Anoro Ellipta 55/22mcg (umeclidinium and vilanterol) for the Treatment of Chronic Obstructive Pulmonary Disease (COPD)

Anoro Ellipta 55/22mcg (umeclidinium and vilanterol) for the Treatment of Chronic Obstructive Pulmonary Disease (COPD) Medicines Evidence Pack to Support Formulary and Guidelines Decision Making Prescribing information is provided at the back of this document

CONTENTS Anoro Ellipta Overview in COPD 3 Background to COPD 4 Efficacy Studies 5 Active Comparator Studies 6 Placebo Study 10 Safety 12 National Health Technology Assessment 14 Administration 15 Patient Experience 16 Adherence 16 Cost 17 Information Sources 17 References 18 Prescribing Information 20 2

Anoro Ellipta Overview in COPD Brand Name Generic Name Device COPD Licensed Indication BNF Class Anticipated Place in Therapy Dose Administration Anoro Ellipta 55/22mcg Umeclidinium bromide (long-acting muscarinic receptor antagonist, LAMA) and vilanterol (long-acting β 2 agonist; LABA) combination Ellipta multi-dose dry powder inhaler device Anoro Ellipta is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). 3.1 Respiratory System, Bronchodilators Anoro Ellipta is a suitable treatment for symptomatic COPD patients requiring maintenance bronchodilator therapy eg. after a SABA, or those patients who are uncontrolled on their currently prescribed maintenance bronchodilator eg. step up from LAMA to combination LAMA/LABA One inhalation once daily of Anoro Ellipta 55/22mcg Inhaled via an Ellipta multi dose dry powder inhaler device Cost The 30-day cost of Anoro Ellipta is 32.50 3

Background to COPD Burden of COPD COPD is the second most common cause of emergency admission to hospital (Department of Health 2011). Even a mild grade of breathlessness is an independent marker of an increased risk of moderate-to-severe exacerbations (Mullerova et al. 2014) and patients with increased exacerbations are hospitalised more frequently (Thomas et al. 2013). Breathlessness is the most prevalent symptom of COPD and seriously impacts on a patient s quality of life. (de Oliveira et al. 2013) Breathlessness leads to a reduction in physical activity resulting in a sedentary lifestyle which further increases symptoms. (ZuWallack et al. 2007) Around 40% of patients are forced to retire early due to their symptoms. (Fletcher et al. 2011) The total cost of managing breathlessness is 4-10 times more costly than exacerbation management due to frequent GP visits. (Punekar et al. 2013) The total annual direct healthcare cost of COPD to the NHS is estimated to be over 800 million. (Department of Health 2011) Current Management Bronchodilators are central to symptom management in COPD (GOLD, 2017). The current standard of care to relieve symptoms is treatment with a single bronchodilator; long-acting muscarinic antagonist (LAMA). (NICE 2010). In the UK, COPD treatment is managed through following NICE guidelines. NICE guidelines: Management of chronic obstructive pulmonary disease in primary and secondary care can be found at www.nice.org.uk Internationally, the Global initiative for Chronic Obstructive Lung Disease (GOLD) guidelines is utilised. The GOLD global strategy for diagnosis, management and prevention of COPD can be found at www.goldcopd.org 4

Efficacy Studies The airflow classification and GOLD groups in the efficacy studies in this document are based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016 Strategy Three randomised, multicentre, double dummy, blinded, parallel group comparative efficacy studies were conducted comparing once daily Anoro Ellipta 55/22mcg (umeclidinium/ vilanterol) versus Spiriva HandiHaler 18mcg (tiotropium) in breathless (MRC 3) patients with moderate to severe COPD. These were superiority studies with the hypothesis that Anoro Ellipta would demonstrate superior efficacy over tiotropium. The placebo controlled study was a randomised, multicentre, double-blinded, parallel group comparative efficacy study conducted comparing once daily Anoro Ellipta versus placebo in patients with moderate to severe COPD. Table 2 Summary of Clinical Endpoints for Active Comparator and Placebo Controlled Trials Primary: Trough FEV 1 Active Comparator Studies Anoro Ellipta vs. tiotropium (Maleki-Yazdi MR et al 2014, Decramer et al. 2014) Secondary: 0-6hr weighted mean FEV 1 Other efficacy endpoints: Rescue medication use SGRQ, TDI* Placebo Study Anoro Ellipta vs. placebo (Donohue et al. 2013, Resp Med) Primary: Trough FEV 1 Secondary: TDI 0-6hr weighted mean FEV 1 Other efficacy endpoints: SGRQ 24 weeks 24 weeks Patient Population Clinical history of COPD in accordance with the ERS definition Post salbutamol FEV 1 / FVC ratio of 0.70 and FEV 1 70% predicted normal Dyspnoea score of 3 on the MRC Dyspnoea Scale 10 pack year smoking history Patients were excluded if they were on long term oxygen therapy or who had poorly controlled COPD leading to Hospitalisation in the previous 12 weeks Acute worsening of COPD that needed either corticosteroids, antibiotics, or required treatment prescribed by a physician in the previous 6 weeks Medical Research Council (MRC), Transition Dyspnoea Index (TDI) focal score, Quality of life measured by the St George s Respiratory Questionnaire (SGRQ) *TDI was not investigated in ZEP117115 study (Maleki). Details of the blinding process for all tiotropium comparator studies discussed in this document can be found on page 474 in Decramer M et al. Lancet Respir Med 2014; 2: 472 486.5 5

