinium (UMEC) 55 mcg cmpared with titrpium (TIO) 10 mcg in patients with COPD 4,5 Incruse Ellipta (UMEC) 55 mcg significantly imprves lung functin versus (TIO) 10 mcg in patients with mderate t severe COPD Study design A 12-week, multicentre, randmised, blinded, duble-dummy, head-t-head, parallel-grup, lung functin study cmparing UMEC 55 mcg versus TIO HandiHaler 10 mcg in patients with mderate t severe COPD. This was a nninferirity study t investigate whether treatment with UMEC 55 mcg OD was nn-inferir t TIO 10 mcg, assessed by trugh FEV1 n treatment Day 85. COPD = chrnic bstructive pulmnary disease; FEV 1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; OD = nce daily; PP = per-prtcl; R = randmisatin; TIO = titrpium; UMEC = umeclidinium After screening, patients entered a 7 14 day run-in perid prir t randmisatin After the run-in perid, patients were randmised (1:1) t receive either UMEC 55 mcg via the Ellipta inhaler plus placeb via the HandiHaler r TIO 10 mcg via the HandiHaler plus placeb via the Ellipta inhaler fr 12 weeks Patients were prvided with albuterl/salbutaml fr use as a rescue medicatin Details f the blinding prcess fr the tptrpium cmparatr trial discussed in this dcument can be fund n page 1 f the Supplementary material, Feldman et al., Int J COPD 2016;11: Patient ppulatin 40 years with a diagnsis f COPD Current r frmer cigarette smker with ten r mre pack-years cigarette smking histry Pre- and pst-albuterl/salbutaml FEV1/frced vital capacity (FVC) rati f <0.70 Pst-albuterl/salbutaml FEV1 f 30% 70% f predicted nrmal values 2 mmrc dyspnea scre at Visit 1 The intent-t-treat (ITT) ppulatin cmprised all patients randmized t treatment wh received at least ne dse f study medicatin; the per-prtcl (PP) ppulatin cmprised all patients in the ITT ppulatin, including thse wh did nt cmplete the study, wh did nt have a prtcl deviatin cnsidered t impact efficacy Date f preparatin: March

5 Endpints Primary endpint Trugh FEV1 n Day 85 (defined as the mean f the FEV1 values btained 23 and 24 hurs after dsing n Day 84) in the PP ppulatin The PP ppulatin was used fr analysis f the primary endpint nly, t avid bias f the results twards equivalence, which culd make a truly inferir treatment appear nn-inferir. This apprach was intended t maximise any true differences between treatments Secndary and ther endpints Trugh FEV1 n Days 2, 28, 56, 84 and 85 (ITT ppulatin) Trugh frced vital capacity (FVC) n Days 2, 28, 56, 84 and 85 (ITT ppulatin) Weighted mean (wm) FEV1 ver 0 2, and 0 24 hurs pst-dse, each n Days 1 and 84 (TFH ppulatin*) Serial FEV1 n Days 1 and 84 (TFH ppulatin) As the study was nt designed t detect nn-inferirity n ther endpints, the ITT ppulatin was used fr nnprimary endpints because it adheres t the randmisatin prcedure and is generally cnservative * The 24-hur (TFH) ppulatin cmprised all patients in the ITT ppulatin fr whm 24-hur spirmetry was perfrmed (n=295) Patient reprted utcmes Transitin Dyspnea Index (TDI) fcal scre and prprtin f TDI respnders (thse with 1 unit TDI fcal scre) n Days 28, 56 and 84 St Gerge s Respiratry Questinnaire (SGRQ) ttal scre and prprtin f respnders (thse with reductin frm baseline f 4 units ttal SGRQ scre) n Days 28 and 84 COPD Assessment Test (CAT) scre and prprtin f respnders (reductin frm baseline f 2 units) n Days 28 and 84 Mean number f puffs/day f rescue medicatin and percentage rescue-free days ver the study duratin (Weeks 1 12) Patient preference fr inhaler type was assessed at the end f the treatment phase, with ease f use rating assessed n Days 28 and 84 Inhaler errrs (IEs) were assessed in a subset f patients n Days 1, 28 and 84; The IE ppulatin cmprised all patients in the ITT ppulatin wh cmpleted the IE checklist; UMEC 55 mcg n=480; TIO 10 mcg n=484. A critical errr was predefined as an errr that was mst likely t result in n r nly minimal medicatin being inhaled Safety Safety f study treatments were assessed by mnitring the incidence f adverse events (AEs) and vital sign measurements Date f preparatin: March

6 Baseline demgraphics and clinical characteristics (ITT ppulatin) Characteristic UMEC 55 mcg (n=509) TIO 10 mcg (n=508) Mean age, years Female sex, n (%) 145 (28) 137 (27) Current smker at screening, n (%) 259 (51) 260 (51) Smking pack-years a 41.2 (21.4) 41.9 (21.9) Pst-salbutaml FEV1 (L), b mean ± SD 1.49 ± ± 0.44 Pst-salbutaml FEV1/FVC (L), b mean ± SD 48.9 ± ± 10.1 a Smking pack-years = (number f cigarettes smked per day/20) x number f years smked; b n=508 in UMEC, n=508 in TIO FEV 1 = frced expiratry vlume in 1 secnd; FVC = frced vital capacity; ITT = intent-t-treat; SD = standard deviatin; TIO = titrpium; UMEC = umeclidinium Results Primary endpint Trugh FEV1 n Day 85 (PP ppulatin) The least squares (LS) mean change frm baseline in trugh FEV1 was greater in the UMEC 55 mcg OD grup than with the TIO 10 mcg grup at Day 85 in the PP ppulatin (154 ml vs 95 ml, respectively; difference: 59 ml, 95% CI 29, 88; p<0.001) (Figure 1) Figure 1: LS mean change frm baseline in trugh FEV1 (PP ppulatin) Adapted frm Feldman et al., 2016 CI = cnfidence interval; FEV 1 = frced expiratry vlume in 1 secnd; LS = least squares; PP = per-prtcl; SE = standard errr; TIO = titrpium; UMEC = umeclidinium Secndary endpints Trugh FEV1 n Day 85 (ITT ppulatin) The change frm baseline was significantly greater in the UMEC 55 mcg than the TIO 10 mcg grup at Day 85 in the ITT ppulatin (147 ml vs 94 ml: difference 53 ml; 95% CI 25, 81; p<0.001) Date f preparatin: March

