BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE

BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE September 2015 Review Date: September 2018 Bulletin 219: Choice of Long Acting Muscarinic Agent (LAMA) inhaler for COPD JPC Recommendation: The availability of a new LAMA inhaler, umeclidinium, the impending loss of patent protection for tiotropium and subsequent availability of a branded generic and interest in using aclidinium Genuair led to the need to review the LAMA inhaler choices within the COPD guidelines. The Committee agreed that tiotropium remained a good first-line LAMA inhaler choice based on clinical effectiveness grounds, choice of 2 different devices and the likely availability of a less costly branded generic inhaler in the near future. The Committee agreed to keep the existing recommendations on choice of LAMA inhaler for the treatment of COPD (with the updated MHRA drug safety advice regarding tiotropium (Feb 2015), unless new evidence emerges or the economic picture merits a review of the choice of products in the future. Choice of Long Acting Muscarinic Antagonist (LAMA) First Choice: Tiotropium* (Spiriva HandiHaler ) - One 18 microgram capsule inhaled once daily or Tiotropium* Respimat ( 2.5 micrograms per puff) - Two puffs once daily or Tiotropium* branded generic inhaler (when available) Second Choice: Inhaled aclidinium* bromide (Eklira Genuair ) 400 micrograms - one inhalation twice daily or inhaled glycopyrronium* bromide (Seebri Breezhaler ) 50 micrograms - one capsule inhaled once daily *Tiotropium, aclidinium and glycopyrronium 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). (www.medicines.org.uk & www.gov.uk/government/uploads/system/uploads/attachment_data/file/409046/february_2015_drug_safety_updat e 1_.pdf) Page 1 of 24

Medicine The Long Acting Muscarinic Agent (LAMA) inhalers (1) currently available are: 1. Aclidinium bromide 375 microgram (Eklira Genuair ) Multidose dry powder inhaler 2. Glycopyrronium 44 microgram (Seebri Breezhaler ) Single dose dry powder inhaler 3. Tiotropium 18 microgram (Spiriva HandiHaler ) Single dose dry powder inhaler 4. Tiotropium 2.5 microgram (Spiriva Respimat ) Multiple dose inhalation solution 5. Umeclidinium bromide 55 microgram (Incruse Ellipta ) Multiple dose dry powder inhaler Document status Final approved by the Bedfordshire and Luton Joint Prescribing Committee (JPC), 9 th September 2015 Date of last revision 3 June 2015 Proposed Sector of Primary Care / Secondary Care prescribing Introduction Summary Key points Evidence level Aclidinium, glycopyrronium, tiotropium, and umeclidinium are licensed for the maintenance treatment of patients with chronic obstructive pulmonary disease. These four drugs are available in a total of 5 devices. 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. The evidence base shows that all the LAMA inhalers are effective bronchodilators which produce clinically significant improvements in lung function (FEV1). The evidence base for improvements in patientorientated outcomes including breathlessness (TDI), quality of life (SGRQ), reductions in the risk of exacerbations and reduced exacerbations leading to hospitalisations is clinically significant for tiotropium. The other LAMA inhalers show clinically significant improvements in some but not all of these patient-orientated outcomes. Aclidinium has shown clinically significant improvements in breathlessness, quality of life and, although reductions in exacerbations were seen, the studies were not statistically powered to detect this. Glycopyrronium has shown a clinically significant reduction in exacerbations, but not all studies showed clinically significant improvements in breathlessness and quality of life. Umeclidinium has shown clinically significant improvements in quality of life, but improvements seen in breathlessness were not statistically significant in one study and although reductions in exacerbations were seen, the studies were not statistically powered to detect this. All the LAMA inhalers can be used in mild renal impairment. Aclidinium and umeclidinium may be used in any form of renal impairment. Glycopyrronium should only be used in severe and endstage renal failure if the benefits outweigh the risks. Tiotropium should only be used in moderate or severe renal failure if the benefits Page 2 of 24

The intervention Mechanism of action Licensed indication Formulation/Available Products and usual dosage outweigh the risks. All LAMA inhalers, except umeclidinium, may be used in hepatic impairment. Umeclidinium should be used in caution in patients with severe hepatic impairment. All the LAMA inhalers are used once daily except aclidinium which is used twice daily. All but Tiotropium Respimat are dry powder inhalers. Glycopyrronium Breezhaler and tiotropium HandiHaler are single dose devices (where a capsule needs to be inserted into the inhaler device) whereas aclidinium Genuair, tiotropium Respimat and umeclidinium Ellipta are multiple dose devices. The LAMA inhalers cost between 333.67 and 407.84 per year, a difference of 74.17 per year between the least costly and mostly costly inhaler. Glycopyrronium Breezhaler is currently the least costly LAMA inhaler at 27.50 for 30 days. With the loss of patent protection for tiotropium in September 2015, there is likely to be branded generic inhaler versions at a lower cost available towards the end of 2015. Author s recommendation: Tiotropium appears to remain to be a good first-line LAMA inhaler choice based on clinical effectiveness grounds, choice of two different devices and the likely availability of a less costly branded generic inhaler in the near future. For patients with renal impairment, aclidinium Genuair is a second-line alternative. However, if twice daily use or the Genuair device is not suitable for the patient, umeclidinium Ellipta is an alternative second-line choice (but not if the patient has severe hepatic impairment). Inhaled long-acting muscarinic antagonist (LAMA) bronchodilators. All the inhaled LAMAs are indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD) (2-6). 1. Aclidinium bromide 375 microgram (Eklira Genuair ) Multidose dry powder inhaler- One inhalation twice daily. 2. Glycopyrronium 44 microgram (Seebri Breezhaler ) - Single dose dry powder inhaler- Inhale one capsule once daily. Page 3 of 24

