Evidence Review for Prescribing Clinical Network

Summary page Evidence Review for Prescribing Clinical Network Treatment: LABA/LAMA Combination devices in COPD Anoro Ellipta, Ultibro and Duaklir Genuair Prepared by: Noreen Devanney Topic Submitted by: Noreen Devanney Date: May 2015 How strong is the evidence for claimed efficacy? (Grade A = > 1 RCT or meta-analysis; Potential advantages in terms of: efficacy, compliance, pharmacokinetics, drug interactions and adverse effects? This combination provides an option for improved compliance for patients who are indicated to have treatment with combined LAMA/LABA as per NICE 1 or GOLD 2 Guidelines. Is there a clear place in therapy / treatment pathway? (E.g. patient type / characteristics, and relationship to other therapies) A) as per NICE 1 when ICS are declined or not tolerated B) as per GOLD 2 when is preferred option to LABA/ICS in patients at low risk of exacerbations ( 1 exacerbation per year) but with significant symptoms. Is monitoring for toxicity required? No Is monitoring for efficacy required? Desirable to assess efficacy. Review people with mild or moderate COPD at least once a year and those with very severe COPD at least twice a year. Is dose titration required? No Traffic light status -Green Role of the specialist (if applicable)? Role of GP (if applicable)? Financial implications? Could give possible cost benefit if used where clinically appropriate as per GOLD 2 guidelines, instead of initiating LABA/ICS combination. National Guidance available NICE 1 / GOLD 2 as above Recommendations PCN to assess evidence for Duaklir Genuair, Ultibro and Anoro Ellipta for COPD and to review place in therapy 1. Is there sufficient evidence to include these drugs in local formulary? 2. Is there any preference for one or more of these over the other? 3. If so where should these drugs be positioned in therapy? 1

VERSION CONTROL SHEET Version Date Author Status Comment 1 15/4/14 Noreen Devanney 2

1. Purpose of the Review To review the evidence for currently available LABA/LAMA combination inhalers for COPD. Ultibro, Anoro Ellipta and Duaklir Genuair have all been accepted by the SMC. Ultibro and Anoro Ellipta have been accepted by the All Wales Medicines Group. Duaklir has not yet been reviewed by the All Wales Medicines Group. Ultibro (Indacaterol Maleate 110 micrograms /50micrograms) Ultibro Breezhaler is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Summary of Product Characteristics: https://www.medicines.org.uk/emc/medicine/29533 Review by Scottish Medicines Consortium: http://www.scottishmedicines.org.uk/files/advice/indacaterol_maleate Ultibro_Breezhaler ABBREVI ATED_FINAL_Nov_2013_for_website.pdf NICE Evidence Review: https://www.nice.org.uk/advice/esnm33 Review by All Wales Medicines Group: http://www.awmsg.org/awmsgonline/app/appraisalinfo/1535 Anoro Ellipta (umeclidinium/vilanterol 55/22 micrograms) Anoro Ellipta is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Summary of Product Characteristics: https://www.medicines.org.uk/emc/medicine/28949 Review by Scottish Medicines Consortium: http://www.scottishmedicines.org.uk/files/advice/umeclidinium_vilanterol Anoro RESUBMISSION_ FINAL_Jan_2015_for_website.pdf NICE Evidence Review: https://www.nice.org.uk/advice/esnm49 Review by All Wales Medicines Group: http://www.awmsg.org/awmsgonline/app/appraisalinfo/1038 Duaklir Genuair (aclidinium/formoterol fumarate 340/12) Duaklir Genuair is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Summary of Product Characteristics: https://www.medicines.org.uk/emc/medicine/29652 Review by Scottish Medicines Consortium: http://www.scottishmedicines.org.uk/files/advice/aclidinium_formoterol Duaklir_Genuair FINAL_Ma rch_2015amended_08.04.14_for_website.pdf The following pages have a summary of some of the main points from NICE and SMC Reviews. These should be read in conjunction with the reviews as per above links. All references are included in the reviews. 3