7 Trugh FEV1 n Days 2, 28, 56 and 84 (per-prtcl ppulatin) UMEC 55 mcg had a statistically significant difference in LS mean change frm baseline trugh FEV1 versus the TIO 10 mcg grup at Days 28, 56, and 84 (all p 0.003) but nt at Day 2 (p=0.254) Trugh FVC n Days 2, 28, 56, 84 and 85 (ITT ppulatin) The UMEC 55 mcg grup shwed a statistically significant difference in LS mean change frm baseline trugh FVC versus TIO 10 mcg at: Day 2: 152 ml vs 131 ml: difference 21 ml (95% CI -17, 60; p=0.274) Day 28: 194 ml vs 138 ml: difference 56 ml (95% CI 13, 99; p=0.011) Day 56: 174 ml vs 118 ml: difference 56 ml (95% CI 11, 102; p=0.016) Day 84: 187 ml vs 108 ml: difference 79 ml (95% CI 34, 125; p<0.001) Day 85: 192 ml vs 112 ml: difference 80 ml (95% CI 34, 127; p<0.001) wmfev1 ver 0 12, and 0 24 hurs pst-dse, each n Days 1 and 84 (TFH ppulatin) Treatment with UMEC 55 mcg was similar t TIO 10 mcg in terms f 0 12 and 0 24 hurs pst-dse wmfev1 at Day 84 (0 12 hurs pst-dse: 152 ml vs 113 ml; difference 39 ml; 95% CI -24, 101; p=0.222; and 0 24 hurs pst-dse: 104 ml vs 49 ml; difference 55 ml; 95% CI -2, 113; p=0.058) UMEC 55 mcg resulted in statistically significant imprvements in hurs pst-dse wmfev1 at Day 84 cmpared with TIO 10 mcg (55 ml vs 15 ml; difference 70 ml; 95% CI 14, 127; p=0.015) The difference between treatment grups in LS mean change frm baseline in serial FEV1 n Day 1 was similar at all time pints thrugh 24 hurs pst-dse and did nt shw the effect reprted n Day 85. The difference n Day 84 favured UMEC 55 mcg thrugh 24 hurs pst-dse, with statistically significant differences at pre-dse (p=0.005) and frm 21 hurs nward (21 hurs pst-dse: 76 ml; 95% CI 11, 141, p=0.022; and 24 hurs pst-dse: 67 ml; 95% CI 8, 126; p=0.026) Patient reprted utcmes TDI ttal scres and respnders at Day 84 There were similar imprvements in TDI scre fr UMEC 55 mcg and TIO 10 mcg (1.96 vs 1.90; difference 0.06; 95% CI 0.30, 0.42; p=0.746) Apprximately half f patients in each treatment grup were cnsidered t be respnders t TDI: 55% (n=277) and 55% (n=279) in UMEC 55 mcg and TIO 10 mcg, respectively. There were n significant differences in the likelihd f being a respnder versus nn-respnder (OR 0.97; 95% CI 0.76, 1.25, p=0.816) SGRQ ttal scres and respnders at Day 84 There were similar imprvements in SGRQ scre fr UMEC 55 mcg and TIO 10 mcg ( 6.03 vs 5.57; difference 0.46; 95% CI 2.40, 1.13; p=0.571) Apprximately half f patients in each treatment grup were cnsidered t be respnders t SGRQ: 48% (n=241) and 47% (n=237) in UMEC 55 mcg and TIO 10 mcg, respectively. There were n significant differences in the likelihd f being a respnder versus nn-respnder (OR 1.05; 95% CI 0.81, 1.35, p=0.727) CAT ttal scres and respnders at Day 84 There were similar imprvements in CAT scre fr UMEC 55 mcg and TIO 10 mcg ( 1.83 vs 1.62; difference 0.21; 95% CI 0.91, 0.48; p=0.547) Apprximately half f patients in each treatment grup were cnsidered t be respnders t CAT: 50% (n=253) and 45% (n=228) in UMEC 55 mcg and TIO 10 mcg, respectively. There were n significant differences in the likelihd f being a respnder versus nn-respnder (OR 1.24; 95% CI 0.96, 1.60, p=0.104) Date f preparatin: March

8 Rescue medicatin use There were n differences between treatment grups in the LS mean change frm baseline in rescue medicatin use ver Weeks 1 12 ( 0.9 vs 0.8; difference 0.0 puffs/day, 95% CI 0.2, 0.1), r in the median percentage f rescue-free days (difference 0.0 days, 95% CI 0.00, 0.18) Patient preference A larger prprtin f patients indicated an verall device preference fr the Ellipta inhaler cmpared with the HandiHaler (57% [n=570] and 19% [n=189], respectively) The Ellipta inhaler was rated very easy r easy t use by 95% f patients n Day 84 (n=902), while the HandiHaler was rated very easy r easy t use by 78% f patients (n=736) Inhaler errrs (Inhaler errr ppulatin n=168; n=64 in each treatment arm) Critical errrs ranged between 1% and 4% and were very lw at clinic visits fr bth inhaler types. The prprtin f patients with at least ne verall errr ranged between 8% (n=5) and 13% (n=8) and was similar between bth treatment grups Safety On-treatment AEs were similar acrss treatment grups (32% in the UMEC 55 mcg grup and 30% in the TIO 10 mcg grup; Table 1) The mst cmmn treatment-related AEs were headache (6% fr bth treatments) and naspharyngitis (5% fr bth treatment grups; Table 1) N clinically relevant effects n vital signs were bserved A ttal f 11% patients in the UMEC 55 mcg grup and 9% patients in the TIO 10 mcg grup experienced an ntreatment COPD exacerbatin (Table 1) Table 1. Summary f safety results (ITT ppulatin) UMEC 55 mcg (n=509) TIO 10 mcg (n=508) Any n-treatment AE, n (%) 165 (32) 153 (30) Mst cmmn n-treatment AEs reprted by 3% f patients in either treatment grup, n (%) Headache 30 (6) 32 (6) Naspharyngitis 27 (5) 23 (5) Any n-treatment nn-fatal SAEs, n (%) 17 (3) 14 (3) Any n-treatment fatal SAEs, n (%) 0 2 (<1) Any n-treatment drug-related AEs, n (%) 17 (3) 8 (2) Number f patients with a COPD exacerbatin, n (%) 58 (11) 48 (9) AE = adverse event; ITT = intent-t-treat; SAE = serius adverse event; TIO = titrpium; UMEC = umeclidinium An increase in the incidence f pneumnia, including pneumnia requiring hspitalisatin, has been bserved in patients with COPD receiving inhaled crticsterids. There is sme evidence f an increased risk f pneumnia with increasing sterid dse but this has nt been demnstrated cnclusively acrss all studies. There is n cnclusive clinical evidence fr intra-class differences in the magnitude f the pneumnia risk amng inhaled crticsterid prducts. Physicians shuld remain vigilant fr the pssible develpment f pneumnia in patients with COPD as the clinical features f such infectins verlap with the symptms f COPD exacerbatins. Risk factrs fr pneumnia in patients with COPD include current smking, lder age, lw bdy mass index (BMI) and severe COPD. Date f preparatin: March