3. Tiotropium 18 microgram (Spiriva HandiHaler ) - Single dose dry powder inhaler -Inhale one capsule once daily. 4. Tiotropium 2.5 microgram (Spiriva Respimat ) - Multiple dose inhalation solution -Two puffs once daily. 5. Umeclidinium bromide 55 microgram (Incruse Ellipta ) - Multiple dose dry powder inhaler -One inhalation once daily. Treatment alternatives/ place in therapy The NICE COPD Clinical Guideline (7) recommends that in people with stable COPD who remain breathless or have exacerbations, despite use of short-acting bronchodilators as required, the following be considered as maintenance therapy: If FEV1 is 50% predicted, use either a LAMA or LABA Page 4 of 24

If FEV1 is <50% predicted, use either a LABA/ICS or a LAMA. If an ICS cannot be tolerated then a LABA plus LAMA combination is an alternative. 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. 11.88 144.08 Atimos Modulite Formoterol CFC free MDI. 12 microgram per dose, 100 dose unit. 1 puff twice daily, maximum 4 daily. 18.04 218.84 Olodaterol (Striverdi Respimat ) 2.5 micrograms / metered inhalation, 60 dose unit. Two puffs once daily. 26.35 319.71 Salmeterol 25micrograms/dose inhaler CFC free (Serevent Evohaler ). Two puffs twice daily. 29.26 355.02 Salmeterol 50micrograms/dose dry powder inhaler (Serevent Accuhaler ). One blister inhaled twice daily. 29.26 355.02 Indacaterol (Onbrez Breezhaler ) 150 or 300 microgram capsules for inhalation in the Breezhaler device. One capsule inhaled once daily. 29.26 355.02 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. 29.32 355.75 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. 29.97 363.64 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. 29.97 363.64 Page 5 of 24

Alternative LABA/LAMAs Drug & Dosage 30 day cost / per patient Annual Cost per patient Anoro Ellipta 55 micrograms/ 22 micrograms, dry powder for inhalation, (umeclidinium 55 micrograms, vilanterol trifenatate 22 micrograms/inhalation -delivered dose). One inhalation once daily. 32.50 394.33 Duaklir Genuair (aclidinium / formoterol) 340 micrograms /12 micrograms dry powder for inhalation. One inhalation twice daily. 32.50 394.33 Ultibro Breezhaler (indacaterol / glycopyrronium) 85 micrograms/43 micrograms capsule for inhalation through the Breezhaler. One capsule inhaled once daily. 36.88 447.48 Future alternatives Potential future alternatives include (8): LAMA Branded generic tiotropium inhaler (tiotropium UK patent expiry 1/9/2015). Likely to be a less costly alternative to Spiriva HandiHaler / Respimat LABA Vilanterol mono inhaler currently in clinical trials. ICS /LABA AirFluSal Forspiro DPI (Fluticasone & Salmeterol) combination inhaler therapeutically equivalent to Seretide Accuhaler and likely to be less costly, possible launch later this year. ICS / LAMA /LABA inhalers, e.g. fluticasone furoate + umeclidinium + vilanterol in phase III trials. National and local guidance The NICE COPD Clinical Guideline recommends that in people with stable COPD who remain breathless or have exacerbations, despite use of short-acting bronchodilators as required, the following be considered as maintenance therapy: If FEV1 is 50% predicted, use either a LAMA or LABA If FEV1 is <50% predicted, use either a LABA/ICS or a LAMA. If an ICS cannot be tolerated then a LABA plus LAMA combination is an alternative. 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 Page 6 of 24

the NICE Clinical Guideline (9). Second-line LAMA inhaler options are also included where Tiotropium HandiHaler is not suitable for an individual patient. These currently are: Aclidinium bromide 375 microgram (Eklira Genuair ) Multidose dry powder inhaler- One inhalation twice daily. Glycopyrronium 44 microgram (Seebri Breezhaler ) - Single dose dry powder inhaler- Inhale one capsule once daily. Tiotropium 2.5 microgram (Spiriva Respimat ) - Multiple dose inhalation solution -Two puffs once daily. Nb. Umeclidinium Ellipta was launched after the COPD Guidelines were updated in 2013. In the Global Initiative for chronic obstructive lung disease (GOLD) Guidelines updated 2015, a LAMA inhaler is recommended for first line choice in all patient groups (10). Evidence for use The table in Appendix 2 summarises the outcomes reported in trials for the four LAMA inhalers. Tiotropium The Cochrane review of tiotropium versus placebo for COPD shows that tiotropium treatment was associated with a significant improvement in patients quality of life and it reduced the risk of exacerbations, with a number needed to treat to benefit of 16 to prevent one exacerbation (11). Tiotropium also reduced exacerbations leading to hospitalisations but no significant difference was found for hospitalisation of any cause or mortality. The trials included in the review showed a difference in the risk of mortality when compared with placebo depending on the type of tiotropium delivery device used. Page 7 of 24