2. Summary of SMC/NICE recommendations to be read in conjunction with full review Anoro Ellipta Ultibro Duaklir Trial participants were all 40 years, ex cigarette smokers 10 pack year smoking history. FEV1/FVC<0.7 and FEV1 70%, moderate to severe COPD. MRC 2.Allowed to continue with inhaled corticosteroids at a stable dose of 1000micrograms fluticasone daily or equivalent and rescue salbutamol. Trial participants were all 40 years, moderate to severe COPD. SPARK trial -75% of patients on ICS. Trial participants were all 40 years, ex cigarette smokers 10 pack year smoking history. FEV1/FVC<0.7 and FEV1 30% and <80%, moderate to severe COPD. Allowed to continue with inhaled corticosteroids, low doses of oral steroids, oxygen therapy, methylxanthines and Effectiveness NICE ESNM49 Nov 14 Statistically significant improvement from baseline in trough FEV1 of 0.090 litres with umeclidinium/vilanterol 62.5/25 micrograms compared with both vilanterol alone and tiotropium 18 micrograms (1 RCT; n=846; 24 weeks). Statistically significant improvement from baseline in trough FEV1 of 0.112 litres with umeclidinium/vilanterol 62.5/25 micrograms compared with tiotropium 18 micrograms (1 RCT; n=905; 24 weeks). Statistically significant improvement from baseline in trough FEV1 with umeclidinium/vilanterol 62.5/ 25 micrograms of 0.052 litres compared with umeclidinium 62.5 micrograms and 0.095 litres compared with vilanterol 25 micrograms (1 RCT; n=1532; 24 weeks). Statistically significant improvement in transition dyspnoea index (TDI) score with umeclidinium/vilanterol compared NICE ESNM33 Dec 14 Overall, indacaterol/glycopyrronium showed a small but statistically significant improvement in lung function (forced expired volume in 1 second [FEV1]) compared with active comparators (tiotropium, seretide,indacaterol glycopyrronium) in people with moderate to very severe COPD. Indacaterol/glycopyrronium also showed small statistically significant improvements in dyspnoea,health status and use of rescue medication compared with active comparators, which were of uncertain clinical benefit. Indacaterol/glycopyrronium statistically significantly reduced the rate of moderate or severe exacerbations compared with glycopyrronium alone in people with severe or very severe COPD.However, the European Medicines Agency considered that the reduction was insufficient to support an indication for reducing exacerbations. salbutamol. SMC No. (1034/15) March 15 In the two 24-week phase III studies, treatment with aclidinium/formoterol 340/12 microgram resulted in statistically significant improvements in FEV1 pre-dose (versus formoterol and placebo) and post-dose (versus aclidinium and placebo). However, the improvement in pre-dose FEV1 for aclidinium/formoterol versus formoterol and improvements in TDI versus aclidinium and versus formoterol were not considered to be clinically significant. The European Medicines Agency (EMA) commented that post hoc responder analysis for clinically meaningful effect on FEV1 (as well as symptomatic endpoints) provides reassurance that aclidinium contributes to the overall effect of the aclidinium/formoterol combination. There were statistically significant differences in exacerbation rates for aclidinium/formoterol 340/12 versus placebo in the 24-week studies but not 4

with placebo of 1.2 units. No statistically significant difference in TDI score compared with umeclidinium or vilanterol monotherapy (1 RCT; n=1532; 24 weeks). SMC No. (978/14) July14. The submitting company did not present a sufficiently robust clinical and economic analysis to gain acceptance by SMC. SMC No. (978/14) Jan 15 SMC Re-submission 9/1/15 included additional LAMA and LABA comparators Two randomised controlled studies demonstrated that after 24 weeks of treatment, umeclidinium/vilanterol significantly improved lung function compared with an inhaled longacting 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. SMC concluded umeclidinium /vilanterol is cost saving compared to tiotropium monotherapy, tiotropium /indacaterol tiotropium/salmeterol and tiotropium/formoterol. The European Medicines Agency noted that, although the differences between treatments were often not large enough to be clinically relevant in the total population, responder analyses have shown that differences can be important to individual patients. in the extension study. However, the reduction in exacerbations (by EXACT criteria) relative to placebo of 0.33/patient/year for aclidinium/formoterol 340/12 in the 24- week studies are unlikely to be clinically significant. Safety Anoro Ellipta Ultibro Duaklir NICE ESNM49 Nov 14 The summary of product characteristics(spc) states that NICE ESNM33 Dec 14 The summary of product characteristics reports that up to15 months' SMC The adverse effect profiles of the constituents (aclidinium and formoterol) 5