9 Vestb et al., 2016 (SLS-COPD) Effectiveness f fluticasne furate-vilanterl fr COPD in clinical practice 6,7 Relvar Ellipta 92/22 mcg OD significantly reduced mderate/severe exacerbatins vs. twice daily ICS/LABA, f which a high prprtin were n fluticasne prpinate/salmeterl, withut a greater risk f serius adverse events Study design An pen-label, randmised, cntrlled study cmparing the effectiveness and safety f FF/VI 92/22 mcg OD with usual care (GP r investigatr s free chice f COPD maintenance treatment) in a large ppulatin intended t reflect patients with COPD seen in everyday practice. * ICS mntherapy nt indicated in COPD ** Patient allwed t remain n LAMA in additin t their randmised treatment if already receiving LAMA therapy at randmisatin COPD = chrnic bstructive pulmnary disease; FF/VI = fluticasne furate/vilanterl; ICS/LABA/LAMA = inhaled crticsterid/lngacting β 2-agnist/lng-acting muscarinic antagnist; LABA = lng-acting β 2-agnist; OD = nce daily; R = randmisatin Usual care was determined by the GP: Nn-ICS cntaining treatment: n=391 (14%) ICS*, ICS/LABA r ICS + LAMA: n=958 (34%) Triple therapy in multiple inhalers: n= 1,450 (52%) Randmisatin stratified by recent exacerbatin status and existing COPD maintenance therapy at baseline Patients randmly assigned t FF/VI 92/22 mcg OD wh were previusly treated with tw lng-acting brnchdilatrs and an inhaled gluccrticid were allwed t cntinue taking a LAMA in additin t FF/VI 92/22 mcg If at mnths 3, 6 and 9, patients had n cntact with their general practice within the previus 8 weeks, they were cntacted fr assessments f adverse events r adverse drug reactins Treatment adjustment was at HCP discretin; patients culd switch frm FF/VI 92/22 mcg t usual care, but patients in the usual care grup culd nt switch t the FF/VI 92/22 mcg grup Patients in each treatment grup were trained in the crrect inhaler techniques and dsing Patient ppulatin 40 years with a diagnsis f COPD GP diagnsis f COPD 1 mderate/severe COPD exacerbatin in the previus 3 years Date f preparatin: March

10 Regular maintenance inhaler therapy (ICS and/r LAMA and/r LABA; nte ICS mntherapy is nt indicated in COPD) There were n restrictins regarding smking histry r spirmetric values Endpints Primary endpint Mean annual rate f mderate r severe exacerbatins, defined as any wrsening f respiratry symptms that led t treatment with antibitic agents r systemic gluccrticids (r bth), t hspital admissin, r t scheduled r unscheduled hspital visits (assessed in the mdified ITT ppulatin [patients wh had undergne randmisatin, received a prescriptin f trial medicatin and had 1 exacerbatin in the preceding year]) Secndary endpints (assessed in the ITT ppulatin [all patients wh underwent randmisatin and received a prescriptin f trial medicatin]) Rate f first exacerbatins, as assessed by time-t-event analysis Annual rates f primary and secndary healthcare cntacts COPD Assessment Test (CAT) scre Eurpean Quality f Life-5 Dimensins (EQ-5D) questinnaire results Safety and tlerability Safety and tlerability were assessed by mnitring serius adverse events f pneumnia, the frequency and type f ther serius adverse events, and adverse drug reactins Demgraphics and baseline characteristics Characteristic FF/VI 92/22 mcg (n=1,396) Entire trial ppulatin Usual care (n=1,403) Entire trial ppulatin (n=2,799) Mdified ITT ppulatin (n=2,269) Mean age, years Female sex, n (%) 698 (50) 671 (48) 1,369 (49) 1,122 (49) Current smking, n (%) 623 (45) 666 (47) 1289 (46) 1046 (46) Cexisting cnditin, n (%) 1069 (77) 1076 (77) 2145 (77) 1758 (77) Number f exacerbatins during 12 m befre randmisatin 1.98 ± ± ± ± 1.93 Pstbrnchdilatr FEV1 (L) 1.62 ± ± ± ± 0.64 Values are mean ± SD unless specified therwise FEV 1 = frced expiratry vlume in 1 secnd; FF/VI = fluticasne furate/vilanterl; m = mnths Results Primary endpint Mean annual rate f mderate r severe exacerbatins The rate f mderate r severe exacerbatins in the mdified ITT ppulatin was 1.74 exacerbatins per year in the FF/VI 92/22 mcg grup cmpared with 1.90 per year in the usual care grup, indicating an 8.4% (95% CI 1.1, 15.2) lwer rate in the FF/VI 92/22 mcg grup (p=0.02) (Figure 2) In the ITT ppulatin, the rate f mderate r severe exacerbatins was 1.50 per year in the FF/VI 92/22 mcg grup cmpared with 1.64 per year in the usual care grup, indicating an 8.4% (95% CI 1.4, 14.9) lwer rate in the FF/VI 92/22 mcg grup (p=0.02) (Figure 2) FF/VI can help prevent ne additinal mderate r severe COPD exacerbatin fr every seven patients treated ver 12 mnths cmpared with twice daily ICS/LABA (NNT=6.25; 95% CI 3.47, 46.99) Date f preparatin: March

11 Figure 2: Treatment effect n mderate r severe exacerbatins Adapted frm Vestb et al, 2016 CI = cnfidence interval; ITT = intent t treat Secndary endpints Rate f first exacerbatins There was n significant difference in the rate f first mderate r severe exacerbatin in the time-tevent analysis in the ITT ppulatin (prbability f event 68.9% [n=947] vs 70.4% [n=997]; HR [FF/VI 92/22 mcg vs usual care] 0.93; 95% CI 0.85, 1.02) There was n significant difference in the rate f first severe exacerbatin in the time-t-event analysis (prbability f event 8.9% [n=122] vs 7.0% [n=97]; HR [FF/VI 92/22 mcg vs usual care] 1.27; 95% CI 0.98, 1.66; p=0.08) There was n significant difference in the rate f severe exacerbatins between the FF/VI 92/22 mcg grup (0.09 exacerbatins per year) and the usual care grup (0.08 exacerbatins per year); the rate was 9.7% higher in the FF/VI 92/22 mcg grup (95% CI 16.9, 44.7; p=0.52) Annual rates f primary and secndary healthcare cntacts The annual rate f COPD-related cntact was 1.7% lwer (95% CI 5.1, 8.0) in the FF/VI 92/22 mcg grup (2.42) than in the usual care grup (2.46); there was n significant difference between grups The annual rate f all primary care cntacts was slightly higher (12.3%; 95% CI 5.4, 19.6) in the FF/VI 92/22 mcg grup (21.2) than in the usual care grup (18.9) CAT scre There were n significant differences in the rates f secndary healthcare cntacts A ttal f 45% f patients in the FF/VI 92/22 mcg grup (n=1,317) had a decrease f 2 pints (indicating an imprvement in COPD-related health status) in their CAT scre, cmpared with 36% in the usual care grup (n=1,325; OR 1.51; 95% CI 1.28, 1.77; p<0.001) EQ-5D questinnaire results Safety There was n significant between-grup difference in the change frm baseline in the EQ-5D scre The incidence f SAEs was similar in the FF/VI 92/22 mcg grup and the usual care grup, with events ccurring in 404 patients (29%) and 383 patients (27%), respectively There was n ntable difference in ccurrence f AE f special interest (AESI) between treatment grups (Table 2) A ttal f 94 patients (7%) in the FF/VI 92/22 mcg grup had 1 pneumnia SAE cmpared with 83 (6%) in the usual care grup (incidence rati [IR] 1.1; 95% CI 0.9, 1.5) Fr the incidence f SAEs f pneumnia, the nn-inferirity margin fr the rati f the prprtins f patients with 1 SAE f pneumnia n FF/VI versus usual care was set at 2 A ttal f 13 patients (1%) in each treatment grup had an event f pneumnia (AESI) with a fatal utcme Date f preparatin: March