However, these results have not been confirmed in a recent trial when 2.5 mcg or 5 mcg of tiotropium via Respimat was used in a direct comparison to the 18 mcg HandiHaler. NICE Evidence summaries: new medicine are available for aclidinium, glycopyrronium, and umeclidinium and may be found at www.nice.org.uk (12-14). Aclidinium The evidence to support the efficacy of aclidinium in COPD comes from the results of two similarly designed phase III studies, one of 24 week duration (ATTAIN) and one of 12 week duration (ACCORD I). The studies primarily compared lung function (assessed by FEV1) of aclidinium and placebo and the results demonstrated significant improvements. In the 24-week study, more patients had clinically significant improvements in the patientorientated secondary outcomes of health status and dyspnoea with aclidinium bromide than with placebo. The reduction in moderate to severe COPD exacerbations was not significantly different between aclidinium and placebo in either study but in a pooled analysis, the difference achieved statistical significance. (N.B. Neither study was powered to detect differences in exacerbation data.). There are no relevant fully published clinical data comparing aclidinium with an active comparator, particularly tiotropium. Glycopyrronium Two phase III randomised controlled trials (GLOW 1and 2) have shown glycopyrronium to be significantly more effective than placebo in reducing trough forced expiratory volume in one second (FEV1) after 12 weeks of treatment in patients with moderate to severe COPD. It was also shown to be superior to placebo in terms of increasing exercise endurance, with a treatment difference of 88.9 seconds between treatment groups after 21 days of treatment (GLOW3). Statistically significant improvements in breathlessness and health status were seen with glycopyrronium bromide compared with placebo in both key studies, however, the differences were not all clinically significant. The difference considered to be clinically important for health status was not reached in GLOW1 or GLOW2. For breathlessness, the difference considered to be clinically important was achieved in GLOW1 but not GLOW2. GLOW2 included an open-label comparison with tiotropium. Tiotropium was statistically significantly more effective than placebo for the primary and 2 key secondary outcomes, showing similar results to glycopyrronium bromide. No significant differences were seen between glycopyrronium bromide and tiotropium for these outcomes. (The study was not powered to compare glycopyrronium versus tiotropium) GLOW 1 and GLOW 2 showed a statistically significant decrease in the risk of moderate to severe COPD exacerbations in terms of time to first exacerbation in patients treated with glycopyrronium Page 8 of 24

bromide compared with placebo (GLOW1: [HR] 0.69, 95%[CI] 0.50 to 0.95, p=0.023; GLOW2: [HR] 0.66, 95% [CI] 0.52 to 0.85, p=0.001. (Both trials also give information on rates of exacerbation but go on to say that the trials are not powered to detect statistically significant differences for this endpoint.) Improvements were also seen with glycopyrronium bromide in terms of use of rescue medication in both studies. Umeclidinium There are no published studies which directly compare umeclidinium 55 micrograms with a currently available LAMA or LABA. Triveldi et al. 2014 compared umeclidinium with placebo only. Donohue et al. 2013 compared the umeclidinium/vilanterol combination inhaler with its individual components and placebo. Comparisons were also made between umeclidinium and vilanterol alone and placebo. Trivedi et al. 2014 compared umeclidinium with placebo for a FEV1 primary outcome. Compared with placebo, there was a statistically significant improvement from baseline in trough FEV1 of 0.127 litres with umeclidinium 55 micrograms, which is greater than the improvement that the full NICE guideline on COPD considers to be clinically important (0.100 litres or more). However, the lower 95% CI was less than 0.100 litres. In Donohue et al. 2013 there was also a statistically significant improvement from baseline in trough FEV1 of 0.115 litres with umeclidinium 55 micrograms compared with placebo, although again the lower 95% CI was less than the 0.100 litres or more considered to be clinically important. This study also included vilanterol 22 micrograms (a long acting beta2 agonist) as a comparator arm. However, no direct comparison between umeclidinium and vilanterol was made and in addition, vilanterol as a single component inhaler is not currently available. Trivedi et al. 2014 and Donohue et al. 2013 both included patientorientated secondary and additional outcomes. Donohue et al. 2013 found a statistically significant improvement in the TDI score of 1.0 unit with umeclidinium 55 micrograms compared with placebo. The full NICE guideline on COPD considers 1.0 unit to be the minimum clinically important difference for TDI score. However, in Trivedi et al. 2014 there was no statistically significant difference between umeclidinium 55 micrograms and placebo for this outcome. Trivedi et al. 2014 found an improvement in the SGRQ score of 7.90 points with umeclidinium compared with placebo. This is greater than the improvement that the full NICE guideline considers to be clinically important ( 4 points or more). There was also a statistically significant reduction in the mean number of salbutamol puffs per day with umeclidinium 55 micrograms compared with placebo. However the clinical significance of this Page 9 of 24

