BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE

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1 BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE Bulletin 218: September 2015 Review Date: September 2018 LAMA / LABA combination inhalers in COPD- Place in therapy review and choice of therapy JPC Recommendations: The Committee reviewed the place in therapy of LAMA / LABA combination inhalers in the COPD treatment pathway and agreed the following recommendations: 1)Place in therapy A LAMA /LABA combination inhaler is recommended as an alternative to a LABA / ICS inhaler in adult COPD patients where the ICS is contra-indicated / not tolerated or declined in line with NICE Clinical Guideline 101. A LAMA /LABA combination inhaler is recommended in new and existing adult COPD patients who are already prescribed separate LAMA and LABA inhalers. Prior to switching to a combination inhaler, patients should be reviewed to assess if they still require both a LAMA and a LABA component. For patients with an FEV1 50% who have had a partial response to a LAMA inhaler (i.e they remain breathless) after an appropriate trial with the LAMA inhaler and who have satisfactory compliance with therapy and inhaler technique. On initiation of a LAMA /LABA combination inhaler within primary care, all patients should be reviewed after 4 weeks to assess effectiveness. 2)Choice of therapy The Committee agreed to support a joint first line choice of LAMA /LABA inhaler consisting of tiotropium / olodaterol (Spiolto Respimat ) or aclidinium / formoterol (Duaklir Genuair ). These products were chosen as they incorporate the BCCG & LCCG first line choice of individual LAMA (tiotropium) and LABA (formoterol) components. The advantages of each product are specified below and it was noted that it is best to offer a joint first line choice of combination inhaler as this allows for patient preference to be taken into account. Joint First Line choice: Tiotropium* / olodaterol (Spiolto Respimat ) This is a preferred choice LAMA / LABA combination inhaler as: it has demonstrated clinically significant improvements in FEV1 (>100ml) compared to giving the single components; and tiotropium is the LAMA inhaler choice in the Bedfordshire COPD guidelines; it is given once daily; it is a multiple dosing device. OR Aclidinium* / formoterol (Duaklir Genuair ) This is also a preferred choice LAMA / LABA inhaler as it is used twice daily which might suit some patient s symptom pattern and it may be used in patients with renal or hepatic impairment. * Tiotropium and aclidinium should be used with caution in patients with a history of cardiovascular disease. For full prescribing information, including details of this caution, prescribers should refer to individual SPCs and the MHRA drug safety update relating to tiotropium (Feb 2015). ( & _Update 1_.pdf) Page 1 of 32

2 Medicine LAMA / LABA combination inhalers in COPD- Place in therapy review and choice Document status Final approved by the Bedfordshire and Luton Joint Prescribing Committee (JPC), 9 th September 2015 Date of last revision 9 August 2015 Proposed Sector of Primary care / Secondary Care prescribing Introduction Summary Key points Evidence level There are now 4 LAMA/ LABA combination inhalers available for maintenance bronchodilator treatment to relieve the symptoms of COPD in adults. As the current (Chronic Obstructive Pulmonary Disease) COPD guidelines do not specifically list LAMA/ LABA combination inhalers in the current pathway, the JPC is asked to consider their place in therapy (if any) and also product choice between the 4 currently available inhalers should their place in the pathway be agreed. The choice of treatment for a person with COPD depends on drug efficacy, tolerability to treatment, possible adverse events and the suitability of different inhaler devices to the person. All 4 LAMA / LABA combination inhalers have clinical evidence to support their use as a maintenance bronchodilator. However, only tiotropium / olodaterol demonstrated a clinically significant improvement in lung function (>100ml difference in FEV1) above that seen with the single components used alone. It could be argued that clinically meaningful improvement in FEV1 cannot be achieved by adding a second bronchodilator to the first because people with moderate to severe COPD generally have limited airways reversibility. Quality of life and dyspnoea measures were statistically improved for all 4 LAMA/ LABA combination inhalers, but were not found to be clinically significantly better than using monotherapy. Statistical, but not clinically significant reductions in exacerbations were seen with aclidinium / formoterol and glycopyrronium / indacaterol but not umeclidinium / vilanterol. There was a reduction in exacerbations with Tiotropium / olodaterol, but the study was not powered to detect a difference between the combination inhaler and the separate inhalers. Using a LAMA/ LABA combination inhaler as an alternative to a LABA / ICS where the ICS is contra-indicated / not tolerated or declined is in line with NICE Clinical Guideline 101, but would result in additional costs of between and per patient per year. The Bedfordshire COPD audit 2013 found that 2% of COPD patients audited were prescribed a LABA inhaler plus a LAMA inhaler. Where patients are already prescribed separate LAMA and LABA inhalers, use of a LAMA / LABA combination inhaler would be cost saving and more convenient for patients. Using a LAMA / LABA combination inhaler after a LAMA inhaler alone rather than changing to a LABA alone would result in an additional cost of to per patient per year. However, the additional clinical benefits of using a combination inhaler above using monotherapy has not been demonstrated using patient orientated outcomes. Page 2 of 32

3 In patients with renal impairment, aclidinium / formoterol and umeclidinium / vilanterol can be used whereas glycopyrronium / indacaterol should only be used if the benefit outweighs the risks if the patient has severe renal impairment or end-stage renal disease requiring dialysis. Tiotropium / olodaterol should only be used in moderate / severe renal impairment only if benefit outweigh risks. Aclidinium / formoterol can be used in patients with hepatic failure whereas glycopyrronium / indacaterol, umeclidinium / vilanterol and tiotropium / olodaterol should be used in caution in patients with severe hepatic impairment. All 4 LAMA /LABA combination inhalers are used once or twice daily. Tiotropium / olodaterol (Spiolto Respimat ) is an inhalation solution whereas the other 3 LAMA/LABA combination inhalers are dry powder inhaler devices. Glycopyrronium / indacaterol (Ultibro Breezhaler ) is a single dose device and may be unsuitable for patients with manual dexterity problems whereas the Genuair, Ellipta and Respimat devices are multiple dose devices that do not required a capsule to be loaded. Currently, glycopyrronium / indacaterol (Ultibro Breezhaler ) is the most costly product at 447 per year and is more costly than LAMA inhalers alone, LABA inhalers alone, ICS/LABA inhalers and the other 3 LAMA /LABA inhalers aclidinium / formoterol, umeclidinium / vilanterol and tiotropium / olodaterol (these are the same cost at 394 per year.) However, the cost of glycopyrronium / indacaterol (Ultibro Breezhaler ) will be reduced to 394/year from 14th September 2015 according to the manufacturer and so all the current LAMA/LABA inhalers will be the same cost from this date. From this time, the 4 LAMA / LABA inhalers will be less costly than tiotropium, but more costly than other LAMA inhalers alone, LABA inhalers alone, and ICS/LABA inhalers. The intervention Mechanism of action Licensed indication Formulation/Available Products Combined inhaled long-acting muscarinic antagonist (LAMA) and long-acting beta2 agonist (LABA) bronchodilator. All the LAMA/LABA combination inhalers are indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). (1-3, 13) 1. Aclidinium and formoterol fumarate dihydrate (Duaklir Genuair ) 340 micrograms /12 micrograms inhalation powder. 2. Glycopyrronium and indacaterol (Ultibro Breezhaler) 85 micrograms/43 micrograms, inhalation powder hard capsules. Page 3 of 32