12 One patient in each grup died frm a SAE that was recrded as being related t the study medicatin (pneumnia in 1 patient in the usual care grup, and pulmnary emblism and deep-vein thrmbsis in 1 patient in the FF/VI 92/22 mcg grup) Table 2. Summary f adverse events f special interest Cardivascular event, n (%) Any event Cardiac arrhythmia Cardiac failure Cardiac ischemia Hypertensin Strke FF/VI 92/22 mcg (n=1,396) 108 (8) 52 (4) 28 (2) 34 (2) 0 21 (2) Usual care (n=1,403) 107 (8) 54 (4) 28 (2) 33 (2) 1 (<1) 25 (2) At least ne incidence f pneumnia, n (%) 94 (7) 83 (6) LRTI, excluding pneumnia, n (%) 64 (5) 58 (4) Decreased bne mineral density and assciated fracture, n (%) 45 (3) 45 (3) Effects n glucse level, n (%) 23 (2) 16 (1) Hypersensitivity, n (%) 10 (1) 10 (1) Effects n ptassium level, n (%) 2 (<1) 2 (<1) Gluccrticid-assciated eye disease, n (%) 2 (<1) 2 (<1) Lcal effects frm gluccrticids, n (%) 0 1 (<1) Serius adverse events f interest during treatment (entire trial ppulatin) that were assciated with the knwn pharmaclgic actin f inhaled gluccrticids r lng-acting β-agnists. FF/VI = fluticasne furate/vilanterl; LRTI = lwer respiratry tract infectin; OD = nce daily An increase in the incidence f pneumnia, including pneumnia requiring hspitalisatin, has been bserved in patients with COPD receiving inhaled crticsterids. There is sme evidence f an increased risk f pneumnia with increasing sterid dse but this has nt been demnstrated cnclusively acrss all studies. There is n cnclusive clinical evidence fr intra-class differences in the magnitude f the pneumnia risk amng inhaled crticsterid prducts. Physicians shuld remain vigilant fr the pssible develpment f pneumnia in patients with COPD as the clinical features f such infectins verlap with the symptms f COPD exacerbatins. Risk factrs fr pneumnia in patients with COPD include current smking, lder age, lw BMI and severe COPD. Date f preparatin: March

13 Lipsn et al., 2017 (FULFIL) FULFIL Trial: nce-daily triple therapy fr patients with chrnic bstructive pulmnary disease 8 Trelegy Ellipta 92/55/22 mcg OD significantly imprves lung functin and symptmatic endpints versus Symbicrt Turbhaler 320/9 mcg BD Study design A Phase III, randmised, multicentre, duble-blind, duble-dummy, parallel-grup, 24-week lung functin study cmparing FF/UMEC/VI 92/55/22 mcg OD using a single Ellipta inhaler against budesnide/frmterl (BUD/FOR) 320/9 mcg BD using the Turbhaler in patients with mderate-t-severe COPD. BD = twice daily; BUD/FOR = budesnide/frmterl; CAT = COPD Assessment Test; COPD = chrnic bstructive pulmnary disease; FEV 1 = frced expiratry vlume in 1 secnd; FF/UMEC/VI = fluticasne furate/umeclidinium/vilanterl; OD = nce daily; R = randmisatin; SD = standard deviatin; SGRQ = St Gerge s Respiratry Questinnaire Patient ppulatin 40 years f age with a diagnsis f COPD and: FEV1 <50% and CAT 10, r FEV % and CAT 10 and either 2 mderate r 1 severe exacerbatins in the past year A mderate exacerbatin was defined as having wrsening symptms f COPD that required treatment with ral/systemic crticsterids and/r antibitics; a severe exacerbatin was defined as wrsening symptms f COPD that required treatment with in-patient hspitalisatin Regular daily maintenance inhaler fr 3 mnths Endpints C-primary endpints Mean change frm baseline in pre-dse (trugh) FEV1 Change frm baseline in SGRQ ttal scre Secndary endpints Prprtin f patients with a clinically meaningful change frm baseline ( 100 ml) in trugh FEV1 Prprtin f patients with a clinically meaningful imprvement frm baseline ( 4 unit decrease) in SGRQ ttal scre Incidence f mderate/severe COPD exacerbatins Change frm baseline in Evaluating Respiratry Symptms in COPD scre (E-RS: COPD) Date f preparatin: March

14 Safety and tlerability Safety and tlerability f study treatments were assessed by mnitring AEs, SAEs, pneumnia and supprting radigraphy, cardivascular events including pre-specified majr cardivascular events analysis, bne fractures and ther AESI Demgraphics and baseline characteristics FF/UMEC/VI BUD/FOR Characteristic 92/55/22 mcg 320/9 mcg ITT ppulatin (24 weeks) (n=911) (n=899) Mean age, years Female sex, n (%) 233 (26) 236 (26) Current smkers, n (%) 400 (44) 394 (44) Smking pack-years, mean ± SD 39.5 ± ± 22.2 CV risk factrs*, n (%) 599 (66) 602 (67) Mderate/severe COPD exacerbatin in previus 12 mnths, n (%) (34) 317 (35) (28) 253 (28) (38) 329 (37) Mean FEV1, % predicted nrmal ± SD 45.5 ± ± 13.6 SGRQ Ttal scre ± SD 51.8 ± ± 16.7 EXT ppulatin (52 weeks) (n=210) (n=220) Mean age, years Female sex, n (%) 53 (25) 58 (26) Current smkers, n (%) 95 (45) 97 (44) Smking pack-years, mean ± SD 39.8 ± ± 23.1 CV risk factrs*, n (%) 144 (69) 152 (69) Mderate/severe COPD exacerbatin in previus 12 mnths, n (%) 0 62 (30) 72 (33) 1 77 (37) 79 (36) 2 71 (34) 69 (31) Mean FEV1, % predicted nrmal ± SD 47.1 ± ± 14.9 SGRQ ttal scre ± SD 53.0 ± ± 15.5 * CV risk factrs included, but were nt limited t, hypertensin, hyperchlesterlemia, crnary heart disease and diabetes mellitus BD = twice daily; BUD/FOR = budesnide/frmterl; COPD = chrnic bstructive pulmnary disease; EXT = extensin; FEV 1 = frced expiratry vlume in 1 secnd; FF/UMEC/VI = fluticasne furate/umeclidinium/vilanterl; ITT = intent-t-treat; SD = standard deviatin; SGRQ = St Gerge s Respiratry Questinnaire Results C-primary endpints LS mean difference in clinic visit trugh FEV1 In the ITT ppulatin, the differences in trugh FEV1 at Week 24 between FF/UMEC/VI 92/55/22 mcg (142 ml; 95% CI 126, 158) and BUD/FOR 320/9 mcg ( 29 ml; 95% CI 46, 13) was significant (171 ml; 95% CI, 148, 194; p<0.001) In the ITT ppulatin, the difference in the change frm baseline in trugh FEV1 between treatments were statistically significant in favur f FF/UMEC/VI at all study time pints (p<0.001; Figure 3) Date f preparatin: March