Demographics and Baseline Characteristics Table 3 Patient Demographics and Baseline Characteristics ZEP117115 (Maleki-Yazdi MR et al. 2014) Tiotropium n - 451 Anoro Ellipta 55/22mcg n = 454 DB2113360 (Maleki Yazdi MR et al. 2014; Decramer et al 2014) Tiotropium n = 203 Anoro Ellipta 55/22mcg n = 207 DB2113374 (Decramer et al 2014; Maleki Yazdi MR et al. 2014) Tiotropium n = 215 Anoro Ellipta 55/22mcg n = 217 DB2113373 (Donohue et al. 2013) Placebo n = 280 Anoro Ellipta 55/22mcg n = 413 Age (mean in years) 62.3 62.9 64.6 63.1 Male (%) 68 69 68 71 White (%) 97 86 76 850 Predicted FEV 1 (%), Mean MRC Scale (median) 46.4 47.7 47.1 47.4 3.0 3.0 3.0 3.0 Active Comparator Studies Anoro Ellipta vs. tiotropium Primary Efficacy Endpoint In three efficacy studies Anoro Ellipta improved trough FEV 1 by 112ml (p<0.001), 90ml (p<0.001), and 60ml (p=ns*) respectively compared to tiotropium. (Maleki-Yazdi MR et al. 2014, Decramer et al. 2014) (Figure 1) Figure 1 Change From Baseline in Trough FEV 1 at day 169 250 LS mean change from baseline (ml) 200 150 100 50 112ml (p<0.001) 93ml 205ml 90ml (p<0.001) 121ml 211ml 60ml (p=ns*) 149ml 208ml 0 120% relative increase (n=905) 74% relative increase (n=410) 40% relative increase (n=432) TIO 18mcg Anoro Ellipta 55/22mcg *p=non significant due to statistical heirarchy Details of the blinding process for all tiotropium comparator studies discussed in this document can be found on page 474 in Decramer M et al. Lancet Respir Med 2014; 2:472-486 6

Maintenance Naive Patients Anoro Ellipta showed significant improvements in trough FEV 1 vs tiotropium in IMT* and ITT* populations. There was a 2.4 times greater lung function improvement vs. tiotropium in maintenance naive patients at week 24. P<0.001, pooled post hoc data: 252ml vs. 107ml change in trough FEV 1 from baseline for Anoro Ellipta Vs. Tiotropium respectively. Individual patient-level data from studies DB2113360, DB2113374 and ZEP117115 were pooled and statistical re-analysis was performed. Figure 2 Change in Mean FEV 1 vs. Tio in IMT and ITT 300 Difference: 146ml (95% CI 102, 189) p<0.001 LS mean change from baseline (ml) 250 200 150 100 50 Difference: 95ml (95% CI 71, 118) p<0.001 116 211 107 252 0 All patients Maintenance-naive subgroup TIO 18mcg Anoro Ellipta 55/22mcg All patients n = 1,747 (TIO n = 869; Anoro Ellipta n = 878); Maintenance-naive subgroup n = 533 (TIO n = 258; Anoro Ellipta n = 275) *IMT = Initial Maintenance Therapy; ITT = Intent to Treat Details of the blinding process for all tiotropium comparator studies discussed in this document can be found on page 474 in Decramer M et al. Lancet Respir Med 2014; 2:472-486 7