4 3. Umeclidinium and vilanterol (Anoro Ellipta ) 55 micrograms/22 micrograms inhalation powder, pre-dispensed. 4. Tiotropium and Olodaterol (Spiolto Respimat ) 2.5 micrograms/2.5 micrograms solution for inhalation. Usual dosage Treatment alternatives/ place in therapy 1. Aclidinium and formoterol fumarate dihydrate (Duaklir Genuair ) 340 micrograms /12 micrograms inhalation powder. One inhalation twice daily. 2. Glycopyrronium and indacaterol (Ultibro Breezhaler) 85 micrograms/43 micrograms, inhalation powder hard capsules. One inhalation once daily. 3. Umeclidinium and vilanterol (Anoro Ellipta ) 55 micrograms/22 micrograms inhalation powder, pre-dispensed. One inhalation once daily. 4. Tiotropium and Olodaterol (Spiolto Respimat ) 2.5 micrograms/2.5 micrograms inhalation solution. Two puffs once daily, at the same time of the day. A combination of a LAMA and a LABA inhaler (although not specifically mentioned as either separate inhalers or a combination inhaler) is listed as an option in the NICE COPD Clinical Guideline 101 treatment pathway (4) when an inhaled corticosteroid (ICS) is declined, contra-indicated or not tolerated and have: Page 4 of 32

5 FEV1 is <50% predicted with exacerbations or persistent breathlessness despite as required use of a short acting beta2 agonist (SABA) or short acting muscarinic antagonist (SAMA) OR FEV1 is 50% predicted with persistent exacerbations or breathlessness despite maintenance treatment with a LABA. Illustrated in figure 1 below. Figure 1: Red arrows illustrate where use of a combination of a LAMA inhaler and a LABA inhaler is recommended within NICE CG 101. The tables below lists alternative inhaled therapy in COPD, please also refer to Appendix 1 (Prices taken from Chemist & Druggist May 2015). Alternative LABAs Drug & Dosage 30 day cost / per patient Annual Cost per patient Easyhaler Formoterol breath-actuated DPI. 12 microgram per dose, 120 dose unit. 1 inhalation twice daily Atimos Modulite Formoterol CFC free MDI. 12 microgram per dose, 100 dose unit. 1 puff twice daily, maximum 4 daily Olodaterol (Striverdi Respimat ) 2.5 micrograms / metered inhalation, 60 dose unit. Two puffs once daily Salmeterol 25micrograms/dose inhaler CFC free (Serevent Evohaler ). Two puffs twice daily Page 5 of 32

6 Salmeterol 50micrograms/dose dry powder inhaler (Serevent Accuhaler ). One blister inhaled twice daily Indacaterol (Onbrez Breezhaler ) 150 or 300 microgram capsules for inhalation in the Breezhaler device. One capsule inhaled once daily Alternative ICS/LABAs Drug & Dosage 30 day cost / per patient Annual Cost per patient Fostair cfc free inhaler (beclometasone dipropionate 100mcg / formoterol fumarate dihydrate 6mcg per dose). 2 puffs twice daily DuoResp Spiromax (budesonide 160mcg/formoterol fumarate dihydrate 4.5mcg dry powder inhaler (equivalent to a metered dose of 200mcg budesonide and 6mcg formoterol fumarate dihydrate) per dose). Two inhalations twice daily DuoResp Spiromax (budesonide 320mcg formoterol fumarate dihydrate 9mcg dry powder inhaler (equivalent to a metered dose of 400mcg budesonide and 12mcg formoterol fumarate dihydrate) per dose). One inhalation twice daily Alternative LAMAs Drug & Dosage 30 day cost / per patient Annual Cost per patient Aclidinium bromide 375 microgram (Eklira Genuair ) - One inhalation twice daily. Glycopyrronium 44 microgram (Seebri Breezhaler ) - Inhale one capsule once daily. Tiotropium 18 microgram Capsules for Spiriva HandiHaler ) - Inhale one capsule once daily. Tiotropium 18 microgram (Spiriva Combopak * Capsules + HandiHaler ) - Inhale one capsule once daily. Tiotropium 2.5 microgram (Spiriva Respimat ) Two puffs once daily. Umeclidinium bromide 55 microgram (Incruse Ellipta ) - One inhalation once daily * based on the use of one Combopak per year and use of refill packs for the remainder of the year. N.B. Doses are for general comparison and do not imply therapeutic equivalence. Page 6 of 32

7 Future alternatives National and local guidance The LAMA/LABA combination inhalers are included within the National Tariff in secondary care. Tiotropium and Olodaterol combination inhaler (Spiolto Respimat ) was launched in August The choice of treatment for a person with COPD depends on drug efficacy, tolerability to treatment, possible adverse events and the suitability of different inhaler devices to the person. The Bedfordshire and Luton COPD Guidelines simplify the NICE guidelines and recommend that a LAMA is used as maintenance therapy in people with stable COPD who remain breathless or have exacerbations, despite use of short-acting bronchodilators as a LAMA can be used in both situations if the FEV1 is above or below 50% in the NICE Clinical Guideline 101 (5). A combination of a LAMA and a LABA inhaler (although not specifically listed as either separate inhalers or a combination inhaler) is listed as an option in the NICE COPD Clinical Guideline 101 treatment pathway (4) when an inhaled corticosteroid (ICS) is declined, contra-indicated or not tolerated and have: FEV1 is <50% predicted with exacerbations or persistent breathlessness despite as required use of a short acting beta2 agonist (SABA) or short acting muscarinic antagonist (SAMA) OR FEV1 is 50% predicted with persistent exacerbations or breathlessness despite maintenance treatment with a LABA. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) produce evidence based guidelines on the management of chronic obstructive lung disease (6). GOLD was launched in 1997 in collaboration with the National Heart, Lung, and Blood Institute, National Institutes of Health, USA, and the World Health Organization. In the GOLD guidelines updated 2015, patients are classified into 4 groups, A,B,C,D, according to their symptoms and risk for exacerbations: Group A patients have few symptoms and a low risk of exacerbations Group B patients have more symptoms but still a low risk of exacerbations. Group C patients have few symptoms but a high risk of exacerbations Group D patients have many symptoms and a high risk of exacerbations. A LAMA inhaler used alone is a recommended first line choice in all patient groups A to D. A combination of a LAMA inhaler plus a LABA inhaler (although not specifically listed as either separate inhalers or a combination inhaler) is recommended as an alternative choice for patients in B, C, and D categories. The Bedfordshire COPD Guidelines include the following relevant inhalers: LABA inhalers Formoterol MDI (+/- spacer) 12mcg/dose Second Choice: Formoterol breath actuated Easyhaler (Nb. This is now first line choice on the BCCG Medicines Formulary) Page 7 of 32

