New Medicines Committee Briefing Updated July 2017

Glycopyrronium bromide (Seebri® Breezhaler) for maintenance treatment of adults with stable COPD

Primary Care  Seebri® Breezhaler is to be reviewed for use within: Secondary Care 

Summary:

 Glycopyrronium (Seebri® Breezhaler) dry-powder inhaler is a once-daily, long-acting (LAMA).  Seebri® was launched in the UK in November 2012, as a maintenance for treatment of airflow obstruction in adult patients with chronic obstructive pulmonary disease (COPD).

 Seebri® was previously reviewed in July 2013 and the Area Prescribing Committee (APC) concluded that Seebri® should not be included within the North Staffordshire Joint Formulary as at that time there were no direct comparator trials with other active , lack of long term safety data and little local experience of its use.

 There is no updated guidance available from NICE, SMC, RDTC, MTRAC or Cochrane since July 2013 but there are now two new clinical trials (GLOW5 and GEM3 study)1,2 that has compared Seebri with active bronchodilators

 The GLOW5 study – a randomised double blinded evaluation of the efficacy and safety of glycopyrronium versus tiotropium demonstrated similar efficacy and safety over 12 weeks, with glycopyrronium having a faster onset of action on day 1 in comparison to tiotropium in patients with moderate-to-severe COPD.

 The GEM3 study – a randomised double blinded parallel study of the long term safety of glycopyrronium in comparison to demonstrated a similar safety profile over 52 weeks in patients with moderate-to-severe COPD.

 Seebri® is a black triangle drug ( ) and is monitored intensively by the MHRA.

1 Chapman K, Beeh K, Beier J et al. A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study. BMC pulmonary medicine 2014; 14; 4 2 Mahler D, Gifford A, Satti A et al. Long-term safety of glycopyrrolate: A randomized study in patients with moderate- to-severe COPD (GEM3) with moderate-to-severe COPD (GEM3)/ Respiratory Medicines 2016; 115; 39-45 1 | P a g e

Formulary application Consultant submitting application: Dr Imran Hussain (Respiratory Consultant) Clinical Director supporting application: Dr Anthony Cadwgan (Clinical Director)

Dr Hussain has requested for Seebri® to be re-considered for inclusion in the North Staffordshire Joint Formulary for the maintenance treatment of adult patients with stable COPD. Seebri® was previously reviewed in July 2013 and not approved by the Area Prescribing Committee (APC) for inclusion within the North Staffordshire Joint Formulary as at that time there were no direct comparator trials with other active bronchodilators, lack of long term safety data and little local experience of its use. Dr Hussain states that there is now greater experience with Seebri® within the respiratory team as well as long term safety and tolerability data compared to other bronchodilators. Dr Hussain noted that there is no cost difference between Seebri® and the alternative treatments included on the formulary. He also stated the following as potential benefits from having Seebri® on the formulary:  if Ultibro® is accepted onto the formulary, then this would help in terms of device familiarity for patients

 The drug has a faster rate of onset compared to the other LAMAs (tiotropium and aclidinium), which may improve patient functioning faster

 The device requires a lower inspiratory flow rate compared to the Ellipta® and Genuair® devices which increases the likelihood that patients will be able to use the device as their disease progresses. This will also provide an option for trialling patients on this device prior to consideration of escalation to a combination inhaler or nebuliser. He intends that Seebri® be initiated by both hospital and primary care prescribers.

Current formulary status

The North Staffordshire Joint Formulary currently lists the following agents.

3.1.2 Antimuscarinic Bronchodilators  At a Incruse Ellipta® (Umeclidinium) For use in COPD only glance guide:

Stable COPD  At a glance guide: For use in COPD with end of day deterioration Eklira Genuair® (Aclidinium) Stable COPD  MTRAC  At a Ipratropium glance guide:

Stable COPD For use in COPD only

Braltus Zonda® (Tiotropium) 10 microgram per delivered dose Spiriva Respimat® 2 For use in only  MTRAC (Tiotropium)  Seebri® Breezhaler (Glycopyrronium Not approved for inclusion in the North Staffordshire Joint Medicines Review bromide) Formulary Verdict Sheet

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Guidance and Evidence Summary

There is no updated guidance available from NICE, SMC, RDTC, MTRAC or Cochrane since July 2013 but there are now two new clinical trials (GLOW5 and GEM3 study)3,4 that have compared Seebri® with active bronchodilators.