15 In the EXT ppulatin, the differences in trugh FEV1 at Week 52 between FF/UMEC/VI 92/55/22 mcg (126 ml; 95% CI 92, 159) and BUD/FOR 320/9 mcg ( 53 ml; 95% CI 87, 20) was significant (179 ml; 95% CI, 131, 226; p<0.001) (Figure 3) Figure 3: Mean change frm baseline in trugh FEV1 ver A: 24 weeks (ITT ppulatin) and B: 52 weeks (EXT ppulatin) Adapted frm Lipsn et al., 2017 p<0.001 at all time pints in the ITT ppulatin BUD/FOR = budesnide/frmterl; CI = cnfidence interval; EXT = extensin; FEV 1 = frced expiratry vlume in 1 secnd; FF/UMEC/VI = fluticasne furate/umeclidinium/vilanterl; ITT = intent-t-treat; LS = least squares Mean difference in SGRQ Ttal scre Secndary endpints In the ITT ppulatin, clinically meaningful imprvements in SGRQ Ttal scre at Week 24 were bserved in bth treatment grups cmpared with baseline (FF/UMEC/VI 92/55/22 mcg: 6.6 units; 95% CI 7.4, 5.7; BUD/FOR 320/9 mcg: 4.3 units; 95% CI 5.2, 3.4) and there was a statistically significant treatment differences between FF/UMEC/VI 92/55/22 mcg and BUD/FOR 320/9 mcg ( 2.2 units; 95% CI 3.5, 1.0; p<0.001) In the EXT ppulatin, an imprvement in SGRQ Ttal scre at Week 52 was bserved in bth treatment grups cmpared with baseline (FF/UMEC/VI 92/55/22 mcg: 4.6 units; 95% CI 6.5, 2.6; BUD/FOR 320/9 mcg: 1.9 units; 95% CI 3.9, 0.1); hwever, the between-treatment difference did nt meet significance Mderate/severe COPD exacerbatins In the ITT ppulatin at Week 24, the incidence f mderate/severe exacerbatins was 10% (n=95) and 14% (n=126) in the FF/UMEC/VI 92/55/22 mcg and BUD/FOR 320/9 mcg grups, respectively The mean annualised rate f mderate/severe exacerbatins was 0.22 and 0.34 in the FF/UMEC/VI 92/55/22 mcg and BUD/FOR 320/9 mcg grups, respectively; the reductin in rate was significant (35%; 95% CI 14%, 51%, p=0.002) In the EXT ppulatin at Week 52, the mean annualised rate f mderate/severe exacerbatins was 0.20 and 0.36 in the FF/UMEC/VI 92/55/22 mcg and BUD/FOR 320/9 mcg grups, respectively; the reductin in rate was significant (44%; 95% CI 15%, 63%, p=0.006) Prprtin f patients with a clinically meaningful change frm baseline in trugh FEV1 ( 100 ml) In the ITT ppulatin at Week 24, an increase f 100 ml frm baseline in trugh FEV1 was achieved by a larger prprtin f patients in the FF/UMEC/VI 92/55/22 mcg grup (453; 50%) than in the BUD/FOR 320/9 mcg grup (184; 21%; OR, 4.03; 95% CI 3.27, 4.97; p<0.001) In the EXT ppulatin at Week 52, an increase f 100 ml frm baseline in trugh FEV1 was achieved by a larger prprtin f patients in the FF/UMEC/VI 92/55/22 mcg grup (96; 46%) than in the BUD/FOR 320/9 mcg grup (34; 16%; OR, 4.79; 95% CI 3.02, 7.61; p<0.001) Date f preparatin: March

16 Prprtin f patients with a clinically meaningful imprvement frm baseline ( 4 unit decrease) in SGRQ Ttal scre Safety In the ITT ppulatin at Week 24, a clinically meaningful imprvement frm baseline in SGRQ Ttal scre was experienced by a larger prprtin f patients in the FF/UMEC/VI 92/55/22 mcg grup (448; 50%) than in the BUD/FOR 320/9 mcg grup (368; 41%; OR, 1.41; 95% CI 1.16, 1.70; p<0.001) In the EXT ppulatin at Week 52, a clinically meaningful imprvement frm baseline in SGRQ Ttal scre was experienced by a larger prprtin f patients in the FF/UMEC/VI 92/55/22 mcg grup (91; 44%) than in the BUD/FOR 320/9 mcg grup (73; 33%; OR, 1.50; 95% CI 1.01, 2.24; p=0.046) In the ITT ppulatin at Week 24, n-treatment AEs were similar acrss treatment grups (FF/UMEC/VI 92/55/22 mcg: 38.9%, BUD/FOR 320/9 mcg: 37.7%; Table 3) In the ITT ppulatin at Week 24, n-treatment SAEs were similar acrss treatment grups (FF/UMEC/VI 92/55/22 mcg: 5.4%, BUD/FOR 320/9 mcg: 5.7%). The mst cmmn n-treatment SAEs were COPD exacerbatin (FF/UMEC/VI 92/55/22 mcg: 1.3%, BUD/FOR 320/9 mcg: 2.3%) and pneumnia (FF/UMEC/VI 92/55/22 mcg: 1.0%, BUD/FOR 320/9 mcg: 0.3%; Table 3) In the ITT ppulatin at Week 24, the incidence f pre-specified AESI f cardivascular effects and pneumnia were reprted by 4.3% and 2.2% f FF/UMEC/VI 92/55/22 mcg patients, and 5.2% and 0.8% f BUD/FOR 320/9 mcg patients, respectively (Table 3) There were 12 n-treatment deaths, six in each treatment grup In the EXT ppulatins, n-treatment SAEs were similar acrss treatment grups (FF/UMEC/VI 92/55/22 mcg: 10.0%, BUD/FOR 320/9 mcg: 12.7%; Table 3) There were n clinically significant differences between treatment grups in vital signs, electrcardigrams, Hlter findings r labratry values Table 3. Summary f adverse events and adverse events f special interest FF/UMEC/VI 92/55/22 mcg ITT ppulatin BUD/FOR 320/9 mcg FF/UMEC/VI 92/55/22 mcg EXT ppulatin BUD/FOR 320/9 mcg (n=911) (n=899) (n=210) (n=220) On treatment AEs, % On treatment SAEs, % Mst cmmn n treatment SAE, % COPD exacerbatin Pneumnia Mst frequent AEs ccurring in 2% in any grup, n (%) Naspharyngitis 64 (7) 43 (5) 23 (11) 22 (10) Headache 44 (5) 53 (6) 17 (8) 22 (10) URTI 20 (2) 19 (2) 6 (3) 10 (5) COPD 15 (2) 23 (3) 5 (2) 22 (10) Back pain 19 (2) 18 (2) 4 (2) 5 (2) Arthalgia 17 (2) 13 (1) 5 (2) 6 (3) Pneumnia 19 (2) 7 (<1) 4 (2) 4 (2) Pharyngitis 15 (2) 9 (1) 5 (2) 1 (<1) Orpharyngeal pain 9 (<1) 10 (1) 6 (3) 1 (<1) Dizziness (<1) 6 (3) Date f preparatin: March