8 Third Choice: Salmeterol MDI (+/- spacer) LAMA inhaler Tiotropium bromide 18mcg inhalation powder, hard capsule LAMA (Second Choices) Inhaled aclidinium bromide (Eklira Genuair ) 400 micrograms one inhalation twice daily or inhaled glycopyrronium bromide (Seebri Breezhaler ) 50 micrograms one capsule inhaled once daily or inhaled tiotropium (Spiriva Respimat 2.5 micrograms per puff)- two puffs once daily Evidence for use (taken from NICE Evidence summary: new medicines (7-9) and Reference 14) ICS/LABA inhalers Fostair 100/6 MDI, 2 puffs twice daily +/- spacer or Symbicort 400/12 Turbohaler, 1 puff twice daily or Symbicort 200/6 Turbohaler, 2 puffs twice daily Nb. The Bedfordshire Clinical Commissioning Group (BCCG) Medicines Formulary also includes DuoResp Spiromax budesonide 160mcg/formoterol fumarate dihydrate 4.5mcg dry powder inhaler (equivalent to a metered dose of 200mcg budesonide and 6mcg formoterol fumarate dihydrate) per dose and DuoResp Spiromax budesonide 320mcg formoterol fumarate dihydrate 9mcg dry powder inhaler (equivalent to a metered dose of 400mcg budesonide and 12mcg formoterol fumarate dihydrate) per dose Second Choice: Seretide 500 Accuhaler 1 inhalation twice daily. The table in Appendix 2 summarises the outcomes reported in trials for the three LAMA /LABA combination inhalers. Aclidinium and formoterol fumarate dihydrate (Duaklir Genuair ) 340 micrograms /12 micrograms inhalation powder. In a pooled analysis of 2 RCTs (n=1729 and n=1692) aclidinium/formoterol statistically significantly improved: 1 hour post-dose FEV1 more than aclidinium monotherapy (difference 118 ml, p<0.0001) and placebo (difference 293 ml, p<0.0001) trough FEV1 more than formoterol monotherapy (difference 68 ml, p<0.0001: not clinically important) and placebo (difference 138 ml, p<0.0001) breathlessness compared with placebo (difference 1.43 units, p<0.0001) and aclidinium (difference 0.44 units, p=0.016: not clinically important) and formoterol monotherapy (difference 0.47 units, p=0.009: not clinically important) exacerbations of any severity compared with placebo (difference 0.33 exacerbations per patient/year, p=0.01: clinical importance unclear). There are no published studies comparing the efficacy and safety of aclidinium/formoterol with other single or combination treatments. Glycopyrronium and indacaterol (Ultibro Breezhaler) 85 micrograms/43 micrograms, inhalation powder hard capsules. Indacaterol/glycopyrronium statistically significantly reduced the rate of moderate or severe exacerbations compared with Page 8 of 32

9 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. Overall, indacaterol/glycopyrronium showed a small but statistically significant improvement in lung function (forced expired volume in 1 second [FEV1]) compared with active comparators 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. 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. Umeclidinium and vilanterol (Anoro Ellipta ) 55 micrograms/22 micrograms inhalation powder, pre-dispensed. Statistically significant improvement from baseline in trough FEV1 of 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 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 litres compared with umeclidinium 62.5 micrograms and 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 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). Tiotropium and Olodaterol (Spiolto Respimat ) 2.5 micrograms/2.5 micrograms inhalation solution. (14) Two replicate, randomised, double-blind, parallel-group, activecontrolled phase III studies (TOnado 1 and TOnado 2) assessed the efficacy and safety of treatment with tiotropium and olodaterol in a once-daily fixed-dose combination (FDC) versus monotherapy components in patients with Global initiative for chronic Obstructive Lung Disease (GOLD) stage 2 4 [moderate to very-severe] chronic obstructive pulmonary disease (COPD). Page 9 of 32

10 The studies included 5,162 eligible patients (n=2,624 in TOnado 1 and n=2,538 in TOnado 2) who were randomised in a 1:1 ratio to tiotropium and olodaterol FDC 5/5mcg (T+O 5/5mcg) or tiotropium and olodaterol FDC 2.5/5mcg (T+O 2.5/5mcg) or the individual monotherapies (olodaterol 5mcg, tiotropium 2.5mcg or tiotropium 5mcg), all administered via the Respimat inhaler for 52 weeks. Baseline demographics were generally similar across treatment groups. The primary efficacy end points were forced expiratory volume in one second (FEV1) area under the curve from 0 to 3 hours (AUC0-3h) response in each individual study, trough FEV1 response (i.e. change from baseline) in each individual study and St George s Respiratory Questionnaire (SGRQ) total score (pre-specified to be analysed after combining the data from the two studies), evaluated after 24 weeks.14 Safety end points included adverse events (AEs), which were recorded throughout the 52-week study regardless of causality. Aggregated safety end points reflecting cardiac safety as well as major adverse cardiac events (MACE) were compared across all treatment groups and in a sub-group of patients with a history of cardiac disease. Data from the phase III TOnado studies demonstrated that T+O 5/5mcg significantly improved FEV1 AUC0-3h and trough FEV1 responses and SGRQ total score versus the monotherapy components in both studies. Primary endpoints results Table. Results for FEV1 AUC0-3h response (ml) and trough FEV1 response (ml) at 24 weeks Olodaterol 5mcg Tiotropium 5mcg T+O 5/5mcg FEV 1 AUC 0-3h response TOnado TOnado Trough FEV 1 responses TOnado TOnado Improvements in adjusted mean FEV1 AUC0-3h and adjusted mean trough FEV1 with T+O 5/5mcg compared to the individual components in the individual studies and the combined analysis were statistically significant (FEV1 AUC0-3: treatment difference of 0.123L vs. olodaterol 5mcg and 0.117L vs. tiotropium 5mcg in TONADO 1; 0.132L vs. olodaterol 5mcg and 0.103L vs. tiotropium 5mcg in TONADO 2 [all p<0.0001]. Trough FEV1: 0.082L vs. olodaterol 5mcg and 0.071L vs. tiotropium 5mcg in TONADO 1 [both p<0.0001]; 0.088L vs. olodaterol 5mcg and 0.050L vs. tiotropium 5mcg in TONADO 2 [p< and p= respectively]). Similar results were apparent during post-hoc investigation of maintenance naïve patients, patients who had previously received ICS and patients stratified by GOLD stage. Page 10 of 32

11 After 24 weeks, the pre-specified analysis of the adjusted mean SGRQ total score revealed statistically significant improvements for T+O 5/5mcg over corresponding individual components (versus olodaterol 5mcg: (0.553), p<0.01; versus tiotropium 5mcg: (0.551), p<0.05). Improvements in SGRQ that exceeded the minimum clinically important difference of 4 units for this measure were seen in all treatment arms, but the difference between the fixed-dose combinations and the individual components did not meet this threshold. The increases in responder rate for T+O 5/5mcg over its individual components were statistically significant (nominal p<0.05). Table. Adjusted mean SGRQ total score (mean ± SE) and SGRQ responders [n (%)] after 24 weeks for the combined data set Olodaterol 5mcg n=954 Tiotropium 5mcg n=955 T+O 5/5mcg n=979 SGRQ total scores 38.4 ± ± ± 0.4 SGRQ responders* 427 (44.8) 465 (48.7) 563 (57.5) * Responders were defined as a decrease in SGRQ total score 4.0 units which is the minimum clinically important difference Key secondary endpoints results Transition dyspnoea index (TDI) (pooled-analysis) T+O 5/5mcg significantly improved Mahler TDI focal score at 24 weeks compared to the individual components (adjusted mean difference of vs. olodaterol 5mcg, p<0.005; adjusted mean difference of vs. tiotropium 5mcg, p<0.05). Safety (taken from NICE Evidence summary: new medicines (7-9), SPCs and refs 13,14) Exacerbations (pooled analysis) T+O 5/5mcg showed a trend towards improvement in exacerbations compared to the individual components (vs. olodaterol 5mcg: Risk Ratio (RR) , p=0.0332; vs. tiotropium 5mcg: RR , p=0.3631). Please note that the trial was not powered to detect differences in this endpoint. Rescue medication Tiotropium+olodaterol provided reductions in adjusted weekly mean daily (24-h) rescue medication use compared to the monotherapy components throughout the 52-week treatment period, but the clinical significance is unclear (reduction of less than 1 puff / day weekly mean daily rescue medication use.) Aclidinium and formoterol fumarate dihydrate (Duaklir Genuair ) 340 micrograms /12 micrograms inhalation powder. According to the European Public Assessment Report for aclidinium/ formoterol, the number of drug-related adverse events was generally low in the studies and did not give rise to any major safety concerns. Page 11 of 32