Pooled post hoc analysis: lung function according to GOLD category and ICS use Anoro Ellipta demonstrated statistically significant improvements in trough FEV 1 vs. tiotropium at day 169 (95ml, p<0.001; CI 71-119ml) Anoro Ellipta showed statistically significant improvements vs. TIO in sub groups based on: GOLD classification (B and D: 119 and 77ml, respectively; p<0.001 for both) ICS users and non-users (70 and 121ml, respectively; p<0.001 for all subgroups) Figure 3 Mean Change from Baseline in Trough FEV 1 LS mean change from baseline (ml) 250 200 150 100 50 *** *** 221 211 116 102 *** *** 202 195 125 125 227 *** 106 0 Total GOLD B GOLD D ICS users ICS non-users Anoro Ellipta 55/22mcg TIO 18mcg ***P<0.001 Analysis based on a post hoc, pooled sub-group analysis of three 24-week, randomised, doubledummy, active-controlled, blinded, multi-centre, parallel-group studies. CI=Confidence Interval The airflow classification and GOLD groups in the efficacy studies in this document are based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016 Strategy 8

Secondary Efficacy Endpoint Anoro Ellipta improved weighted mean FEV 1 over 0-6 hours by 105ml (p<0.001), 74ml (p<0.005), and 96ml (p=ns*) respectively compared to tiotropium at week 24 (Maleki Yazdi MR et al. 2014; Decramer et al. 2014) *p=non significant due to statistical hierarchy Other Efficacy Endpoints Rescue Medication Use Anoro Ellipta demonstrated a reduction in rescue medication use by -0.5 (p<0.001), -0.6 (p=0.022), and -0.6 (p=ns) mean puffs/day respectively compared to tiotropium (Maleki Yazdi MR et al. 2014; Decramer et al. 2014) (Figure 4) Figure 4 Change in Mean Number of Puffs of Rescue Medication Per Day Over 24 Weeks Change in mean number of puffs/day 0-0.5-1 -1.5-2 -2.5-3 63% relative reduction (n=905) -0.8-0.5 puffs/day (p<0.001) -1.3 42% relative reduction (n=410) -1.4-0.6 puffs/day (p=0.022) -2.0 28% relative reduction (n=432) -2.1-0.6 puffs/day (p=ns) -2.7 TIO 18mcg Anoro Ellipta 55/22mcg SGRQ Both Anoro Ellipta and tiotropium demonstrated improvements in total SGRQ score from baseline (>4 unit change). In two studies Anoro Ellipta improved SGRQ score by -6.87 and -9.95 units from baseline. The differences between Anoro Ellipta and tiotropium were not statistically significant (p=ns) (Decramer et al. 2014). In one study, Anoro Ellipta improved SGRQ score by -7.27 units from baseline, and improved SGRQ score by 2.10 units compared to tiotropium (P=0.006) (Maleki - Yazdi MR et al. 2014) TDI Both Anoro Ellipta and tiotropium demonstrated clinically meaningful improvements in TDI focal scores of greater than 1 unit (Mahler et al. 2005) Anoro Ellipta improved TDI focal score by 2.3 units from baseline in 2 studies. Comparisons between Anoro Ellipta and tiotropium were not statistically significant (p=ns) (Decramer et al. 2014) 9

Placebo Study Anoro Ellipta vs. Placebo Primary Endpoints Treatment with Anoro Ellipta resulted in a 167ml improvement in the primary efficacy endpoint of trough FEV 1 versus placebo (p<0.001) at day 169. An improvement 100ml is considered clinically meaningful (Donohue et al. 2005, COPD; Donohue et al. 2013, Resp Med) (Figure 5) Figure 5 - Change from Baseline in Trough FEV 1 at Day 169 180 LS mean change from baseline (ml) 160 140 120 100 80 60 40 20 0 167ml (p<0.001) 4ml 171ml Placebo (n=280) Anoro Ellipta 55/22mcg (n=413) Secondary Endpoints Anoro Ellipta demonstrated a statistical and clinically meaningful improvement in TDI focal score of 1.2 units versus placebo (p<0.001) (Donohue et al. 2013, Resp Med) Anoro Ellipta improved weighted mean FEV 1 over 0-6 hours versus placebo, an improvement of 242ml (p=ns*). (Donohue et al. 2013, Resp Med). Other Analyses Anoro Ellipta demonstrated a clinically meaningful improvement of -5.51 units in SGRQ total score compared to placebo (p=ns*). (Donohue et al. 2013) Anoro Ellipta studies were specifically designed for breathless patients (MRC 3) and were not designed to evaluate the effect of treatments on COPD exacerbations. Patients were withdrawn from the study if an exacerbation occurred. *p=non significant due to statistical hierarchy 10