17 Bld pressure increased 4 (<1) 8 (<1) 0 4 (2) Dyspnea (2) Vertig (2) Adverse events f special interest, n (%) Cardivascular effects 39 (4.3) 47 (5.2) 18 (8.6) 22 (10.0) Pneumnia 20 (2.2) 7 (0.8) 4 (1.9) 4 (1.8) Lcal sterid effects 19 (2.1) 24 (2.7) 8 (3.8) 7 (3.2) Antichlinergic syndrme 16 (1.8) 17 (1.9) 4 (1.9) 12 (5.5) Hypersensitivity 10 (1.1) 10 (1.1) 3 (1.4) 1 (0.5) Hyperglycemia/diabetes 5 (0.5) 4 (0.4) 0 4 (1.8) Decreased bne mineral density 4 (0.4) 6 (0.7) 1 (0.5) 1 (0.5) LRTI (excluding pneumnia) 3 (0.3) 4 (0.4) 1 (0.5) 0 Ocular effects 1 (0.1) 4 (0.4) - - Urinary retentin 1 (0.1) Asthma/brnchspasm 0 1 (0.1) - - AE = adverse event; BD = twice daily; BUD/FOR = budesnide/frmterl; COPD = chrnic bstructive pulmnary disease; EXT = extensin; FF/UMEC/VI = fluticasne furate/umeclidinium/vilanterl; ITT = intent-t-treat; LRTI = lwer respiratry tract infectin; URTI = upper respiratry tract infectin An increase in the incidence f pneumnia, including pneumnia requiring hspitalisatin, has been bserved in patients with COPD receiving inhaled crticsterids. There is sme evidence f an increased risk f pneumnia with increasing sterid dse but this has nt been demnstrated cnclusively acrss all studies. There is n cnclusive clinical evidence fr intra-class differences in the magnitude f the pneumnia risk amng inhaled crticsterid prducts. Physicians shuld remain vigilant fr the pssible develpment f pneumnia in patients with COPD as the clinical features f such infectins verlap with the symptms f COPD exacerbatins. Risk factrs fr pneumnia in patients with COPD include current smking, lder age, lw BMI and severe COPD. Date f preparatin: March

18 Van der Palen et al., 2016 (Critical errrs) A randmised pen-label crss-ver study f inhaler errrs, preference and time t achieve crrect inhaler use in patients with COPD r asthma: cmparisn f Ellipta with ther cmmnly used inhaler devices 9,10 The Ellipta inhaler is easy t use and significantly fewer patients made critical errrs cmpared with ther cmmnly used devices after reading the patient infrmatin leaflet (PIL) Study design A randmised, multicentre, single visit, pen-label, crss ver study cmparing the Ellipta inhaler device against ther devices in patients with asthma and patients with COPD. The results belw fcus nly n COPD studies; asthma results are nt presented. COPD = chrnic bstructive pulmnary disease; MDI = metered-dse inhaler; R = randmisatin Patients entering the study were naïve t Ellipta and at least ne ther device Each substudy was individually pwered Critical errrs were assessed by trained respiratry nurses after patients had read the patient infrmatin leaflet (PIL). A critical errr is defined as an errr that is likely t result in the inhalatin f significantly reduced, minimal r n medicatin If the patient made errrs, the investigatr demnstrated the crrect use f the inhaler, and the patient demnstrated inhaler use again Patient ppulatin 18 years with a physician diagnsis f COPD and currently receiving treatment fr COPD Naïve t Ellipta inhaler use Endpints Primary endpint Critical errrs using the devices after reading the PIL nly Secndary endpints Overall errrs using the devices after reading the PIL nly Instructin frm trained respiratry nurse n use f the devices Time t crrect inhaler use Ease f use f the devices Patient preference fr devices Date f preparatin: March

19 Demgraphics and baseline characteristics Characteristic Ttal (N=567) Ellipta vs Accuhaler (n=171) Ellipta vs MDI (n=80) Ellipta vs Turbhaler (n=100) Ellipta vs HandiHaler (n=118) Ellipta vs Breezhaler (n=98) Mean age, years Female sex, n (%) 225 (40) 68 (40) 27 (34) 33 (33) 46 (39) 51 (52) COPD histry, n (%) 6 mnths 10 years 422 (74) 135 (79) 59 (74) 62 (62) 92 (78) 74 (76) years 123 (22) 29 (17) 18 (22) 32 (32) 23 (19) 21 (21) 25 years 22 (4) 7 (4) 3 (4) 6 (6) 3 (3) 3 (3) COPD = chrnic bstructive pulmnary disease; MDI = metered-dse inhaler Results Primary endpint Critical errrs using the devices after reading the PIL nly Cmpared with ther cmmnly used inhalers, fewer patients using Ellipta made critical errrs (Figure 4) After reading the PIL, the prprtin f patients with COPD wh made at least ne critical errr was significantly lwer with the Ellipta device cmpared with all thers (all p<0.001) Fr the Ellipta inhaler, the mst cmmn critical errr was exhaling directly int the muthpiece (31/567 [5%] patients with COPD) Fr the Accuhaler device, the lever was nt pushed back prperly by 33% f patients with COPD (56/171) Fr the MDI device, pr press-and-breathe crdinatin was bserved in 43% (34/80) f patients with COPD Fr the Turbhaler device, 29% (29/100) patients with COPD did nt twist the base prperly and hear the click Fr bth the HandiHaler and the Breezhaler, the capsule did nt rattle with 36% (42/118) and 43% (42/98) f patients with COPD, respectively Date f preparatin: March