12 Page 12 of 32 The SPC states that adverse effects associated with aclidinium/formoterol are similar to those of the individual components. The adverse effects most frequently reported with the combination are nasopharyngitis (7.9%) and headache (6.8%). As for other LAMA/ LABA combination inhalers, warnings about cardiovascular risk are included in the SPC. Glycopyrronium and indacaterol (Ultibro Breezhaler) 85 micrograms/43 micrograms, inhalation powder hard capsules. The SPC reports that up to 15 months' 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 LAMA/ LABA and inhaled corticosteroid (ICS)/LABA. Although the combination inhaler delivers the same clinically effective dose of indacaterol as the singlecomponent inhaler, the stated doses are different which may confuse prescribers and patients. Umeclidinium and vilanterol (Anoro Ellipta ) 55 micrograms/22 micrograms inhalation powder, pre-dispensed. The SPC states that the most frequently reported adverse reaction with umeclidinium/vilanterol was nasopharyngitis (9%). 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. Consistent with its antimuscarinic activity, umeclidinium/vilanterol should be used with caution in patients with urinary retention or with narrow-angle glaucoma. Common side effects include: Urinary tract infection, sinusitis, pharyngitis, upper respiratory tract infection, cough, oropharyngeal pain, gastrointestinal disorders, constipation and dry mouth. Tiotropium and Olodaterol (Spiolto Respimat ) 2.5 micrograms/2.5 micrograms inhalation solution. The SPC states that many of the listed undesirable effects can be assigned to the anticholinergic properties of tiotropium bromide or to the ß2-adrenergic properties of olodaterol, the components of Spiolto Respimat. Dry mouth was a common side effect. Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation, intestinal obstruction including ileus paralytic and urinary retention. Undesirable effects related to the betaadrenergic agonist class, which are not listed above, should be taken into consideration, such as, arrhythmia, myocardial ischaemia, angina pectoris, hypotension, tremor, nervousness, muscle spasms, fatigue, malaise, hypokalaemia, hyperglycaemia, and metabolic acidosis.

13 Use in special populations (Refs. 1-3, 13) There is no relevant use in paediatrics and adolescents for any of the LAMA / LABA combination inhalers. None of them should be used in asthma. Aclidinium / formoterol (Duaklir Genuair ) - No dosage adjustments required in the elderly or patients with renal or hepatic impairment. Glycopyrronium / indacaterol (Ultibro Breezhaler ) No dosage adjustments required in the elderly and those with mild or moderate renal impairment or mild or moderate hepatic impairment. In patients with severe renal impairment or end-stage renal disease requiring dialysis it should be used only if the expected benefit outweighs the potential risk. In patients with severe hepatic impairment caution should be observed as there is no data on use in these patients. Umeclidinium / vilanterol (Anoro Ellipta ) - No dosage adjustments required in the elderly and those renal impairment or mild or moderate hepatic impairment. The use of Anoro has not been studied in patients with severe hepatic impairment and should be used with caution. Tiotropium and Olodaterol (Spiolto Respimat ) 2.5 micrograms/2.5 micrograms inhalation solution. No dosage adjustments required in the elderly. There is no long term experience in patients with severe renal impairment. As plasma concentration of tiotropium increases with decreased renal function in patients with moderate to severe renal impairment (creatinine clearance 50ml/min) Spiolto Respimat should be used only if the expected benefit outweighs the potential risk. Costs (Chemist & Druggist August 2015) Tariff status Activity costs LAMA/ LABA Combination Inhaler & Dosage 30 day cost / per patient Annual Cost per patient Tiotropium /olodaterol 5/5 micrograms, (Spiolto Respimat ) - Two puffs once daily. Duaklir Genuair (aclidinium / formoterol) 340 micrograms /12 micrograms dry powder for inhalation. One inhalation twice daily. Ultibro Breezhaler (indacaterol / glycopyrronium) 85 micrograms/43 micrograms capsule for inhalation through the Breezhaler. One capsule inhaled once daily ( from 14/9/15) ( from 14/9/15) Anoro Ellipta 55 micrograms/ 22 micrograms, dry powder for inhalation, (umeclidinium 55 micrograms, vilanterol trifenatate 22 micrograms/inhalation -delivered dose). One inhalation once daily N.B. Doses are for general comparison and do not imply therapeutic equivalence Cost effectiveness The LAMA / LABA combination inhalers are Included within the National Tariff in secondary care. Refer to cost comparison tables also. Page 13 of 32

14 (if available) The Scottish Medicines Consortium (SMC) has considered the health economic evidence for 3 LAMA/LABA combination inhalers and the 4 th is ongoing. SMC Aclidinium / formoterol (10) The submitting company presented a cost-minimisation analysis which compared aclidinium/formoterol against the following LAMA/LABA combinations: tiotropium+formoterol, umeclidinium/vilanterol, indacaterol/glycopyrronium, salmeterol+tiotropium and indacaterol+tiotropium. The cost-minimisation analysis focused on medicine costs only and no other costs were considered in the analysis. The results of the cost-minimisation analysis indicated that the cost per year of aclidinium/formoterol was , which was the same as the estimated yearly cost of umeclidinium/vilanterol. In addition, the cost per year of aclidinium/formoterol was reported as less than the associated costs of indacaterol/glycopyrronium, tiotropium+formoterol, indacaterol+tiotropium and salmeterol+tiotropium which were estimated as , , and respectively. On this basis, aclidinium/ formoterol would be considered a cost-effective treatment option. The main weakness related to the evidence base underpinning the economic analysis. Two of the comparators, salmeterol+tiotropium and indacaterol+tiotropium, were not formally evaluated in the network meta-analysis (NMA). The company justified not including other LAMA and LABA combinations in the NMA as no studies met the inclusion criteria. However, the New Drugs Committee concluded that comparable efficacy of aclidinium/formoterol with an appropriate range of LAMA plus LABA comparators had been adequately demonstrated. SMC Glycopyrronium / indacaterol (11) -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. SMC Umeclidinium / vilanterol (12) The submitting company presented a cost-minimisation analysis comparing umeclidinium/ vilanterol for adult patients with COPD eligible for treatment with tiotropium monotherapy or tiotropium in combination with a LABA with the following comparators: Tiotropium monotherapy Tiotropium plus indacaterol Tiotropium plus formoterol Tiotropium plus salmeterol. A cost-utility analysis was also provided comparing umeclidinium/vilanterol with tiotropium monotherapy and tiotropium plus indacaterol. However, SMC clinical expert responses indicate that tiotropium plus formoterol and tiotropium plus salmeterol are the key comparators and therefore the cost-minimisation analysis was considered to be the relevant analysis. Page 14 of 32