Anoro Ellipta showed a significant improvement of 112ml in FEV 1 at 15 minutes vs. Placebo Figure 6 Change from baseline in FEV 1 at 15 mins Change from baseline in FEV 1 at 15 min post dose (ml) 110 90 70 50 30 10-10 Anoro 55/22mcg (N=413) 112ml (p<0.001) Placebo (N=280) Summary of Efficacy and Patient Reported Outcomes Table 4 Summary of Clinical Endpoints Treatment difference 1 (95% confidence intervals, p-value) Treatment comparisons with ANORO Ellipta 55/22mcg Trough FEV 1 (ml) TDI Focal Score SGRQ Total Score Use of Rescue medication 3 Anoro Ellipta (N = 413) versus Placebo (N = 280) 167 (128, 207) p<0.001 1.2 (0.7,1.7) p<0.001-5.51 (-7.88, -3.13) p=ns* -0.8 (-1.3, -0.3) p=ns* Anoro Ellipta (N = 454) versus tiotropium 18mcg (N = 451) (Maleki-Yazdi MR et al. 2014) 112 (81, 144) p<0.001 n/e -2.10 (-3.61, -0.59) p=0.006-0.5 (-0.7, -0.2) p<0.001 Anoro Ellipta (N = 207) versus tiotropium 18mcg (N = 203) (Anzueto et al. 2013, Decramer et al. 2014) Anoro Ellipta (N = 217) versus tiotropium 18mcg (N = 215) (Decramer et al. 2014) 90 (39, 141) p<0.001 60 (10, 109) p=0.018* 0.1 2 (-0.4, 0.5) p=0.817 0.75 (-2.12, 3.63) p=0.607-0.17 (-2.85, 2.52) p=0.904-0.7 (-1.2, -0.1) p=0.022-0.6 (-1.2, 0.0) p=0.069 N=number in Intent-to-treat population, mcg = micrograms, n/e = not evaluated 1) Least squares mean 2) Pooled data from two active comparator studies (Anzueto, 2013, Decramer,2013) 3) Difference in the mean number of puffs per day over Weeks 1-24. *p=non significant due to statistical hierarchy Details of the blinding process for all tiotropium comparator studies discussed in this document can be found on page 474 in Decramer M et al. Lancet Respir Med 2014; 2:472-486 11

Safety (Anoro Ellipta Summary of Product Characteristics 2017) The safety profile of Anoro Ellipta is based on safety experience with umeclidinium/vilanterol and the individual components from the clinical development program comprising of 6,855 patients with COPD. This includes 2,354 patients who received umeclidinium/vilanterol once daily in the phase III clinical studies, of whom 1,296 patients received the recommended dose of 55/22 micrograms in 24-week studies, 832 patients received a higher dose of 113/22 micrograms (unlicensed dose within the UK) in 24 week studies and 226 patients received 113/22 micrograms in a 12 month study. Table 6 Summary of Adverse Events Frequency of adverse event Common adverse reactions ( 1/100 to <1/10) Other important adverse reactions include: Frequency uncommon ( 1/1,000 to <1/100) Frequency rare ( 1/10,000 to <1/1,000) Adverse Event Urinary tract infection, sinusitis, nasopharyngitis, pharyngitis, upper respiratory tract infection, headache, cough, oropharyngeal pain, constipation and dry mouth. Atrial fibrillation, supraventricular tachycardia, rhythm idioventricular, tachycardia, supraventricular extrasystoles, palpitations, and hypersensitivity reactions including rash. Anaphylaxis, angioedema, and urticaria. Glaucoma, vision blurred, intraocular pressure increased and paradoxical bronchospasm. No dose adjustment for Anoro Ellipta is needed in: patients with renal impairment patients with mild or moderate hepatic impairment patients aged over 65 years (Please consult the full Summary of Product Characteristics (SmPC) for other adverse reactions) 12