Recent trials post NMC review 2013

GLOW53 study: A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study The GLOW5 study - a randomised, blinded, double-dummy study of 657 patients - compared glycopyrronium 50micrograms once daily to tiotropium 18micrograms once daily for 12 weeks. The primary objective was to demonstrate non-inferiority of glycopyrronium compared to blinded tiotropium for trough FEV1 after 12 weeks. A key secondary objective was to demonstrate superiority of glycopyrronium compared to tiotropium. Other secondary objectives included the effect of glycopyrronium versus tiotropium on other measures of lung function including forced vital capacity (FVC), peak FEV1, FEV1 area under the curve from 0-4hours (AUC0-4h), and inspiratory capacity (IC); and the effect of glycopyrronium verses tiotropium on breathlessness measured using the Transition Dyspnoea Index (TDI) focal score, health status according to the St George’s Respiratory questionnaire (SGRQ) total score, daily rescue medication use, COPD exacerbations and COPD symptoms over 12 weeks of treatment.

GLOW5 enrolled patients ≥40 years with stable moderate to severe COPD (post-bronchodilator FEV1 30-

79% predicted and FEV1/FVC <0.7), who were current or ex-smokers with at least a 10 pack-year history of smoking. The main exclusion criteria was a respiratory tract infection within 4 weeks or COPD exacerbations requiring treatment within 6 weeks prior to screening, concomitant respiratory diseases or clinically significant cardiovascular disease. Long-acting bronchodilators were discontinued but inhaled corticosteroids (ICS) and short-acting β2-agonists could be continued throughout the study – approximately half of the patients in each group were using ICS at baseline. 96% of patients completed the study. The number of patients who discontinued was similar in both groups. Spirometry: Glycopyrronium met the criteria for non-inferiority to tiotropium for improvement in trough

FEV1 after 12 weeks of treatment (least squares means [LSM] treatment difference 0ml, 95% CI: -32, 31ml, p<0.001). At week 12, peak FEV1, FEV1 at all time points from 0-4h and 24h and FEV1 AUC0-4h was comparable between glycopyrronium and tiotropium. No statistically significant difference was observed between the two treatment groups. Glycopyrronium demonstrated rapid bronchodilation following the first dose on day 1, with significantly higher FEV1 at all time points from 0-4h post-dose versus tiotropium (all p<0.001).

3 Chapman K, Beeh K, Beier J et al. A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study. BMC pulmonary medicine 2014; 14; 4

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Symptoms, health status and exacerbations: Glycopyrronium demonstrated comparable improvements to tiotropium in TDI focal score, SGRQ total score, rescue medication use and the rate of COPD exacerbations. A similar proportion of patients in both groups experienced a clinically meaningful improvement in TDI focal score (≥1 point) [odds ratio 1.06; p = 0.753] and clinically meaningful improvement in SGRQ total score (≥ 4 point reduction) [OR 1.11; p = 0.575]. The number of patients who experienced a moderate or severe COPD exacerbation was similar in both groups (9.7% with glycopyrronium versus 7.5% with tiotropium). Patients on glycopyrronium also had a significantly lower total COPD symptom score versus patients on tiotropium after 12 weeks (treatment difference -0.3, p = 0.035), although the criteria for clinical significance was not defined for this parameter. The use of rescue medication in the two treatment groups was comparable. Safety: Adverse events were reported by a similar percentage of patients receiving glycopyrronium (40.4%) and tiotropium (40.6%). The most frequently reported adverse event was COPD worsening (17.6% in the tiotropium group compared to 15.3% in the glycopyrronium group). Serious adverse events and adverse events leading to discontinuation occurred in a comparable number of patients in both groups. Limitations: The trial was conducted over 12 weeks – a longer timeframe would normally be required for assessment of drug efficacy on outcomes such as exacerbation rates.