15 A five year time horizon was used and the analysis was carried out from an NHS Scotland perspective. The data to support the comparable efficacy between umeclidinium/vilanterol and tiotropium plus indacaterol, tiotropium plus formoterol and tiotropium plus salmeterol were based on indirect treatment comparisons which showed there to be no significant differences between any of the treatments. A Bayesian NMA comparing umeclidinium/vilanterol with tiotropium plus formoterol was also presented, with placebo as the common comparator. The results showed comparable efficacy between umeclidinium/vilanterol and tiotropium plus formoterol for SGRQ total score at 24 weeks. The data to support the comparable efficacy between umeclidinium/vilanterol and tiotropium monotherapy were based on an integrated NMA of the three 24-week studies, for the calculation of the primary outcome (% predicted FEV1). The analysis compared the drug acquisition costs only and after the first year they were discounted at 3.5% in line with normal convention in economic evaluations. The main economic results show that umeclidinium/vilanterol is cost saving compared to tiotropium monotherapy, tiotropium plus indacaterol, tiotropium plus salmeterol and tiotropium plus formoterol. The results also show that umeclidinium/vilanterol is cost saving compared to the weighted cost of the comparator treatments which is calculated using Scottish sales data and assumes the LABA market share is consistent when used in combination with tiotropium. The tiotropium plus LABA weighted cost is based on market shares of 84.3%, 10.6% and 5.1% for tiotropium plus salmeterol, tiotropium plus formoterol and tiotropium plus indacaterol respectively. The results are based on indirect comparisons that had some limitations, but despite these, the economic case has been demonstrated. Tiotropium and Olodaterol (Spiolto Respimat ) 2.5 micrograms/2.5 micrograms inhalation solution. The Scottish Medicines Consortium (SMC) appraisal of Spiolto Respimat is currently ongoing. However, the cost of the combination inhaler is less than the cost of the two individual inhalers prescribed together. Potential number of patients in Bedfordshire and Luton Impact per 100,000 population Affordability considerations COPD prevalence is estimated at 2-4% but the diagnosed prevalence is about 1.5% (1,500 per 100,000) which increases to 10% in men aged over 75. (14) In 2013, the prevalence of COPD in Bedford Borough was 1.32% (or 2,163) and 1.52% (or 4,230) in Central Bedfordshire. COPD prevalence locally is increasing and underdiagnosed. The Bedfordshire and Luton COPD guidelines recommend a LAMA inhaler first line when there is persistent breathlessness or an exacerbation on a SABA alone. Either a LABA alone or ICS/LABA (depending on FEV1) is recommended if there is an inadequate response to a LAMA after 4 weeks. Page 15 of 32

16 The affordability considerations of using a LAMA/LABA combination inhaler in the following scenarios are set out: LAMA cost range per patient per year LABA cost range per patient per year LAMA / LABA combination inhaler cost range per patient per year ICS/ LABA cost range per patient per year Scenario 1: As an alternative to a LABA / ICS where the ICS is contra-indicated / not tolerated or declined (as per NICE CG101) This would result in additional costs of to per patient per year. For using, Aclidinium / Formoterol (Duaklir Genuair ) rather than Fostair 100/6 inhaler after first using Tiotropium HandiHaler would increase costs by per patient per year. Scenario 2: Changing from a LAMA inhaler to a LAMA/LABA combination inhaler rather than changing to a LABA alone. This would result in an additional cost of to per patient per year. For example, using to Aclidinium / Formoterol (Duaklir Genuair ) or Umeclidinium / vilanterol (Anoro Ellipta ) rather than Formoterol Easyhaler after first using Tiotropium HandiHaler would increase costs by per patient per year. Scenario 3: As an alternative to LAMA plus LABA inhalers prescribed separately. The Bedfordshire COPD audit 2013 found that 2% of COPD patients audited were prescribed a LABA inhaler plus a LAMA inhaler. At the time of the audit a LAA / LAMA combination inhaler was not available and so it can be assumed that the inhalers were prescribed separately. The LAMA/ LABA combination inhalers are less costly per year than prescribing two separate LABA and LAMA inhalers as illustrated in table 1 below and would result in cost savings. Table 1: Savings per patient per year by using a LAMA / LABA combination inhaler rather than individual components as separate inhalers Drug Dose Regimen 30 day cost / per patient Cost per year ( ) Page 16 of 32

17 Aclidinium and formoterol (Duaklir Genuair ) 340 micrograms /12 micrograms Aclidinium bromide 375 micrograms (Eklira Genuair ) Easyhaler Formoterol 12 micrograms per dose. Cost of separate inhalers prescribed together One inhalation twice daily One inhalation twice daily One inhalation twice daily Savings per patient per year Glycopyrronium and indacaterol (Ultibro Breezhaler) 85 micrograms/43 micrograms, Glycopyrronium (Seebri Breezhaler) 44 micrograms Indacaterol (Onbrez Breezhaler) 150 or 300 microgram capsules for inhalation. Cost of separate inhalers prescribed together One inhalation once daily One capsule inhaled once daily 150 to 300 micrograms capsule inhaled once daily ( from 14/9/15) ( from 14/9/15) Savings per patient per year Umeclidinium and vilanterol (Anoro Ellipta ) 55/22 micrograms Umeclidinium (Incruse Ellipta ) 55 micrograms Vilanterol Cost of separate inhalers prescribed together Savings per patient per year 55/22 micrograms once daily One inhalation once daily. Not available as monotherapy N/A N/A N/A N/A Drug Tiotropium and Olodaterol (Spiolto Respimat ) 5/5 Tiotropium (Spiriva Respimat ) Olodaterol (Striverdi Respimat ) 2.5 micrograms / metered inhalation. Dose Regimen Two puffs once daily 5 micrograms once daily Two puffs once daily 30 day cost / per patient Cost per year ( ) Page 17 of 32

18 Cost of separate inhalers prescribed together Savings per patient per year N.B. Doses are for general comparison and do not imply therapeutic equivalence. Page 18 of 32

19 Decisions from other bodies NICE- Evidence summary new medicines available for aclidinium / formoterol, glycopyrronium / indacaterol, umeclidinium / vilanterol and are reported under the evidence section in this bulletin. SMC ( ) Aclidinium / formoterol fumarate dihydrate (Duaklir Genuair ) 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). Indacaterol maleate plus glycopyrronium bromide inhalation powder hard capsules (Ultibro Breezhaler ) 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. Umeclidinium/vilanterol (Anoro )-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 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. Tiotropium and Olodaterol appraisal is due to be published November AWMSG ( ) Indacaterol/glycopyrronium (Ultibro Breezhaler ) 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. Umeclidinium/vilanterol (as trifenatate) (Anoro Ellipta ) is recommended as an option for use within NHS Wales as a Page 19 of 32

20 maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Tiotropium and Olodaterol is exempt from assessment as it is an alternative formulation of an established medicine which costs the same or less than the existing established medicine. CCGs Hertfordshire Medicines Management Committee (HMMC) ( ) Umeclidinium / vilanterol (Anoro Ellipta ) Not recommended for prescribing in primary or secondary care. Recommendation will be reviewed when other LAMA/ LABA combination inhalers are launched and the place in therapy in the COPD pathway is further defined with local specialists. Glycopyrronium / indacaterol (Ultibro Breezhaler ) Not recommended for prescribing in primary or secondary care. Recommendation will be reviewed when the local COPD guidelines are reviewed with local specialists to consider place in the treatment pathway for LAMA/LABA. Tiotropium / olodaterol (Spiolto Respimat )- not considered. Cambridgeshire and Peterborough Joint Prescribing Group (CPJPG) ( ) Inhaled vilanterol + umeclidinium (Anoro Ellipta ) - Not recommended. Inhaled Indacaterol plus glycopyrronium (Ultibro Breezhaler) - Not recommended. Tiotropium / olodaterol (Spiolto Respimat ) not considered. Milton Keynes Prescribing Advisory Group (MKPAG) COPD pathway updated June 2014 ( ) Combination inhalers not recommended. Patients are best treated with single ingredient preparations. Northamptonshire Prescribing Advisory Group (NPAG) Formulary updated June 2015 ( ) Specialist initiation only (COPD) Aclidinium bromide (LAMA)/formoterol fumarate (LABA) (Duaklir Genuair) Umeclidinium(LAMA)/vilanterol(LABA) (Anoro Ellipta) Comments sought from Bedfordshire and Luton Respiratory Consultants- Dr S Tariq, Dr T Chapman, Dr E C Thomas, Dr J Ramsay, Dr M Azher, Dr P Pilli. Bedfordshire and Luton COPD nurses Farida Parkar, Lizan Drummond, Fiona Maryan-Instone, Sabu Kakkassery Kuriakose BCCG Respiratory Clinical Lead Dr Dayo Kuku LCCG Respiratory Clinical Lead Dr Talib Abubacker Primary Care Respiratory Nurse Linda Lomax BCCG Clinical Leads Dr Fran Ross, Dr Judy Baxter Page 20 of 32