Cardiovascular Effects Cardiovascular effects, such as cardiac arrhythmias, may be seen after the administration of muscarinic receptor antagonists and sympathomimetic agents, including umeclidinium/ vilanterol. Therefore, Anoro Ellipta should be used with caution in patients with severe cardiovascular disease. Additional Points to Note As with other inhalation therapies, administration of Anoro Ellipta may produce paradoxical bronchospasm. Treatment with Anoro Ellipta should be discontinued immediately if paradoxical bronchospasm occurs. As with other antimuscarinics Anoro Ellipta should be used with caution in patients with urinary retention or with narrow-angle glaucoma. Anoro Ellipta is for the maintenance treatment of COPD. It should not be used for the relief of acute symptoms. Acute symptoms should be treated with an inhaled short-acting bronchodilator. Anoro Ellipta should not be used in patients for the treatment of asthma. 13

National Health Technology Assessment National Institute for Health and Care Excellence (NICE) (www.nice.org.uk) The National Institute for Health and Care Excellence (NICE) have considered Anoro for the treatment of COPD against their selection criteria for technology appraisals and have decided not to progress this beyond topic selection. Therefore Anoro will not be subject to a NICE single technology appraisal. Scottish Medicines Consortium (SMC) (www.scottishmedicines.org.uk) SMC advice (February 2015) for Anoro in COPD is as follows: Advice: following a re-submission. Umeclidinium/vilanterol (Anoro ) is accepted for use within NHS Scotland. Indication under review: As a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease. Two randomised controlled studies demonstrated that after 24 weeks of treatment, umeclidinium/vilanterol significantly improved lung function compared with an inhaled long-acting muscarinic antagonist in patients with moderate to very severe COPD. Indirect comparisons demonstrated comparable efficacy with other combinations of long acting muscarinic antagonist plus long acting beta agonist. All Wales Medicines Strategy Group (AWMSG): (www.awmsg.org) AWMSG recommendation (February 2015) for Anoro in COPD is as follows: Umeclidinium/vilanterol (as trifenatate) (Anoro Ellipta ) is recommended as an option for use within NHS Wales as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). 14

Administration One inhalation of Anoro Ellipta 55/22mcg once daily for adults with COPD. Anoro Ellipta should be administered at the same time of the day, each day (morning or evening). If a dose is missed the next dose should be taken at the usual time the next day. Figure 8 - Anoro Ellipta Inhaler 29 30 29 29 Open Inhale Close See SmPC or PIL for further information on inhaler technique. The Ellipta inhaler consists of two aluminium foil laminate strips of regularly distributed blisters, each containing the active drug. Every time the inhaler cover is opened one dose of medicine is prepared. The Ellipta inhaler has a dose counter which shows how many doses of medicine are left in the inhaler. Before the inhaler has been used, it shows exactly 30 doses It counts down by 1 each time the cover is opened When fewer than 10 doses are left, half of the dose counter shows red After the last dose has been inhaled, the counter shows 0 Anoro Ellipta has a 2 year shelf life. Do not store above 30 C. If stored in a refrigerator allow the inhaler to return to room temperature for at least an hour before use. Keep the inhaler inside the sealed tray to protect from moisture and only remove immediately before first use. To be used within 6 weeks of first opening of the tray. Write the date the inhaler should be discarded on the label in the space provided. The date should be added as soon as the inhaler has been removed from the tray. 15

Patient Experience Ease of use of the Ellipta inhaler in COPD patients has been tested. Following initial instruction on how to use the inhaler in two such studies, 98% (n=618) of COPD patients used the Ellipta inhaler correctly at day one. Correct inhaler use was re-assessed after 6 weeks of treatment using the demonstration inhaler, without further verbal instruction or demonstration to the patient; 99% (n=580) of subjects still used their Ellipta inhaler correctly. After 6 weeks of treatment, ease of use was assessed and 98-99% of patients found their Ellipta inhaler easy or very easy to use (Riley et al. 2013). In 2 six month studies (n=1020) 63% patients preferred the Ellipta inhaler to the HandiHaler device on the basis of time to use and the number of steps required. (Riley et al. 2013) COPD patients across a range of severities were able to generate a peak inspiratory flow rate (PIFR) of greater than 43 L/min through the Ellipta device (Prime et al. 2012). The inhalation profiles generated by a range of COPD patients (42-129ml/min) were then replicated using an electronic lung (GSK) breathing simulator. In vitro, drug delivery to the electronic lung was consistent across the full range of PIFRs, 42-129ml/min. (Hamilton et al. 2012) Adherence Once daily treatment has the potential to improve adherence and simplify treatment in chronic diseases such as COPD, however there is no current data to directly support increased adherence with Anoro Ellipta compared to other (LAMA/LABA combinations in COPD). There is some evidence in the LAMA class that a once daily COPD inhaler therapy may improve compliance. In a retrospective analysis of 50,076 patients in the US, looking specifically at adherence, COPD patients who were initiated on treatment with once-daily dosing (tiotropium; n=3,678) had significantly higher adherence over 12 months than patients initiated on treatments which were dosed twice a day (e.g. Seretide [fluticasone propionate/ salmeterol] and Symbicort; n=25,011); (43.3% vs 37.0%, p<0.0001). (Toy et al. 2011) Patient preference is an important factor when choosing an inhaler device for COPD. in a recently published retrospective observational study of 2138 patients, 44.7% preferred a once daily schedule. (Price et al. 2013) 16