cardiovascular effects, such as cardiac arrhythmias, atrial fibrillation and tachycardia, may be seen after the administration of muscarinic receptor antagonists and sympathomimetics, including umeclidinium/vilanterol. The SPC states that umeclidinium/vilanterol should be used with caution in people with severe cardiovascular disease. Cardiovascular effects, such as cardiac arrhythmias e.g. atrial fibrillation and tachycardia, may be seen after the administration of muscarinic receptor antagonists and sympathomimetics, including umeclidinium/vilanterol. Patients with clinically significant uncontrolled cardiovascular disease were excluded from clinical studies. Therefore, umeclidinium/vilanterol should be used with caution in patients with severe cardiovascular disease. In addition, it states that consistent with its antimuscarinic activity, umeclidinium/vilanterol should be used with caution in people with urinary retention or with narrow-angle glaucoma. The SPC lists urinary tract infection, sinusitis, nasopharyngitis, pharyngitis, upper respiratory tract infection, headache, cough, oropharyngeal pain, constipation and dry mouth as common adverse events (frequency 1 in 10 to 1 in 100 people). treatment with indacaterol/glycopyrronium showed similar adverse reactions to those observed when people were treated with each drug individually. In a 52-week safety study, the overall incidence of adverse events was similar between placebo and indacaterol/ glycopyrronium (p value not reported). Compared with established drugs such as formoterol, salmeterol and tiotropium, the long-term safety of indacaterol and glycopyrronium (alone or in combination) is unclear. A 52-week study that is currently in progress may provide better evidence on the comparative safety and efficacy of LABA/ LAMA and inhaled corticosteroid (ICS)/LABA. The SPC States that patients with unstable ischaemic heart disease, left ventricular failure, history of myocardial infarction, arrhythmia (excluding chronic stable atrial fibrillation), a history of long QT syndrome or whose QTc (Fridericia method) was prolonged (>450 ms) were excluded from the clinical trials, and therefore there is no experience in these patient groups. Ultibro Breezhaler should be used with caution in these patient groups are well characterised and no new issues became evident in the phase III studies. In the placebo-controlled phase III studies, any major adverse cardiac event occurred in 0.8% (6/720) of patients treated with aclidinium/formoterol 340/12 and nonfatal myocardial infarction occurred in 0.6% (4/720) of patients. Event rates were generally similar for the other treatment groups and the majority of patients who experienced cardiac events had pre-existing cardiovascular risk factors. The proportion of patients with cerebrovascular events was <1% in all treatment groups, there were no notable differences between treatments and the majority of events occurred in the 52-week studies The SPC states patients with a myocardial infarction during the previous 6 months, unstable angina, newly diagnosed arrhythmia within the previous 3 months, QTc (Bazett's method) above 470 msec, or hospitalisation within the previous 12 months for heart failure functional classes III and IV as per the New York Heart Association were excluded from the clinical studies, therefore Duaklir Genuair should be used with caution in these patients groups 6