20 Figure 4: Percentage f patients with COPD with at least ne critical errr after reading the PIL Adapted frm van der Palen et al., 2016 MDI = metered-dse inhaler; PIL = patient infrmatin leaflet Secndary endpints Overall errrs using the devices after reading the PIL nly In all five COPD grups, there were significantly fewer patients wh experienced at least ne verall errr with the Ellipta device cmpared with all the thers (p<0.001 in all subgrups) Instructin frm trained respiratry nurse n use f the devices After reading the PIL the majrity f patients with COPD made n errrs using the Ellipta inhaler (57 70% acrss the five sub studies) and did nt require instructin frm a trained respiratry nurse. In cntrast, fr the ther devices the majrity f patients did require instructin frm a trained respiratry nurse (65% Accuhaler, 85% MDI, 71% Turbhaler, 62% HandiHaler and 56% Breezhaler) The difference in the number f nurse instructins required until crrect use was perfrmed was significant between the Ellipta inhaler and all f the ther devices (p<0.001 in all subgrups) When cmpared with the Ellipta inhaler, mre patients required mre than ne instructin fr the use f the Accuhaler (7 versus 27 patients), MDI (3 versus 20 patients), Turbhaler (6 versus 19 patients), HandiHaler (13 versus 29 patients) and Breezhaler (2 versus 15 patients) devices Time t crrect inhaler use In all substudies, median time t crrect inhaler use withut trained respiratry nurse supprt (reading the PIL nly) culd nly be determined fr the Ellipta inhaler as fr the ther devices mre than half f patients with COPD culd nt perfrm crrect use after reading the PIL nly In all substudies, median time t crrect inhaler use reading the PIL and receiving trained respiratry nurse supprt was significantly shrter fr patients using the Ellipta inhaler cmpared with thse using Accuhaler (2.75 versus 3.93 min), MDI (3.79 versus 6.30 min), Turbhaler (2.87 versus 7.80 min), HandiHaler (4.32 versus 8.50 min) and Breezhaler (3.15 versus 8.44 min) (p<0.001 in all subgrups) Date f preparatin: March

21 Ease f use f the devices A larger prprtin in each grup rated the Ellipta inhaler very easy r easy cmpared with the ther devices (Accuhaler: 97% vs 60%; MDI: 92% vs 44%; Turbhaler: 96% vs 55%; HandiHaler: 98% vs 38%; Breezhaler: 94% vs 55%) Between 96% and 100% f COPD patients reprted they fund it very easy t determine hw much medicatin was left in the Ellipta inhaler; 61%, 63%, 45%, 42% and 60% f patients reprted they fund it very easy t determine hw much medicatin was left in Accuhaler, MDI, Turbhaler, HandiHaler and Breezhaler devices, respectively Patient preference fr devices The majrity f patients with COPD preferred Ellipta ver ther cmmnly used inhalers (all p<0.001; Figure 5) Figure 5: Overall device preference reprted in each substudy Adapted frm van der Palen et al., 2016 MDI = metered-dse inhaler The majrity f patients als preferred the Ellipta inhaler fr mst individual criteria (number f steps fr crrect use, time taken t use, size f the device, dse cunter, cmfrt f muthpiece and ease f pening; p<0.001) with sme exceptins where there was n difference: fr the size f the inhaler, similar prprtins f patients preferred Ellipta inhaler and MDI (39% and 33%), Ellipta inhaler and Turbhaler (44% and 38%), and Ellipta inhaler and Breezhaler (41% and 44%) Date f preparatin: March

22 References 1. GlaxSmithKline UK. Trelegy Ellipta (fluticasne furate/umeclidinium/vilanterl 92/55/22 mcg) Summary f Prduct Characteristics. 2. GlaxSmithKline UK. Incruse Ellipta (umeclidinium 55 mcg) Summary f Prduct Characteristics. 3. GlaxSmithKline UK. Relvar Ellipta (fluticasne furate/vilanterl 92/22 mcg) Summary f Prduct Characteristics. 4. Feldman G, Maltais F, Khindri S, et al. A randmized, blinded study t evaluate the efficacy and safety f umeclidinium 62.5 mcg cmpared with titrpium 18 mcg in patients with COPD. Internatinal jurnal f chrnic bstructive pulmnary disease. 2016;11: GlaxSmithKline. Study Clinical Study Reprt. 2016; Online. Accessed Nvember, Vestb J, Leather D, Diar Bakerly N, et al. Effectiveness f Fluticasne Furate-Vilanterl fr COPD in Clinical Practice. The New England jurnal f medicine. 2016;375(13): GlaxSmithKline. Study Clinical Study Reprt. 2017; Online. Accessed Nvember, Lipsn DA, Barnacle H, Birk R, et al. FULFIL Trial: Once-Daily Triple Therapy fr Patients with Chrnic Obstructive Pulmnary Disease. American jurnal f respiratry and critical care medicine. 2017;196(4): van der Palen J, Thmas M, Chrystyn H, et al. A randmised pen-label crss-ver study f inhaler errrs, preference and time t achieve crrect inhaler use in patients with COPD r asthma: cmparisn f ELLIPTA with ther inhaler devices. NPJ primary care respiratry medicine. 2016;26: GlaxSmithKline. GSK Clinical Study Reprt. 2017; Online. Accessed Nvember, Hw t request additinal infrmatin frm GSK Shuld yu require any further infrmatin, please cntact the GSK custmer cntact centre: By phne n Lines are pen frm Mnday t Friday 8.30am t 5.30pm. Outside these hurs and n bank hlidays, an answer phne service is available. By at custmercntactuk@gsk.cm Date f preparatin: March

23 Incruse Ellipta (umeclidinium) Prescribing Infrmatin (Please cnsult the full Summary f Prduct Characteristics (SmPC) befre prescribing) Incruse Ellipta 55mcg (umeclidinium) inhalatin pwder. Each single inhalatin prvides a delivered dse (the dse leaving the muthpiece f the inhaler) f 55 micrgrams umeclidinium (equivalent t 65 micrgrams f umeclidinium brmide). Indicatins: Incruse is indicated as a maintenance brnchdilatr treatment t relieve symptms in adult patients with chrnic bstructive pulmnary disease (COPD). Dsage and administratin: Inhalatin nly. One inhalatin nce daily f Incruse Ellipta at the same time f the day each day. Cntraindicatins: Hypersensitivity t the active substances r t any f the excipients (lactse mnhydrate and magnesium stearate). Precautins: Incruse Ellipta shuld nt be used in patients with asthma. Treatment with Incruse Ellipta shuld be discntinued in the event f paradxical brnchspasm and alternative therapy initiated if necessary. Cardivascular effects may be seen after the administratin f muscarinic receptr antagnists, therefre Incruse Ellipta shuld be used with cautin in patients with severe cardivascular disrders, particularly cardiac arrhythmias. Incruse Ellipta shuld be used with cautin in patients with urinary retentin r narrw angle glaucma. N dsage adjustment is required in renal r mild t mderate hepatic impairment. Acute symptms: Incruse Ellipta is nt indicated fr acute episdes f brnchspasm. Warn patients t seek medical advice if shrt-acting inhaled brnchdilatr use increases, a re-evaluatin f the patient and f the COPD treatment regimen shuld be undertaken. Interactins with ther medicinal prducts: C-administratin with ther lngacting muscarinic antagnists r medicinal prducts cntaining this active substance has nt been studied and therefre, is nt recmmended. Fertility, pregnancy, and breast-feeding: N available human in viv data. Balance risks against benefits. Side effects: Cmmn ( 1/100 t <1/10): Naspharyngitis, upper respiratry tract infectin, urinary tract infectin, sinusitis, headache, tachycardia, cugh. Other imprtant side effects include. Uncmmn ( 1/1,000 t <1/100): Atrial fibrillatin, rhythm idiventricular, supraventricular tachycardia, supraventricular extrasystles. Hypersensitivity reactins including rash, urticaria, pruritus. Nt knwn (cannt be estimated frm available data): Glaucma and visin blurred. Legal categry: POM. Presentatin and Basic NHS cst: Incruse Ellipta 1 inhaler x 30 dses. Incruse Ellipta 55mcg Marketing authrisatin (MA) ns. 55mcg 1x30 dses [EU/1/14/922/002]; MA hlder: Glax Grup Lts, 980 Great West Rad, Brentfr, Middlesex TW8 9GS, UK. Last date f revisin: April UK/INC/0001/17(1). Incruse and Ellipta are registered trademarks f the GlaxSmithKline grup f cmpanies. All rights reserved. Adverse events shuld be reprted. Reprting frms and infrmatin can be fund at Adverse events shuld als be reprted t GlaxSmithKline n Date f preparatin: March