Cost The 30-day cost of Anoro Ellipta 55/22mcg is 32.50. Data to calculate the budget impact of Anoro Ellipta, specific to a locality, can be provided by your local GSK account manager and health outcomes specialists if required. Information sources Should you require further medical information on Anoro Ellipta please contact the GSK medical information team via our customer contact centre: By phone on 0800 221 441. Lines are open from Monday-Friday 8am 6pm. Outside these hours and on bank holidays, an answer phone service is available. By email at customercontactuk@gsk.com www.anoro.co.uk Your local GSK account team of therapy, medical and health outcomes specialists will also be able to support you if required. 17

References Anoro Ellipta SmPC de Oliveira, J. Clinical significance in COPD patients followed in a real practice. Multidiscip. Respir.Med., 8, (1) 43 available from: PM:23806051, 2013. Decramer, M. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomized controlled trials. Lancet Resir Med, 2, (6) 472-486. 2014. Department of Health. Consultation on a strategy for services for chronic obstructive pulmonary disease (COPD) in England. 2010. Department of Health. An outcomes strategy for people with chronic obstructive pulmonary disease (COPD) and asthma in England. 2011. Donohue, J. Minimal clinically important differences in COPD lung function. COPD., 2, (1) 111-124 available from: PM:17136971. 2005. Donohue, J. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25mcg in COPD. Respir.Med., 107, (10) 1538-1546 available from: PM:23830094. 2013. Fletcher, M. COPD uncovered: an international survey on the impact of chronic obstructive pulmonary disease [COPD] on a working age population. BMC. Public Health, 11, 612 available from: PM:21806798. 2011. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Available from: http://goldcopd.org. Hamilton, M. Ex-Vivo Product Performance of Fluticasone Furoate/vilanterol Delivered from a Novel Dry Powder Inhaler, Using the Electronic Lung to Replicate Asthma and COPD Patient Inhalation Profiles. Am J Respir Crit Care Med 185, A2940. 2012. 10-12-2013. Mahler, D. The MCID of the transition dyspnea index is a total score of one unit. COPD., 2, (1) 99-103 available from: PM:17136969. 2005. Maleki-Yazdi MR. Efficacy and safety of uneclidinium/vilanterol 62.5/25mcg and tiotropium 18mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial. Respir Med., 108 (12), 1752-1760/ 2014. Mullerova, H. Prevalence and burden of breathlessness in patients with chronic obstructive pulmonary disease managed in primary care. PLoS.One., 9, (1) e85540 available from: PM:24427316. 2014. NICE. Chronic Obstructive Pulmonary Disease, Management of Chronic Obstructive Pulmonary Disease in Adults in Primary and Secondary Care (partial update). 2010. Continues on next page 18

References Price, D. Characteristics of patients preferring once-daily controller therapy for asthma and COPD: a retrospective cohort study. Prim.Care Respir.J., 22, (2) 161-168 available from: PM:23460035. 2013. Prime D. Comparison Of Inhalation Profiles Through A Novel Dry Powder Inhaler (ndpi) and Lung Function Measurements for Healthy Subjects, Asthma and Chronic Obstructive Pulmonary Disease (COPD) Patients. Am J Respir Crit Care Med 185, A2941. 2012. Punekar, Y. COPD management costs among newly diagnosed COPD patients in the UK primary care setting. Am J Respir Crit Care Med, A4373. 2013. Riley, J. Use of a new dry powder inhaler to deliver umeclidinium/vilanterol in the treatment of COPD. Eur Respir J. 42, 880s. 2013. Thomas, M. No room to breathe: the importance of lung hyperinflation in COPD. Prim.Care Respir.J., 22, (1) 101-111 available from: PM:23429861. 2013. Toy, E. Treatment of COPD: relationships between daily dosing frequency, adherence, resource use, and costs. Respir.Med., 105, (3) 435-441 available from: PM:20880687. 2011. ZuWallack, R. How are you doing? What are you doing? Differing perspectives in the assessment of individuals with COPD. COPD., 4, (3) 293-297 available from: PM:17729076, 2007. http://www.awmsg.org/ (last accessed January 2017) http://www.nice.org.uk/ (last accessed January 2017) http://scottishmedicines.org.uk/home (last accessed January 2017) 19