reduction: 0.7 puffs per day (95% CI 1.3 to 0.1; p=0.025) is unclear. Donohue et al. 2013 also included SGRQ score, rescue salbutamol use and COPD exacerbations as additional patientorientated outcomes. However, a step down statistical testing procedure was used in this study and comparisons for these outcomes were below a comparison that did not achieve statistical significance. Therefore comparisons between umeclidinium and placebo for these outcomes are described, but they are not strictly inferential and the p values are nominal only. In addition the study was not designed or powered to evaluate treatment effects on COPD exacerbations. In Donohue et al. 2013, an improvement in the SGRQ score of 4.69 points was seen with umeclidinium 55 micrograms compared with placebo. However, there was no difference between umeclidinium and placebo for rescue salbutamol use. On treatment COPD exacerbations were reported in 13% of participants in the placebo group and 7% to 9% of participants in the active treatment groups. Trivedi et al. 2014 also included umeclidinium 113 micrograms as a comparator arm. However, umeclidinium 55 micrograms is the dose and strength that has been licensed. The European public assessment report for umeclidinium concluded that although greater differences in efficacy outcomes versus placebo for umeclidinium 113 micrograms compared to umeclidinium 55 micrograms were noted in some studies, these differences were not consistent and tended to be modest. In addition, a dose trend could be seen for some adverse events such as cardiovascular adverse events and respiratory infections. No marketing authorisation for umeclidinium 113 micrograms was sought by the manufacturers. Safety * Dry mouth is the most common side-effect of antimuscarinic bronchodilators; also gastro-intestinal motility disorder (including constipation and diarrhoea), cough, and headache; less commonly nausea, gastro-oesophageal reflux disease, dysphagia, tachycardia, palpitation, atrial fibrillation, throat irritation, pharyngitis, dysphonia, bronchospasm, including paradoxical bronchospasm, urinary retention, mydriasis, angle-closure glaucoma, blurred vision, and nasopharyngitis can occur. Dental caries and dry skin have occurred rarely. In addition, for each individual drug: Aclidinium also sinusitis Glycopyrronium also insomnia; less commonly malaise, hyperglycaemia, hypoaesthesia, rhinitis, epistaxis Tiotropium - also taste disturbance, oropharyngeal candidiasis, dizziness, epistaxis, pruritus; rarely intestinal obstruction (including paralytic ileus), insomnia, sinusitis, gingivitis, glossitis, stomatitis; also reported dehydration, joint swelling. Umeclidinium also less commonly arrhythmias, urinary tract infection, sinusitis, rash. Page 10 of 24

Antimuscarinic bronchodilators should be used with caution in patients with prostatic hyperplasia, bladder outflow obstruction, and those susceptible to angle-closure glaucoma. Use in special populations There is no relevant use in paediatrics and adolescents for any of the LAMAs. Aclidinium- no dosage adjustments needed in the elderly or those with renal or hepatic impairment. Glycopyrronium- no dosage adjustments needed in the elderly or those with hepatic impairment. In patients with severe renal impairment or end-stage renal disease requiring dialysis glycopyrronium should be used only if the expected benefit outweighs the potential risk. Tiotropium- no dosage adjustments needed in the elderly or those with hepatic impairment. As plasma concentration increases with decreased renal function in patients with moderate to severe renal impairment (creatinine clearance 50 ml/min) tiotropium bromide should be used only if the expected benefit outweighs the potential risk. There is no long term experience in patients with severe renal impairment. Umeclidinium- no dosage adjustments needed in the elderly or those with renal impairment. No dosage adjustment is required in patients with mild or moderate hepatic impairment, but umeclidinium has not been studied in patients with severe hepatic impairment and should be used with caution. Costs (Chemist & Druggist May 2015) Tariff status Activity costs Cost effectiveness Drug & Dosage 30 day cost / per patient Annual Cost per patient Aclidinium bromide 375 microgram (Eklira 28.60 347.01 Genuair ) - One inhalation twice daily. Glycopyrronium 44 microgram (Seebri 27.50 333.67 Breezhaler ) - Inhale one capsule once daily. Tiotropium 18 microgram Capsules for 33.50 406.47 Spiriva HandiHaler ) - Inhale one capsule once daily. Tiotropium 18 microgram (Spiriva Combopak 34.87 407.84* Capsules + HandiHaler ) - Inhale one capsule once daily. Tiotropium 2.5 microgram (Spiriva 33.50 406.47 Respimat ) - Two puffs once daily. Umeclidinium bromide 55 microgram (Incruse Ellipta ) - One inhalation once daily. 27.50 333.67 * 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 The LAMA inhalers are included within the National Tariff in secondary care. Refer to Costs box also. Tiotropium is used as the cost comparator in most health economic analyses. The Scottish Medicines Consortium Page 11 of 24