21 Evidence strengths and limitations There are no head to head comparisons of any of the 4 LAMA/LABA combination inhalers either delivered in one combination inhaler or as separate inhalers. Hence, it is not easy to judge how they directly compare to each other. It can be argued that a clinically meaningful improvement of FEV1 cannot be achieved by adding a second bronchodilator to the first because people with moderate to severe COPD generally have limited airways reversibility (7). Aclidinium and formoterol fumarate dihydrate (Duaklir Genuair ) 340 micrograms /12 micrograms inhalation powder (7). The European Public Assessment Report for aclidinium/formoterol states that the chosen co-primary endpoints of the RCTs, 1 hour post-dose and trough FEV1, are appropriate for exploring the contributions of formoterol and aclidinium respectively. In addition, the key secondary symptomatic endpoints of TDI and SGRQ scores are in line with the CHMP guideline on the investigation of medicinal products for the treatment of COPD. In ACLIFORM and AUGMENT, aclidinium/formoterol statistically significantly improved lung function compared with placebo. However, the results compared with aclidinium or formoterol monotherapy are less clear. In both RCTs, a clinically significant improvement in 1-hour Chronic obstructive pulmonary disease: aclidinium/ formoterol post-dose FEV1 was seen in the aclidinium/formoterol group compared with aclidinium monotherapy, suggesting that formoterol contributes to the efficacy of the combination. A clinically significant improvement in trough FEV1 was not seen with aclidinium/formoterol compared with formoterol, raising questions over the contribution aclidinium makes to the efficacy of the combination. In the pooled analysis, aclidinium/formoterol statistically significantly improved trough FEV1 by 68 ml compared with formoterol monotherapy, which is less than the 100 ml improvement threshold generally considered to be clinically relevant. According to the European Public Assessment Report for aclidinium/formoterol, this difference is similar to that seen with other recently licensed LAMA/LABA combinations, and post hoc responder analyses provided by the manufacturer supported the conclusion that aclidinium contributes to a clinically significant extent to the overall positive effect of the combination. The European Public Assessment Report also notes that it has been argued that a clinically meaningful improvement in FEV1 cannot be achieved by adding a second bronchodilator to the first because people with moderate to severe COPD generally have limited airways reversibility. Aclidinium/formoterol statistically significantly improved breathlessness (TDI focal scores) compared with aclidinium or formoterol monotherapy. However, the treatment differences of less than half a unit are below the minimum 1 unit improvement in TDI score which is generally considered to be clinically relevant. The results for health-related quality of life (SGRQ scores) are difficult to interpret because a large placebo effect was seen in ACLIFORM. Post-hoc analyses failed to identify a single reason for this unexpected result and suggest that the cause is likely to have been multi-factorial. In both RCTs, a clinically significant improvement in SGRQ total score of more than 4 units was seen in all active treatment groups. In AUGMENT, a clinically significant improvement was seen with aclidinium/formoterol compared with placebo but not the active treatments. To support their license application, the manufacturer supplied post-hoc responder analyses. These showed that the proportions of people in the pooled aclidinium/formoterol group who achieved a 1 unit improvement in Page 21 of 32

22 TDI focal score (62%) and a 4 unit improvement in SGRQ total score (57%) were similar to the proportions seen in studies of the recently approved LAMA/LABA combinations (umeclidinium/vilanterol, 58% and 49% respectively; and indacaterol/glycopyrronium, 68% and 64% respectively; European Public Assessment Report for aclidinium/formoterol). In a pooled analysis of the 2 RCTs, improvement in all severities of exacerbation with aclidinium/ formoterol compared with placebo was found to be 0.33 exacerbations per patient/year based on the EXACT definition. This means that a patient would need to be treated with the combination for about 3 years to prevent 1 exacerbation (p=0.01). The European Public Assessment Report for aclidinium/formoterol notes that a reduction of at least 1 event per year is currently the best estimate of the minimum clinically important difference in exacerbations and it is debatable whether a reduction of 0.33 exacerbations per year is clinically meaningful. However, the RCTs were too short to assess exacerbations satisfactorily. The study participants had moderate to severe COPD and it is unclear how effective aclidinium/ formoterol is in people with mild or very severe COPD. The length of follow up in ACLIFORM and AUGMENT was 24 weeks only; therefore, the longterm effects of aclidinium/formoterol are uncertain. An extension study to AUGMENT (NCT ) and another long-term safety study (NCT ) have been undertaken but not yet published. Some information on these studies is available in the European Public Assessment Report for aclidinium/formoterol but the results are affected by high dropout rates. It is not known how aclidinium/formoterol compares with other combination treatments for COPD. A study comparing aclidinium/formoterol with salmeterol/fluticasone has been completed but not yet published (NCT ). Glycopyrronium and indacaterol (Ultibro Breezhaler) 85 micrograms/43 micrograms, inhalation powder hard capsules (8). SPARK demonstrated that indacaterol/glycopyrronium statistically significantly reduced the annualised rate of all exacerbations compared with glycopyrronium and open-label tiotropium alone, and of moderate to severe exacerbations compared with glycopyrronium. However, the relative reductions were all below the 20% considered in the full NICE guideline on COPD to be clinically important. In addition, the rate of severe exacerbations was not reduced compared with either active comparator. The European Medicines Agency concluded that the benefits of indacaterol/glycopyrronium in terms of reducing exacerbations were not sufficiently proven to grant a license for this indication. Although there is evidence of a statistically significant improvement compared with placebo in the SHINE study, the clinical significance of improvements in trough FEV1 for indacaterol/ glycopyrronium compared with glycopyrronium alone, open-label tiotropium or the lower licensed dose of indacaterol (150 micrograms) is unclear because the differences did not meet the 100 ml difference considered in the full NICE guideline on COPD to be clinically important. Similar results were seen in SPARK. Interpretation of both SPARK and SHINE, within the context of the NICE pathway on COPD, is complicated because many participants (75% in SPARK and 57% in SHINE) used ICS. This meant that many people in the indacaterol/glycopyrronium group received triple therapy (LAMA/ Page 22 of 32