Anoro Ellipta (umeclidinium bromide/vilanterol [as trifenatate]) Prescribing information (Please consult the full Summary of Product Characteristics (SmPC) before prescribing) Anoro Ellipta (umeclidinium bromide/vilanterol [as trifenatate]) Prescribing information (Please consult the full Summary of Product Characteristics (SmPC) before prescribing) Anoro 55/22mcg (umeclidinium bromide/vilanterol [as trifenatate]) inhalation powder. Each single inhalation provides a delivered dose (the dose leaving the mouthpiece) of 55 micrograms umeclidinium (equivalent to 65 micrograms of umeclidinium bromide) and 22 micrograms of vilanterol (as trifenatate). Indications: Anoro is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage and administration: Inhalation only. One inhalation once daily of Anoro. Contraindications: Hypersensitivity to the active substances or to any of the excipients (lactose monohydrate and magnesium stearate). Precautions: Anoro should not be used in patients with asthma. Treatment with Anoro should be discontinued in the event of paradoxical bronchospasm and alternative therapy initiated if necessary. Cardiovascular effects may be seen after the administration of muscarinic receptor antagonists and sympathomimetics therefore Anoro should be used with caution in patients with severe cardiovascular disease. Anoro should be used with caution in patients with urinary retention, narrow angle glaucoma, convulsive disorders, thyrotoxicosis, hypokalaemia, hyperglycaemia and severe hepatic impairment. No dosage adjustment is required in renal or mild to moderate hepatic impairment. Acute symptoms: Anoro is not indicated for acute episodes of bronchospasm. Warn patients to seek medical advice if short-acting inhaled bronchodilator use increases, a re-evaluation of the patient and of the COPD treatment regimen should be undertaken. Interactions with other medicinal products: Avoid ß-blockers. Caution is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, itraconazole, ritonavir, telithromycin). Anoro should not be used in conjunction with other long-acting ß 2 -adrenergic agonists or medicinal products containing long-acting muscarinic antagonists. Caution is advised with concomitant use with methylxanthine derivatives, steroids or non-potassium-sparing diuretics as it may potentiate possible hypokalaemic effect of ß 2 -adrenergic agonists. Fertility, pregnancy, and breast-feeding: No available data. Balance risks against benefits. Side effects: Common ( 1/100 to <1/10): urinary tract infection, sinusitis, nasopharyngitis, pharyngitis, upper respiratory tract infection, headache, cough, oropharyngeal pain, constipation and dry mouth. Other important side effects include: Uncommon ( 1/1,000 to <1/100) atrial fibrillation, supraventricular tachycardia, rhythm idioventricular, tachycardia, supraventricular extrasystoles, palpitations, and hypersensitivity reactions including rash. Rare ( 1/10,000 to <1/1,000) anaphylaxis, angioedema, and urticaria. Glaucoma, vision blurred, intraocular pressure increased and paradoxical bronchospasm. See SmPC for other adverse reactions. Legal category: POM. Presentation and Basic NHS cost: Anoro Ellipta. 1 inhaler x 30 doses. Anoro Ellipta 55/22mcg - 32.50. Marketing authorisation (MA) no. 55/22mcg 1x30 doses [EU/1/14/898/002]; MA holder: Glaxo Group Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS, UK. Last date of revision: Jan 2017. UK/UCV/0095/15(2). Anoro and Ellipta are registered trademarks of the GlaxoSmithKline group of companies. All rights reserved. Anoro was developed in collaboration with Innoviva Inc. Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to GlaxoSmithKline on 0800 221 441. ANORO ELLIPTA was developed in collaboration with 2017 GSK group of companies. All Rights Reserved.