has provided health economic analysis in their reports on aclidinium, glycopyrronium and umeclidinium. SMC Aclidinium - The submission reported the annual cost with aclidinium would be 343 versus 386 with tiotropium. Given this finding, the economic case was demonstrated. The economics case described above was based on the price of the main comparator at the time of the submission. The price of the comparator has subsequently changed (see Cost of relevant comparators section of this guidance document for the relevant price) but the SMC is satisfied that this has not altered the conclusion that the economic case for aclidinium has been demonstrated. SMC Glycopyrronium -The analysis compared the total cost per patient per year for glycopyrronium versus tiotropium. Only drug acquisition costs were included in the analysis. The results showed that the total cost per patient per year is 334.58 for glycopyrronium compared to 408.95 for tiotropium 18 micrograms and 431.92 for tiotropium 5 micrograms. On this basis glycopyrronium would therefore be the preferred treatment on costminimisation grounds. Sensitivity analysis was not provided given the simple nature of the analysis, but there were no major concerns noted. As such, the economic case has been demonstrated. SMC- Umeclidinium The main economic results are as follows, with umeclidinium 55 micrograms demonstrated to represent cost savings compared to tiotropium and aclidinium, and to be cost neutral compared to glycopyrronium: Savings vs umeclidinium 55 Cumulative discounted savings after: LAMA Year 1 Year 2 Year 3 Year 4 Year 5 (dose/mg) Umeclidinium n/a n/a n/a n/a n/a 55 Tiotropium 18-73.00-143.53 - - - 211.68 277.52 341.13 Tiotropium 2.5-73.00-143.53 - - - 211.68 277.52 341.13 Aclidinium 322-13.38-26.31-38.81-50.88-62.54 Glycopyrronium 0.00 0.00 0.00 0.00 0.00 44 In addition, when umeclidinium 55 micrograms is compared with a weighted comparator cost based on the proportions of patients receiving each of the comparator LAMAs, the cost savings are estimated to be 69.22 in year one rising to a cumulative discounted saving of 323.47 over 5 years. The results are based on indirect comparisons that had some limitations, but despite these, the economic case has been demonstrated. Potential number of patients in 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) An average GP practice of 6,600 patients is likely Page 12 of 24

Bedfordshire and Luton Impact per 100,000 population Affordability considerations 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. Bedfordshire CCG LAMA inhaler usage April 2014 to March 2015 Drug Name Pack Cost Items Tiotropium (Spiriva ) 18 mcg combopak (with HandiHaler ) (30) 215,950 5663 Tiotropium (Spiriva ) 18 mcg refill pack (30) 925,677 24160 Tiotropium (Spiriva Respimat ) 2.5 mcg inhaler 60 dose 113,163 3052 Aclidinium Bromide (Eklira Genuair ) 322 mcg (60 dose) 55,455 1797 Glycopyrronium Bromide (Seebri Breezhaler ) 44 mcg inhalation powder caps (30) 14,036 502 Umeclidinium bromide dry powder inhaler (Incruse Ellipta ) 55 mcg (30 dose) 0 0 Totals 1,324,281 35174 Luton CCG LAMA inhaler usage April 2014 to March 2015 Drug Name Pack Cost Items Tiotropium (Spiriva ) 18 mcg combopak (with HandiHaler ) (30) 82,518 2247 Tiotropium (Spiriva ) 18 mcg refill pack (30) 396,048 9440 Tiotropium (Spiriva Respimat ) 2.5 mcg inhaler 60 dose 78,312 1878 Aclidinium Bromide (Eklira Genuair ) 322 mcg (60 dose) 12,745 413 Glycopyrronium Bromide (Seebri Breezhaler ) 44 mcg inhalation powder caps (30) 839 20 Umeclidinium bromide dry powder inhaler (Incruse Ellipta ) 55 mcg (30 dose) 25 1 Totals 570,486 13999 Page 13 of 24

Decisions from other bodies NICE- Evidence summary new medicines available for aclidinium, glycopyrronium, umeclidinium and are reported under the evidence section in this bulletin. SMC (www.scottishmedicines.org.uk ) Aclidinium (Eklira Genuair ) 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 (COPD). In two phase III studies, aclidinium was statistically superior to placebo in improving lung function (forced expiratory volume in 1 second [FEV1]) after 12 weeks and 24 weeks. Glycopyrronium inhalation powder (Seebri Breezhaler ) 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 (COPD). In two phase III studies, glycopyrronium was statistically superior to placebo in improving lung function (forced expiratory volume in 1 second [FEV1]) after 12 weeks. Tiotropium bromide (Spiriva HandiHaler ) -Recommended for general use within NHS Scotland for the maintenance treatment of chronic obstructive pulmonary disease (COPD). In clinical trials, tiotropium demonstrated superior efficacy to ipratropium and salmeterol in improving lung function (FEV1). Generally, it has greater efficacy than ipratropium, and similar efficacy to salmeterol in improving dyspnoea, the use of rescue medication, the frequency of COPD exacerbations and hospitalisation due to exacerbations. Tiotropium Respimat inhaler (Spiriva Respimat ) following an abbreviated submission is accepted for restricted use within NHS Scotland as maintenance bronchodilator treatment to relieve symptoms of patients with chronic obstructive pulmonary disease. It may be used for patients in whom tiotropium is an appropriate choice of maintenance bronchodilator treatment but it is restricted to patients who have poor manual dexterity and therefore have difficulty using the HandiHaler device. Umeclidinium (Incruse ) is accepted for use within NHS Scotland following a full submission. Indication under review: as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Two randomised controlled, phase III studies demonstrated that after 12 and 24 weeks of treatment umeclidinium improved lung function compared with placebo in patients with moderate to severe COPD. There was also improvement in symptomatic outcomes such as dyspnoea. Umeclidinium is an alternative to other long-acting muscarinic antagonists (LAMAs). AWMSG (www.awmsg.org ) Aclidinium bromide (Eklira Genuair ) is recommended as an option for use within NHS Wales as a maintenance bronchodilator Page 14 of 24

treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease. Glycopyrronium bromide (Seebri 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. Tiotropium (Spiriva Respimat ) in progress Umeclidinium (Incruse ) 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. CCGs Hertfordshire Medicines Management Committee (HMMC) (www.hertsvalleysccg.nhs.uk ) Aclidinium -recommended for restricted use as a treatment option for adult patients with COPD when a LAMA is indicated but who are unable to use tiotropium HandiHaler due to an inability to use the device despite appropriate device education. Glycopyrronium- recommended as a treatment option for adult patients with COPD when a LAMA is indicated but who are unable to use tiotropium HandiHaler due to an inability to use the device despite appropriate device education, in line with Herts COPD guidelines. Tiotropium HandiHaler - first line choice in COPD guidelines. Cambridgeshire and Peterborough Joint Prescribing Group (CPJPG) (www.cambsphn.nhs.uk/cjpg.aspx ) Aclidinium (Eklira Genuair ) - recommended as an alternative 2nd line agent where a patient cannot use the tiotropium or glycopyrronium inhaler. Glycopyrronium (Seebri Breezhaler ) -second line formulary choice for COPD. Tiotropium Respimat second line formulary choice for specialist initiation if inhaler technique problem. Tiotropium HandiHaler - first line choice on formulary Milton Keynes Prescribing Advisory Group (MKPAG) COPD pathway updated June 2014 (www.formularymk.nhs.uk ) 1st line: Tiotropium HandiHaler (Caution if egfr is less than 50mL/min) 2nd line: Tiotropium Respimat (caution with cardiac rhythm disturbance, if egfr is less than 50mL/min. See BNF for details) or 2nd line: Glycopyrronium Breezhaler (caution with unstable ischaemic heart disease, left ventricular failure, arrhythmia, history of myocardial infarction, QT interval prolongation or if egfr less than 30mL/min. See BNF for details) or 2nd line: Aclidinium Genuair (caution with myocardial infarction within last 6 months, unstable angina, newly diagnosed arrhythmia See BNF for more details) Page 15 of 24

Northamptonshire Prescribing Advisory Group (NPAG) Formulary updated June 2015 (www.corbyccg.nhs.uk ) Aclidinium (Eklira Genuair) - COPD only Tiotropium via HandiHaler (Spiriva) - COPD only NB Spiriva Respimat has been linked with a non-significant increase in all-cause mortality compared with placebo so only recommended instead of HandiHaler if patient has poor dexterity. 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 16 of 24

Evidence strengths and limitations Aclidinium There are no published studies which directly compare aclidinium with a currently available LAMA or LABA. The studies demonstrated beneficial effects on lung function in people with moderate to severe COPD. The primary endpoints were disease-orientated outcome of change in FEV1 levels over 12 or 24 weeks. ATTAIN did have patient-orientated secondary outcomes of health status and dyspnoea was sufficiently powered to detect treatment differences in these. Studies reported on COPD exacerbations. The publication of further long term studies to assess outcomes and long-term safety would be useful. Glycopyrronium There is no robust evidence which compares aclidinium with a currently available LAMA or LABA. One study compared glycopyrronium with open-label tiotropium and found similar efficacy. However, the inability to blind tiotropium treatment means these results could be biased. Patient-orientated outcomes, SGRQ and TDI were recorded, but the results were not clinically significant. Reductions in exacerbations were found to be statistically significant along with reductions in use of rescue medication. The publication of further long term studies to assess outcomes and long-term safety would be useful. Umeclidinium There are no published studies which directly compare umeclidinium 55 micrograms with a currently available LAMA or LABA. There are some limited comparative data with tiotropium: a 7-day cross-over study. There are only limited data to support the use of umeclidinium alone as ICS were also permitted in the studies. At baseline between 24% and 51% of the study populations were using ICS. Disease-orientated FEV1 primary outcomes were reported. Patientorientated secondary and additional outcomes were included in 2 studies including TDI score, rescue salbutamol use and SGRQ score. Although time to first on-treatment COPD exacerbations were included, the study which reported these was not designed or powered to evaluate treatment effects on COPD exacerbations. There are limited long-term efficacy and safety data for the licensed dose (12 24 weeks; 52 week safety study used umeclidinium 113 micrograms and did not include the licensed umeclidinium dose). PAC New Drug Template Adapted from East Anglia Medicines Information, NHS Suffolk, NHS Cambridgeshire and NHS Derby templates * Reference BNF. Consult Summary of Prescribing Characteristics for full prescribing details. Page 17 of 24