23 LABA plus ICS), and were compared with a LAMA treatment arm in which a substantial number of people received dual therapy with a LAMA and an ICS. LAMA/ICS is not recommended in the NICE clinical guideline on COPD because of the paucity of evidence. Furthermore, no single component ICS inhalers are licensed for treating COPD in the UK. According to the European public assessment report for indacaterol/glycopyrronium, the improvement in FEV1 AUC0-12h of approximately 140 ml seen in ILLUMINATE is not unexpected because indacaterol/glycopyrronium contains 2 bronchodilators compared with 1 in fluticasone/ salmeterol. In addition, the eligibility criteria for ILLUMINATE permitted enrolment of people with less severe COPD (post-bronchodilator FEV1 between 40% and 80% predicted) than that for which fluticasone/salmeterol is currently licensed in the UK (pre-bronchodilator FEV1 less than 60% predicted). Although statistically significant improvements in several other outcomes have been reported for indacaterol/glycopyrronium (for example, dyspnoea scores, health status scores and use of rescue salbutamol) compared with some active comparators, the differences appear small and are of uncertain clinical importance. Nevertheless, the European Medicines Agency considered that, taking the overall results and the safety profile of glycopyrronium/indacaterol into account, a first-line indication for relieving symptoms in people with COPD is justified. Patients are currently being recruited for a 52-week study comparing the effects of indacaterol/ glycopyrronium and fluticasone/salmeterol on exacerbations in people with moderate to very severe COPD (ClinicalTrials.gov NCT ). In addition to important patient-oriented outcome data, this study is likely to provide better longer-term comparative safety data for the 2 treatments. Umeclidinium and vilanterol (Anoro Ellipta ) 55 micrograms/22 micrograms inhalation powder, pre-dispensed (9). Umeclidinium/vilanterol has been compared with its individual components and the LAMA, tiotropium. Vilanterol is not currently available as monotherapy. Umeclidinium (Incruse) was launched in the UK in October There are no published studies which compare umeclidinium/vilanterol with currently available LAMA and LABA treatment given concomitantly. It is therefore unclear how umeclidinium/vilanterol would compare to combined treatment with a currently available LAMA and LABA. The NICE guideline on COPD recommends that the use of dual therapy with a LAMA and a LABA may be considered if an inhaled corticosteroid (ICS: as part of combination therapy with a LABA) is declined or not tolerated. In Decramer et al. 2014, Maleki-Yazdi et al and Donohue et al participants were allowed to have concomitant treatment with an ICS. Pretreatment use varied across the allocated groups by between 40% and 56%. In Decramer et al 2014 the studies were powered to detect a litre difference between treatments for trough FEV1. However, in both studies the difference in trough FEV1 between umeclidinium/vilanterol and tiotropium, vilanterol or umeclidinium monotherapy was less than litres. The full NICE guideline on COPD considers a minimum clinically important difference in FEV1 to Page 23 of 32

24 be litres. The European public assessment report for umeclidinium/ vilanterol commented that the improvements in trough FEV1 with umeclidinium/vilanterol 62.5/ 25 micrograms compared with tiotropium and the individual components were variable and did not show a consistent clinically relevant change. However, it stated that a minimum clinically important difference of litres is for comparisons with placebo and it may not necessarily be appropriate as a benchmark for clinical significance for comparisons between a combination of 2 bronchodilators (LAMA and LABA) with 1 bronchodilator (either a LAMA or a LABA). The NICE guideline on COPD recommends that the choice of drug treatment should take into account the person's symptomatic response and preference, and the drug's potential to reduce exacerbations, side effects and costs. Decramer et al and Maleki-Yazedi et al both had diseaseorientated FEV1 primary and secondary outcomes. Patient-orientated additional outcomes were measured in both studies, but they were not designed or powered to evaluate these outcomes. Donohue et al did include a patient-orientated outcome (TDI score) which was powered to detect differences between treatment groups. However, in this study umeclidinium/vilanterol was only compared with its individual components and placebo. For both studies in Decramer et al a hierarchical design was used to avoid spurious statistically significant findings arising through chance, given the number of possible comparisons. If a statistical test in the predefined heirarchy had a non-significant result, the results of all further statistical analyses would not be strictly inferential. In study 2 there was no statistically significant difference between umeclidinium/vilanterol 125/25 micrograms and umeclidinium 125 micrograms for the primary outcome, therefore statistical analysis of further comparisons which included umeclidinium/vilanterol 62.5/25 micrograms are presented for descriptive purposes only. Treatment comparisons for additional analyses such as rescue salbutamol use were not controlled for multiplicity. There are limited published long-term efficacy and safety data for the licensed dose. Decramer et al. 2014, Maleki-Yazdi et al and Donohue et al were conducted over 24 weeks only. Tiotropium and olodaterol (Spiolto Respimat ) The improvements in FEV1 for the combination inhaler were clinically significantly better than the separate inhalers given alone. Although a reduction in exacerbations was seen with the combination inhaler, the study was not powered to detect a difference between the combination inhaler and the separate inhalers given alone. The quality of life test, the St Georges Respiratory Questionnaire showed improvements with the combination inhaler compared to separate inhalers, however, the result was less than the 4 point change required to show a clinically significant improvement in quality of life. There was a reduction in the use of rescue medications by around 1 puff per day (weekly mean daily use), but the clinical significance of this is unclear as around 2 puffs per day (weekly mean daily use) of rescue medication were used with the combination inhaler. Page 24 of 32

25 PAC New Drug Template Adapted from East Anglia Medicines Information, NHS Suffolk, NHS Cambridgeshire and NHS Derby templates *Consult Summary of Prescribing Characteristics for full prescribing detail. This guidance is based upon the published information available in English at the time the drug was considered. It remains open to review in the event of significant new evidence emerging. References (1) Duaklir Genuair SPC. AstraZeneca UK Limited. (Last viewed 25/6/15) (2) Ultibro Breezhaler SPC. Novartis Pharmaceuticals UK Ltd. (Last viewed 25/6/15) (3) Anoro Ellipta SPC. GlaxoSmithKline UK. (Last viewed 25/6/15) (4) National Institute for Health and Care Excellence. Clinical Guideline 101- Chronic Obstructive Pulmonary Disease: Management of chronic obstruction pulmonary disease in adults in primary and secondary care (partial update). Issued June (Last viewed 4/6/15). (5) Bedfordshire and Luton COPD Guidelines. Revised April 2014 Version (Last viewed 4/6/15) (6) Global Initiatives Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease updated (Last viewed 4/6/15) (7) National Institute for Health and Care Excellence. Evidence summary: new medicine ESNM57: Chronic Obstructive Pulmonary Disease: aclidinium / formoterol. Published April (8) National Institute for Health and Care Excellence. Evidence summary: new medicine ESNM33: Chronic Obstructive Pulmonary Disease: indacaterol / glycopyrronium (Ultibro Breezhaler). Last updated 8 December (9) National Institute for Health and Care Excellence. Evidence summary: new medicine ESNM49: Chronic Obstructive Pulmonary Disease: umeclidinium / vilanterol combination inhaler (Anoro Ellipta). Published 6 November (10) Scottish Medicines Consortium No. 1034/15. Aclidinium / formoterol fumarate dihydrate 340/12 micrograms inhalation powder (Duaklir Genuair ) 6 March (11) Scottish Medicines Consortium No. 922/13. Indacaterol maleate 143 micrograms with glycopyrronium bromide 63 micrograms inhalation powder hard capsules (Ultibro Breezhaler. 7 November (12) Scottish Medicines Consortium No. 978/14. Umeclidinium /vilanterol, micrograms, inhalation powder (Anoro ) 9 January (13) Spiolto Respimat SPC. Boehringer Ingelheim Limited. (Last viewed 29-Jun-2015) (14) Spiolto Respimat (tiotropium and olodaterol) for the Treatment of Chronic Obstructive Pulmonary Disease (COPD) Formulary Pack. Boehringer Ingelheim Limited. July n:\medicines management\jpc\approved bulletins & papers\from aug 13\sept 15\bulletin 218 laba_lama combination inhalers in copd - place in therapy review and choice.docx Page 25 of 32