Patient Factors Anoro Ellipta Ultibro Duaklir Genuair NICE ESNM49 Nov 14 Umeclidinium/vilanterol is available as a dry powder multi-dose inhaler, which may be more convenient for some people than using 2 separate inhalers (LAMA plus LABA as single component inhalers). Individual patient assessment is needed when choosing an inhaler device. NICE ESNM33 Dec 14 People prescribed a LABA and a LAMA may find it easier to use a combination inhaler, rather than 2 single-component inhalers. NICE advises that treatment and care should take into account a person's needs and preferences. Once daily dosing. Ellipta dry powder device 6 week shelf life when opened SPC updated April 15 patient to write discard date on label. Once daily dosing Breezhaler dry powder device. 30 day shelf life when opened Twice Daily dosing Genuair dry powder device Each inhaler should be disposed of after 30 days of use. Resource Implications Anoro Ellipta Ultibro Duaklir Genuair The cost of Anoro Ellipta is 32.50 for 30 days' supply. The cost of Ultibro is 35.75 for 30 days supply The cost of Duaklir is 32.50 for 30 days supply Budget Impact (SMC) The submitting company estimated there to be 955 patients eligible for treatment with umeclidinium/vilanterol in year 1, rising to 5,014 in year 5, with an estimated uptake rate of 3% and 15% in years 1 and 5 respectively. The submitting company estimated the gross medicines budget impact to be 55k in year 1 and 288k in year 5. As other drugs were assumed to be displaced, the net medicines budget impact was Budget Impact (SMC)-not available Budget Impact (SMC) The submitting company estimated there to be 105,000 patients eligible for treatment with aclidinium/formoterol in year 1 and 111,180 patients in year 5. Treatment uptake was estimated at 2% in year 1, rising to 14% in year 5. The discontinuation rate was estimated to be 0%. This resulted in 2,100 patients assumed to be treated in year 1 rising to 15,009 patients in year 5. The submitting company estimated the 7

estimated to be savings of 50k in year 1 and savings of 260k in year 5. The net budget impact estimates were calculated assuming displacement of a weighted average cost of tiotropium plus a LAMA, as per the analysis presented within the health economic model. (misprint? LABA instead of LAMA?) gross medicines budget impact to be 831k in year 1 and 6m in year 5. As other medicines were assumed to be displaced, the net medicines budget impact was estimated to be a saving of 655k in year 1 rising to a saving of 4.8m in year 5. Summary (NICE/ SMC) NICE Anoro Ellipta is a combination inhaler containing umeclidinium bromide (a longacting muscarinic antagonist [LAMA]) and vilanterol (a long-acting beta2 agonist [LABA]). Umeclidinium/vilanterol is the first LAMA/LABA combination inhaler available in the UK for the treatment of COPD. It is licensed as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. The combination inhaler has been compared in randomised controlled trials (RCTs) with its individual components, tiotropium monotherapy and placebo. Studies suggest that there are benefits for forced expired volume in 1 second (FEV1) with the umeclidinium/vilanterol combination inhaler. However, the clinical relevance of these benefits is unclear. There is limited evidence on patientorientated outcomes such as shortness of breath, quality of life outcomes or exacerbation rates. Copyright NICE Indacaterol/glycopyrronium (Ultibro Breezhaler 85/43 micrograms) is the first long-acting beta2 agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination inhaler to be approved for chronic obstructive pulmonary disease (COPD). It is licensed as a maintenance bronchodilator treatment to relieve symptoms in adults with COPD. Although some small statistically significant improvements in lung function, dyspnoea (breathlessness), health status and use of rescue medication were seen with indacaterol/glycopyrronium compared with active comparators, the clinical importance of these differences is unclear and indacaterol/glycopyrronium's place in therapy is currently difficult to assess. NICE Not reviewed SMC Evaluation of Indirect Comparison to other LABA/LAMAs There are no direct comparative data versus combinations of LABA plus LAMA either delivered in one inhaler or as separate inhalers. Consequently, the submitting company performed a network meta-analysis (NMA) to evaluate the relative efficacy and safety of the combination inhalers, aclidinium/formoterol 340/12 microgram, umeclidinium/vilanterol 55/22 microgram, indacaterol/glycopyrronium 85/43 microgram and tiotropium 18 microgram + formoterol 10 microgram (delivered as separate inhalers). The submitting company concluded that aclidinium/formoterol was shown to be broadly comparable to other LAMA/LABA combinations in terms of bronchodilation, breathlessness, health status and safety. There was no comparison with salmeterol + tiotropium (or indacaterol + tiotropium), delivered as separate inhalers, as no studies met the inclusion criteria. However, the comparable efficacy of 8