24 Relvar Ellipta (fluticasne furate/vilanterl) Prescribing Infrmatin (Please cnsult the full Summary f Prduct Characteristics (SmPC) befre prescribing) Relvar Ellipta (fluticasne furate/vilanterl [as trifenatate]) inhalatin pwder. Each single inhalatin f fluticasne furate (FF) 100 micrgrams (mcg) and vilanterl (VI) 25 mcg prvides a delivered dse f 92 mcg FF and 22 mcg VI. Each single inhalatin f FF 200 mcg and VI 25 mcg prvides a delivered dse f 184 mcg f FF and 22 mcg f VI. Indicatins: Asthma: Regular treatment f asthma in patients 12 years where a lngacting β 2-agnist (LABA) and inhaled crticsterid (ICS) cmbinatin is apprpriate; i.e. patients nt adequately cntrlled n ICS and ''as needed shrt-acting inhaled β 2- agnists r patients already adequately cntrlled n bth ICS and LABA. COPD: Symptmatic treatment f adults with COPD with a FEV 1<70% predicted nrmal (pst-brnchdilatr) and an exacerbatin histry despite regular brnchdilatr therapy. Dsage and administratin: Inhalatin nly. Asthma: Adults and adlescents 12 years: ne inhalatin nce daily f Relvar 92/22 mcg fr patients wh require a lw t mid dse f ICS in cmbinatin with a LABA. If patients are inadequately cntrlled then the dse can be increased t ne inhalatin nce daily Relvar 184/22 mcg. Relvar 184/22 mcg can als be cnsidered fr patients wh require a higher dse f ICS in cmbinatin with a LABA. Regularly review patients and reduce dse t lwest that maintains effective symptm cntrl. COPD: ne inhalatin nce daily f Relvar 92/22 mcg. Relvar 184/22 mcg is nt indicated fr patients with COPD. Cntraindicatins: Hypersensitivity t the active substances r t any f the excipients (lactse mnhydrate & magnesium stearate). Precautins: Pulmnary tuberculsis, severe cardivascular disrders r heart rhythm abnrmalities, thyrtxicsis, uncrrected hypkalaemia, patients predispsed t lw levels f serum ptassium, chrnic r untreated infectins, diabetes mellitus, paradxical brnchspasm. In patients with mderate t severe hepatic impairment 92/22 mcg dse shuld be used. Acute symptms: Nt fr acute symptms, use shrt-acting inhaled brnchdilatr. Warn patients t seek medical advice if shrt-acting inhaled brnchdilatr use increases. Therapy shuld nt be abruptly stpped withut physician supervisin due t risk f symptm recurrence. Asthma-related adverse events and exacerbatins may ccur during treatment. Patients shuld cntinue treatment but seek medical advice if asthma symptms remain uncntrlled r wrsen after initiatin f Relvar. Systemic effects: Systemic effects f ICSs may ccur, particularly at high dses fr lng perids, but much less likely than with ral crticsterids. Pssible Systemic effects include: Cushing s syndrme, Cushingid features, adrenal suppressin, decrease in bne mineral density, grwth retardatin in children and adlescents. Eye symptms such as blurred visin may be due t underlying serius cnditins such as cataract, glaucma r central serus chriretinpathy (CSCR); cnsider referral t phthalmlgist. Mre rarely, a range f psychlgical r behaviural effects including psychmtr hyperactivity, sleep disrders, anxiety, depressin r aggressin (particularly in children). Increased incidence f pneumnia has been bserved in patients with COPD receiving inhaled crticsterids. Risk factrs fr pneumnia include: current smkers, ld age, patients with a histry f prir pneumnia, patients with a bdy mass index <25 kg/m 2 and patients with a FEV 1<50% predicted. If pneumnia ccurs with Relvar treatment shuld be re-evaluated. Patients with rare hereditary prblems f galactse intlerance, the Lapp lactase deficiency r glucse-galactse malabsrptin shuld nt take Relvar. Interactins with ther medicinal prducts: Interactin studies have nly been perfrmed in adults. Avid β-blckers. Cautin is advised when c-administering with strng CYP3A4 inhibitrs (e.g. ketcnazle, ritnavir, cbicistat-cntaining prducts). Cncmitant administratin f ther sympathmimetic medicinal prducts may ptentiate the adverse reactins f FF/VI. Relvar shuld nt be used in cnjunctin with ther lng-acting β 2-adrenergic agnists r medicinal prducts cntaining lng-acting β 2- adrenergic agnists. Pregnancy and breast-feeding: Experience limited. Balance risks against benefits. Side effects: Very Cmmn ( 1/10): headache, naspharyngitis. Cmmn ( 1/100 t <1/10): candidiasis f the muth and thrat, dysphnia, pneumnia, brnchitis, upper respiratry tract infectin, influenza, rpharyngeal pain, sinusitis, pharyngitis, rhinitis, cugh, abdminal pain, arthralgia, back pain, fractures, pyrexia, muscle spasms. Other imprtant side effects include: Uncmmn ( 1/1,000 t <1/100); blurred visin. Rare ( 1/10,000 t <1/1,000) paradxical brnchspasm and hypersensitivity reactins including anaphylaxis, angiedema, rash, urticaria. See SmPC fr ther adverse reactins. Legal categry: POM. Presentatin and Basic NHS cst: Relvar Ellipta. 1 inhaler x 30 dses. Relvar Ellipta 92/ Relvar Ellipta 184/ Marketing authrisatin (MA) ns. 92/22 mcg 1x30 dses [EU/1/13/886/002]; 184/22 mcg 1x30 dses [EU/1/13/886/005]. MA hlder: Glax Grup Ltd, 980 Great West Rad, Brentfrd, Middlesex TW8 9GS, UK. Last date f revisin: January2018. UK/FFT/0227/15(4). Trademarks are wned by r licensed t the GSK grup f cmpanies GSK grup f cmpanies r its licensr. Relvar Ellipta was develped in cllabratin with Innviva Inc. Adverse events shuld be reprted. Reprting frms and infrmatin can be fund at r search fr MHRA Yellwcard in the Ggle Play r Apple App Stre. Adverse events shuld als be reprted t GlaxSmithKline n Date f preparatin: March