26 Bedfordshire and Luton Joint Prescribing Committee (JPC) Assessment against Ethical and Commissioning Principles Treatment assessed (September 2015): LAMA / LABA combination inhalers in COPD- Place in therapy review and choice JPC Recommendations The Committee reviewed the place in therapy of LAMA / LABA combination inhalers in the COPD treatment pathway and agreed the following recommendations: 1)Place in therapy A LAMA /LABA combination inhaler is recommended as an alternative to a LABA / ICS inhaler in adult COPD patients where the ICS is contra-indicated / not tolerated or declined in line with NICE Clinical Guideline 101. A LAMA /LABA combination inhaler is recommended in new and existing adult COPD patients who are already prescribed separate LAMA and LABA inhalers. Prior to switching to a combination inhaler, patients should be reviewed to assess if they still require both a LAMA and a LABA component. For patients with an FEV1 50% who have had a partial response to a LAMA inhaler (i.e they remain breathless) after an appropriate trial with the LAMA inhaler and who have satisfactory compliance with therapy and inhaler technique. On initiation of a LAMA /LABA combination inhaler within primary care, all patients should be reviewed after 4 weeks to assess effectiveness. 2)Choice of therapy The Committee agreed to support a joint first line choice of LAMA /LABA inhaler consisting of tiotropium / olodaterol (Spiolto Respimat ) or aclidinium / formoterol (Duaklir Genuair ). These products were chosen as they incorporate the BCCG & LCCG first line choice of individual LAMA (tiotropium) and LABA (formoterol) components. The advantages of each product are specified below and it was noted that it is best to offer a joint first line choice of combination inhaler as this allows for patient preference to be taken into account. Joint First Line choice: Tiotropium* / olodaterol (Spiolto Respimat ) This is a preferred choice LAMA / LABA combination inhaler as: it has demonstrated clinically significant improvements in FEV1 (>100ml) compared to giving the single components; and tiotropium is the LAMA inhaler choice in the Bedfordshire COPD guidelines; it is given once daily; it is a multiple dosing device. OR Aclidinium* / formoterol (Duaklir Genuair ) This is also a preferred choice LAMA / LABA inhaler as it is used twice daily which might suit some patient s symptom pattern and it may be used in patients with renal or hepatic impairment. Page 26 of 32 * Tiotropium and aclidinium should be used with caution in patients with a history of cardiovascular disease. For full prescribing information, including details of this caution, prescribers should refer to individual SPCs and the MHRA drug safety update relating to

27 tiotropium (Feb 2015). ( & ug_safety_update 1_.pdf) 1) Clinical Effectiveness All 4 LAMA / LABA combination inhalers have clinical evidence to support their use as a maintenance bronchodilator. However, only tiotropium / olodaterol demonstrated a clinically significant improvement in lung function (>100ml difference in FEV1) above that seen with the single components used alone. It could be argued that clinically meaningful improvement in FEV1 cannot be achieved by adding a second bronchodilator to the first because people with moderate to severe COPD generally have limited airways reversibility. Quality of life and dyspnoea measures were statistically improved for all 4 LAMA/LABA combination inhalers, but were not found to be clinically significantly better than using monotherapy. Statistical, but not clinically significant reductions in exacerbations were seen with aclidinium / formoterol and glycopyrronium / indacaterol but not umeclidinium / vilanterol. There was a reduction in exacerbations with Tiotropium / olodaterol, but the study was not powered to detect a difference between the combination inhaler and the separate inhalers. In patients with renal impairment, aclidinium / formoterol and umeclidinium / vilanterol can be used whereas glycopyrronium / indacaterol should only be used if the benefit outweighs the risks if the patient has severe renal impairment or endstage renal disease requiring dialysis. Tiotropium / olodaterol should only be used in moderate / severe renal impairment only if benefit outweigh risks. Aclidinium / formoterol can be used in patients with hepatic failure whereas glycopyrronium / indacaterol, umeclidinium / vilanterol and tiotropium / olodaterol should be used in caution in patients with severe hepatic impairment. All 4 LAMA /LABA combination inhalers are used once or twice daily. Tiotropium / olodaterol (Spiolto Respimat ) is an inhalation solution whereas the other 3 LAMA/LABA combination inhalers are dry powder inhaler devices. Glycopyrronium / indacaterol (Ultibro Breezhaler ) is a single dose device and may be unsuitable for patients with manual dexterity problems whereas the Genuair, Ellipta and Respimat devices are multiple dose devices that do not required a capsule to be loaded. 2) Cost Effectiveness Using a LAMA/LABA combination inhaler as an alternative to a LABA / ICS where the ICS is contra-indicated / not tolerated or declined is in line with NICE Clinical Guideline 101, but would result in additional costs of between and per patient per year. The Bedfordshire COPD audit 2013 found that 2% of COPD patients audited were prescribed a LABA inhaler plus a LAMA inhaler. Where patients are already prescribed separate LAMA and LABA inhalers, use of a combination LAMA / LABA inhaler would be cost saving and more convenient for patients. Using a LAMA / LABA combination inhaler after a LAMA inhaler alone rather than changing to a LABA alone would result in an additional cost of to per patient per year. However, the additional clinical benefits of using a combination inhaler above using monotherapy has not been demonstrated. Page 27 of 32

28 Currently, glycopyrronium / indacaterol (Ultibro Breezhaler ) is the most costly product at 447 per year and is more costly than LAMA inhalers alone, LABA inhalers alone, ICS/LABA inhalers and the other 3 LAMA /LABA inhalers aclidinium / formoterol, umeclidinium / vilanterol and tiotropium / olodaterol (these are the same cost at 394 per year.) However, the cost of glycopyrronium / indacaterol (Ultibro Breezhaler ) will be reduced to 394/year from 14th September 2015 according to the manufacturer and so all the current LAMA/LABA inhalers will be the same cost from this date. From this time, the 4 LAMA / LABA inhalers will be less costly than tiotropium, but more costly than other LAMA inhalers alone, LABA inhalers alone, and ICS/LABA inhalers. 3) Equity No impact envisaged. 4) Needs of the community COPD prevalence locally is increasing and underdiagnosed. 5) Need for healthcare (incorporates patient choice and exceptional need) The choice of treatment for a person with COPD depends on drug efficacy, tolerability to treatment, possible adverse events and the suitability of different inhaler devices to the person. Inhaled long-acting bronchodilators have an important role to play in managing COPD. COPD prevalence is estimated at 2-4% but the diagnosed prevalence is about 1.5% (1,500 per 100,000) which increases to 10% in men aged over 75. An average GP practice of 6,600 patients is likely to have about 100 patients on its COPD disease register. This equates to approximately 6,100 and 3,000 patients with COPD in Bedfordshire and Luton respectively. 6) Policy drivers NICE Clinical Guideline 101. Management of COPD in adults in primary and secondary care. Bedfordshire COPD Guidelines Updated ) Disinvestment Potential savings will be generated through not prescribing separate inhalers for LAMA and LABA and prescribing a LAMA/LABA combination inhaler instead. The JPC agreed the following sections within the PCT Ethical and Commissioning Framework were not relevant to JPC discussions: Health Outcomes, Access, and Affordability. Page 28 of 32

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