Summary (SMC) ADVICE: following a re-submission umeclidinium/vilanterol (Anoro Ellipta ) 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. ADVICE: following an abbreviated submission indacaterol maleate plus glycopyrronium bromide inhalation powder hard capsules (Ultibro Breezhaler ) is accepted for use within NHS Scotland. Indication under review: maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). For patients in whom the combination of indacaterol maleate and glycopyrronium bromide is an appropriate choice of therapy, Ultibro Breezhaler provides the two ingredients in a single hard capsule at a lower cost than the individual components. aclidinium/formoterol with LABA plus LAMA comparators was accepted. Clinical experts consulted by SMC confirmed that aclidinium/formoterol would be used in patients whose COPD is inadequately controlled with a LAMA or LABA separately, and its us would avoid the requirement for two separate inhalers. ADVICE: following a full submission aclidinium/formoterol fumarate dihydrate (Duaklir Genuair ) is accepted for use within NHS Scotland. Indication under review: Maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease. In two 24-week comparator- and placebo-controlled phase III studies, treatment with aclidinium/formoterol 340/12 microgram resulted in statistically significant improvements in FEV1 % predicted pre-dose (versus a LABA) and post-dose (versus a LAMA). 9

3. National and local guidance 3.1 National guidance: (NICE 1 and GOLD 2 guidance for COPD) Long acting beta 2 agonists (LABA) and long acting anti- muscarinic antagonists (LAMA) are included in both guidance recommendations. NICE May 2010 FEV1 50 advice is to use LABA or LAMA if breathless or exacerbations on short acting bronchodilators If still symptomatic or exacerbations then use combination LABA/ICS. If still symptomatic or exacerbations use LAMA + LABA/ICS LABA+ LAMA used if ICS is declined or not tolerated FEV1<50% advice is to use LAMA or LABA/ICS, then LAMA + LABA/ICS if still symptomatic LABA+ LAMA used if ICS is declined or not tolerated GOLD January 2014 advises that combining bronchodilators of different pharmacological classes may improve efficacy and decrease the risk of side effects compared to increasing the dose of a single bronchodilator. GOLD has segmented patients into four groups according to whether the risk of exacerbation is low or high and whether the symptomatic impact of the disease in the patient is low or high in relation to the patients spirometric classification. Patient Characteristic Spirometric Classification Exacerbations Per year A Low risk Less symptoms B Low risk * More symptoms C High Risk Less symptoms D High Risk More symptoms Group A: Low risk of exacerbations and fewer symptoms: first choice - shorting-acting bronchodilators as required or SAMA; second choice - LAMA or LABA or SAMA + SABA Group B: Low risk of exacerbations and more symptoms: first choice - LAMA or LABA second choice -LAMA + LABA Group C: High risk of exacerbations and fewer symptoms: first choice - LAMA or ICS+ LABA second choice - LAMA + LABA Group D: High risk of exacerbations and more symptoms: first choice - LAMA or ICS +LABA; second choice - ICS + LAMA or ICS + LABA +LAMA or ICS +LABA +phosphodiesterase inhibitor or LAMA + LABA or LAMA + phosphodiesterase inhibitor mmrc (Medical research Council ) GOLD1-2 1 0-1 <10 GOLD1-2 1 2 10 GOLD 3-4 2 0-1 <10 GOLD 3-4 2 2 10 CAT (COPD assessment test) 10