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) British National Formulary (BNF) May 2015. www.medicinescomplete.com (Last viewed 26/5/15). (2) Eklira Genuair SPC. AstraZeneca UK Limited. www.medicines.org.uk (Last viewed 26/5/15) (3) Seebri Breezhaler SPC. Novartis Pharmaceuticals UK Ltd. www.medicines.org.uk (Last viewed 26/5/15) (4) Spiriva 18 micrograms inhalation powder, hard capsules for use in HandiHaler SPC, Boehringer Ingelheim Limited. www.medicines.org.uk (Last viewed 26/5/15) (5) Spiriva Respimat 2.5 micrograms Inhalation Solution SPC, Boehringer Ingelheim Limited. www.medicines.org.uk (Last viewed 26/5/15) (6) Incruse 55 micrograms inhalation powder, pre-dispensed SPC. GlaxoSmithKline UK. www.medicines.org.uk (Last viewed 26/5/15). (7) 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 2010. www.nice.org.uk (Last viewed 26/5/15). (8) UKMI New Drugs Online. www.ukmi.nhs.uk (Last viewed 20/5/15- user registration required.) (9) Bedfordshire and Luton COPD Guidelines. Revised April 2014 Version 2.0 www.gpref.bedfordshire.nhs.uk (Last viewed 26/5/15) (10) Global Initiatives Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease updated 2015. www.goldcopd.org (11) Karner C, Chong J, Poole P. The Cochrane Collaboration. Tiotropium versus placebo for chronic obstructive pulmonary disease (Review) 2014, Issue 7. (12) National Institute for Health and Care Excellence. Evidence summary: new medicine ESNM8: Chronic obstructive pulmonary disease: aclidinium bromide. Last updated 07 January 2013. www.nice.org.uk (13) National Institute for Health and Care Excellence. Evidence summary: new medicine ESNM9: Chronic obstructive pulmonary disease: glycopyrronium bromide. Last updated 07 January 2013. www.nice.org.uk (14) National Institute for Health and Care Excellence. Evidence summary: new medicine ESNM52: Chronic obstructive pulmonary disease: umeclidinium inhaler (Incruse ) Last updated January 2015. www.nice.org.uk (15) UK Medicines Information. Prescribing Outlook, New Medicines. Sept 2012. Page 18 of 24

Appendix 1- LAMA, LABA, ICS/LABA and LABA/LAMA inhaled therapy for COPD annual cost per patient LAMA, LABA, ICS/LABA and LABA/LAMA Inhaled Therapy for COPD annual cost per patient 500 450 406 406 408 394 394 400 347 355 355 355 356 364 364 350 334 334 320 300 447 250 200 150 100 50 0 144 219 Page 19 of 24

Appendix 2: Comparison of LAMA Inhalers Outcomes reported in trials Improvements Reduction in in lung exacerbations function LAMA Aclidinium (Eklira Genuair ) Glycopyrronium (Seebri Breezhaler ) Tiotropium HandiHaler Tiotropium Respimat Umeclidinium Ellipta but studies not statistically powered to detect difference. Reduction in exacerbations leading to hospitalisation not clinically significant result SGRQ TDI Renal impairment Use in special populations Hepatic impairment Dosage frequency Single / multiple dose device Device Cost / 30 days Twice daily Multiple DPI 28.60 not all clinically significant results Use in severe renal impairment or end-stage renal disease requiring dialysis only if benefit outweighs risk. Use in moderate to severe renal impairment only if expected benefit outweighs risk. No long term experience in severe renal impairment. Use in moderate to severe renal impairment only if expected benefit outweighs risk. No long term experience in severe renal but studies not statistically powered to detect difference. one study not statistically significant impairment. Once daily Single DPI 27.50 Once daily Single DPI 34.87 Refill 33.50 Once daily Multiple MDI 33.50 Severe hepatic impairment use with caution. Once daily Multiple DPI 27.50 Page 20 of 24

Bedfordshire and Luton Joint Prescribing Committee (JPC) Assessment against Ethical and Commissioning Principles Treatment assessed (September 2015): Choice of Long Acting Muscarinic Agent (LAMA) inhaler for COPD JPC Recommendation The availability of a new LAMA inhaler, umeclidinium, the impending loss of patent protection for tiotropium and subsequent availability of a branded generic and interest in using aclidinium Genuair led to the need to review the LAMA inhaler choices within the COPD guidelines. The Committee agreed that tiotropium remained a good first-line LAMA inhaler choice based on clinical effectiveness grounds, choice of 2 different devices and the likely availability of a less costly branded generic inhaler in the near future. The Committee agreed to keep the existing recommendations on choice of LAMA inhaler for the treatment of COPD (with the updated MHRA drug safety advice regarding tiotropium (Feb 2015), unless new evidence emerges or the economic picture merits a review of the choice of products in the future. Choice of Long Acting Muscarinic Antagonist (LAMA) First Choice: Tiotropium* (Spiriva HandiHaler ) - One 18 microgram capsule inhaled once daily or Tiotropium* Respimat ( 2.5 micrograms per puff) - Two puffs once daily or Tiotropium* branded generic inhaler (when available) Second Choice: Inhaled aclidinium* bromide (Eklira Genuair ) 400 micrograms - one inhalation twice daily or inhaled glycopyrronium* bromide (Seebri Breezhaler ) 50 micrograms - one capsule inhaled once daily *Tiotropium, aclidinium and glycopyrronium 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). (www.medicines.org.uk & www.gov.uk/government/uploads/system/uploads/attachment_data/file/409046/february_2015_drug_safety _Update 1_.pdf) 1) Clinical Effectiveness The evidence base shows that all the LAMA inhalers are effective bronchodilators which produce clinically significant improvements in lung function (FEV1). The evidence base for improvements in patient-orientated outcomes including breathlessness (TDI), quality of life (SGRQ), reductions in the risk of exacerbations and reduced exacerbations leading to hospitalisations is clinically significant for tiotropium. The other LAMA inhalers show clinically significant improvements in some but not all of these patient-orientated outcomes. Aclidinium has shown clinically significant improvements in breathlessness, quality of life and, although reductions in exacerbations were seen, the studies were not statistically powered Page 21 of 24