*NB Group (B) patients who are at low risk of exacerbations and more symptoms are indicated for LAMA+LABA prior to ICS/LABA. 3.2. Local Surrey Prescribing Clinical Network (PCN) statements (for individual inhalers) NB Subject to ratification by individual CCGs PCN Policy Statement 61-2013 (May 13): Glycopyrronium (Seebri Breezhaler ) to be the first line LAMA of choice on the basis of evidence and cost effectiveness. Aclidinium (Eklira Genuair ) can be considered as an alternative device for patients who are unable to use the Seebri Breezhaler / Spiriva Handihaler devices The network concurred that glycopyrronium and aclidinium are currently a more cost effective treatment option for patients with COPD; noting that tiotropium however currently has more long term safety data. 4.1 Potential Benefits over existing therapy 1. These available combination LAMA/LABA treatments may be an option for patients currently indicated for separate LABA and LAMA inhalers who may benefit from increased bronchodilation and who may not be indicated for LABA/ICS therapy as per NICE 1 or GOLD 2 as per NICE 1 when ICS are declined or not tolerated as per GOLD 2 when is preferred option over LABA/ICS in patients at low risk of exacerbations ( 1 exacerbation per year) but with significant symptoms. 2. Availability of LABA and LAMA in single device may confer improved compliance. 3. Potential cost savings if patients use this compared to currently available LABA and LAMA or LABA/ICS devices. (however please note tiotropium patent expiry 2016) 4. It has been established that there is a risk of pneumonia with inhaled corticosteroids in some patients with COPD. LABA/LAMA therapy may be an option for those patients. For further information: NICE Medicines Evidence Commentary Published: March 2014 COPD: risk of pneumonia with inhaled corticosteroids https://arms.evidence.nhs.uk/resources/hub/1033610/attachment&rct=j&frm=1&q=&esrc=s&sa=u&ei= 0Cw2VeS0A4axsAH2soSwBQ&ved=0CBQQFjAA&usg=AFQjCNERh2FpHVkhOqlObiVCPqRZiialfg 5. There have been recent studies conducted which examine the implications of stepping patients down from triple therapy to LABA/LAMA in severe but stable COPD. There is ongoing assessment to be done on the implications of this. For further information: NEJM Article Re ICS withdrawal: September 2014 Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD Helga Magnussen, et al, September 8, 2014, http://www.ufrgs.br/ppgpneumo/red/download/2014/clube_revista/12-05.pdf 4.2 Potential disadvantages 1. Although studies have shown a statistically significant improvement from baseline in trough FEV1 in all three combinations compared to comparators (LAMA or LABA alone) the clinical relevance of this is unclear as clinically significant patient orientated outcomes were not demonstrated.ie improvements in shortness of breath, quality of life outcomes or exacerbations as recommended by the EMA. 2. Although LABA/LAMA is licensed for dual therapy for patients not on ICS, in the majority of the trials patients remained on ICS. 3. The combinations have not been directly compared to other LAMA/LABA combinations and each other although Astra Zeneca has performed a network meta-analysis of the three combinations which 11

the SMC has accepted. This showed that aclidinium /formoterol 340/12 was broadly comparable to indacaterol/glycopyrronium 85/43, umeclidinium 55/22 in terms of bronchodilation, breathlessness, health status and safety. 4. Compared with established LAMA and LABA inhalers the comparative efficacy and long term safety of the newer agents is unclear, particularly in terms of reducing exacerbations. 5. Anora Ellipta has a six week shelf life and Ultibro has a 30 day shelf life when opened. No special restrictions for Duaklir Genuair. 6. Each of the combinations are black triangle drugs as they contain newly licensed agents. 5. Budgetary Impact 5.1 Cost: Prices from MIMs March 2015. Table 1: Cost of available LABA/LAMAs Drug Dose Regimen Cost per 30 days Cost per year( ) ( ) DuaklirGenuair 1 puff bd 32.50 390 (aclidinium/formoterol340/12) Anoro Ellipta (Umeclidinium/vilanterol 32.50 390 55/22) 1 puff once daily Ultibro (Indacaterol 110/ Glycopyrronium 50)aclidinium/formoterol340/12) 1 puff once daily 36.88 442.56 Table 1: Compared to other bronchodilators Drug Dose Regimen Cost per 30 Cost per year( ) days ( ) Glycopyrronium 44 micrograms 27.50 330 (Seebri Breezhaler ) inhaled once daily Aclidinium 322 micrograms 28.60 343.20 (Eklira Genuair ) inhaled twice daily Tiotropium 18 micrograms 33.50 402 (Spiriva Handihaler )* refill inhaled once daily Tiotropium 2.5 micrograms 33.50 402 (Spiriva Respimat )* 2 puffs od Formoterol Easyhaler 12mcg BD 11.87 142.44 Indacaterol (Onbrez Breezhaler ) 150 or 300 micrograms od 29.26 356 Umeclidinium (Incruse Ellipta ) 55 micrograms od 27.50 330 Table 2: Compared to existing first choice LAMA and LABA individual Drug Dose Regimen Cost per 30 days ( ) Cost per year( ) Spiriva Handihaler +Formoterol Easyhaler As licensed NB Easyhaler is bd 45.37 544.44 Seebri Breezhaler + Formoterol Easyhaler As licensed NB Easyhaler is bd 39.37 472.44 Table 3: compared ICS/LABA combinations licensed in COPD Drug Dose Regimen Cost per 30 days ( ) Cost per year( ) 12