to detect this. Glycopyrronium has shown a clinically significant reduction in exacerbations, but not all studies showed clinically significant improvements in breathlessness and quality of life. Umeclidinium has shown clinically significant improvements in quality of life, but improvements seen in breathlessness were not statistically significant in one study and although reductions in exacerbations were seen, the studies were not statistically powered to detect this. 2) Cost Effectiveness Tiotropium is used as the cost comparator in most health economic analyses. The Scottish Medicines Consortium has provided health economic analysis in their reports on aclidinium, glycopyrronium and umeclidinium. SMC Aclidinium - The submission reported the annual cost with aclidinium would be 343 versus 386 with tiotropium. Given this finding, the economic case was demonstrated. The economics case described above was based on the price of the main comparator at the time of the submission. The price of the comparator has subsequently changed (see Cost of relevant comparators section of this guidance document for the relevant price) but the SMC is satisfied that this has not altered the conclusion that the economic case for aclidinium has been demonstrated. SMC Glycopyrronium -The analysis compared the total cost per patient per year for glycopyrronium versus tiotropium. Only drug acquisition costs were included in the analysis. The results showed that the total cost per patient per year is 334.58 for glycopyrronium compared to 408.95 for tiotropium 18 micrograms and 431.92 for tiotropium 5 micrograms. On this basis glycopyrronium would therefore be the preferred treatment on costminimisation grounds. Sensitivity analysis was not provided given the simple nature of the analysis, but there were no major concerns noted. As such, the economic case has been demonstrated. SMC- Umeclidinium The main economic results are as follows, with umeclidinium 55 micrograms demonstrated to represent cost savings compared to tiotropium and aclidinium, and to be cost neutral compared to glycopyrronium: Savings vs umeclidinium 55 Cumulative discounted savings after: LAMA (dose/mg) Year 1 Year 2 Year 3 Year 4 Year 5 Umeclidinium 55 n/a n/a n/a n/a n/a Tiotropium 18-73.00-143.53-211.68-277.52-341.13 Tiotropium 2.5-73.00-143.53-211.68-277.52-341.13 Aclidinium 322-13.38-26.31-38.81-50.88-62.54 Glycopyrronium 44 0.00 0.00 0.00 0.00 0.00 In addition, when umeclidinium 55 micrograms is compared with a weighted comparator cost based on the proportions of patients receiving each of the comparator LAMAs, the cost savings are estimated to be 69.22 in year one rising to a cumulative discounted saving of 323.47 over 5 years. The results are based on indirect comparisons that had some limitations, but despite these, the economic case has been demonstrated. 3) Equity No impact envisaged. 4) Needs of the community Page 22 of 24

Alternative LAMA inhalers are cheaper than the current first line choice, tiotropium. There is therefore the potential for short term cost savings by using alternative LAMA inhalers. However, when the tiotropium patent expires in September 2015 there are likely to be branded generic tiotropium inhalers available and a reduced cost. Medium to long term savings may be made by keeping to tiotropium first line and this may be larger than any short term savings made by using less costly alternatives before a branded generic tiotropium is available. 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. In Bedfordshire CCG, in 2014/15, 35,174 LAMA inhalers were prescribed at a cost of 1,324,281. In Luton CCG, in 2014/15, 13,999 LAMA inhalers were prescribed at a cost of 570,486. 6) Policy drivers NICE Clinical Guideline 101 on COPD. Bedfordshire and Luton COPD Guidelines. Tiotropium HandiHaler is the current first line choice LAMA inhaler. Second-line LAMA inhaler options where Tiotropium HandiHaler is not suitable for an individual patient are currently: Aclidinium bromide 375 microgram (Eklira Genuair ) Multidose dry powder inhaler- One inhalation twice daily. Glycopyrronium 44 microgram (Seebri Breezhaler ) - Single dose dry powder inhaler- Inhale one capsule once daily. Tiotropium 2.5 microgram (Spiriva Respimat ) - Multiple dose inhalation solution -Two puffs once daily. NB: Umeclidinium Ellipta was launched after the COPD Guidelines were updated in 2013. 7) Disinvestment Potential for disinvestment in LAMA inhalers not recommended for use by the JPC. 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 23 of 24