Seretide 500 Accuhaler One puff bd 40.92 491.04 Symbicort 400 Turbohaler One puff bd 38 456 DuorespSpiromax 320/9 One puff bd 29.97 359.64 Fostair 100/6 Two puffs bd 29.32 351.84 Relvar Ellipta 92/22 One puff od 27.80 333.60 Recommendations PCN to assess evidence for Duaklir Genuair, Ultibro and Anoro Ellipta for COPD and to review place in therapy 1. Is there sufficient evidence to include these drugs in local formulary? 2. Is there any preference for one or more of these over the other? 3. If so where should these drugs be positioned in therapy? Appendix 1: Evidence search Search terms used: Resource National Library for Health (NHL) http://www.library.nhs.uk/default.aspx A gateway site with access to other resources such as Reviews (Bandolier, Cochrane, CRD etc), Guidelines (e.g. NICE), Clinical Knowledge Summaries (CKS) and Journals including AMED, British Nursing Index, CINAHL, E- books, EMBASE, HMIC, MEDLINE, My Journals, PsycINFO, PubMed, Databases from Dialog. National Institute of Health and Clinical Excellence (NICE) http://www.nice.org.uk/ NICE produces national guidance in three areas of health: 1. Public health - guidance on the promotion of good health and the prevention of ill health 2. Health technologies - guidance on the use of new and existing medicines, treatments and procedures within the NHS 3. Clinical practice - guidance on the appropriate treatment and care of people with specific diseases and conditions within the NHS. Bandolier http://www.medicine.ox.ac.uk/bandolier/index.html Used in this review? N/A (through NHL) N/A 13

Bandolier is a website about the use of evidence in health, healthcare, and medicine. Information comes from systematic reviews, meta-analyses, randomised trials, and from high quality observational studies. Centre for Reviews and Dissemination http://www.york.ac.uk/inst/crd/ CRD undertakes high quality systematic reviews that evaluate the effects of health and social care interventions and the delivery and organisation of health care. Databases maintained by CRD include Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED), Health Technology Assessment (HTA) Database Scottish Intercollegiate Guidelines Network (SIGN) http://www.sign.ac.uk/ Scottish equivalent of NICE Medical Services Advisory Committee (Australia) http://www.msac.gov.au/internet/msac/publishing.nsf/content/home- The principal role of the Medical Services Advisory Committee (MSAC) is to advise the Australian Minister for Health and Ageing on evidence relating to the safety, effectiveness and cost-effectiveness of new medical technologies and procedures. Canadian Agency for Drugs and Technologies in Health (CADTH) http://www.cadth.ca/index.php/en/home The Canadian Agency for Drugs and Technologies in Health (CADTH) is a national body that provides Canada s federal, provincial and territorial health care decision makers with credible, impartial advice and evidence-based information about the effectiveness and efficiency of drugs and other health technologies. N/A) N/A N/A N/A Study Design Number of participants Results Title: Citation: Author(s): 14

Appendix 2: Grading of evidence Ia: systematic review or meta-analysis of randomised controlled trials Ib: at least one randomised controlled trial IIa: at least one well-designed controlled study without randomisation IIb: at least one well-designed quasi-experimental study, such as a cohort study III: well-designed non-experimental descriptive studies, such as comparative studies, correlation studies, case control studies and case series IV: expert committee reports, opinions and/or clinical experience of respected authorities Appendix 3: References 1. NICE quick reference guidance (CG101) COPD (update): Management of COPD in adults in primary and secondary care; June 2010. http://www.nice.org.uk/nicemedia/live/13029/49399/49399.pdf 2. GOLD Guideline (2011) updated 2013. Global Strategy for the Diagnosis.Management and Prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 updated 2013 www.goldcopd,org 15