GEM3 Study5: Long term safety of glycopyrrolate: A randomised study in patients with moderate to severe COPD (GEM3) Mahler et al conducted a multi-centre double-blind study comparing glycopyrronium 15.6micrograms twice daily to indacaterol 75micrograms once daily, both delivered via the Neohaler® device, over 52 weeks (n=511). The primary objective was to assess the safety and tolerability in terms of adverse event reporting rates over 52 weeks. Safety related secondary endpoints included time to first moderate or severe COPD exacerbation, measurement of vital signs, ECG and laboratory evaluations over 52 weeks. Efficacy related secondary endpoints included pre-dose trough FEV1 at week 52, FEV1 and FVC measurements at all time points and rescue medication use over the 52 week period.

GEM3 enrolled patients ≥40 years with stable moderate to severe COPD (post-bronchodilator FEV1 30-79% predicted and FEV1/FVC <0.7), who were current or ex-smokers with at least a 10 pack-year history of smoking. The main exclusion criteria were COPD exacerbations requiring treatment within 6 weeks prior to screening, history of asthma, or clinically significant cardiovascular disease. Long-acting bronchodilators and were discontinued but inhaled corticosteroids (ICS) and short-acting β2-agonists could be continued throughout the study. 511 patients were randomised to glycopyrronium (n=254) or indacaterol (n=257). 81.6% of patients completed the 52 week planned treatment period; 66.1% completed the 52 week treatment period, and 15.5% discontinued the study treatment but continued study visits. The most common reason for discontinuation was patient decision, with similar rates between both the treatment groups. Safety: The overall incidence of adverse events was comparable between glycopyrronium (77.3%) and indacaterol (77.0%) groups and the rate of discontinuation of the study medication due to adverse events was low, and comparable between the two groups. The majority of adverse events were mild or moderate in severity and occurred at comparable rates. COPD exacerbation was the most commonly reported adverse event which occurred in 36.3% for glycopyrronium and 37.1% in the indacaterol group. Serious adverse events were reported in 13.1% of patients in the glycopyrronium group compared to 13.3% in the

5 Mahler D, Gifford A, Satti A et al. Long-term safety of glycopyrrolate: A randomized study in patients with moderate- to-severe COPD (GEM3) with moderate-to-severe COPD (GEM3)/ Respiratory Medicines 2016; 115; 39-45 4 | P a g e

indacaterol group. COPD exacerbation was the most commonly reported serious adverse event, with similar rates between glycopyrronium (4.4%) and indacaterol (4.7%) groups. The incidence of major adverse cardiovascular events was low and comparable between the groups. No clinically relevant differences for vital signs or ECG parameters were observed between the two treatment groups.

Efficacy: Glycopyrronium 15.6micrograms twice daily showed comparable improvements in pre-dose FEV1 and FVC from baseline to indacaterol 75 micrograms once daily. No significant differences were seen between the two treatment groups in the time to first moderate or severe COPD exacerbation or the incidence of exacerbations. There was no statistically significant difference in the number of days without rescue medication use or the number of mean night-time puffs of rescue medication used between the two treatment groups. However, the change from baseline in the use of rescue medication was numerically lower in daily (treatment difference, 0.63 puffs, p=0.014) and daytime (treatment difference 0.34 puffs, p=0.014) number of puffs with indacaterol compared to glycopyrronium. Limitations: The dosing of glycopyrronium used in the trial – 15.6micrograms twice daily - is licensed in United States; however the UK licensing is different (50micrograms once daily). The trial compared the use of glycopyrronium to indacaterol, a long acting beta agonist which is not commonly used in UK clinical practice.

Cost Analysis

Comparative Costs and Expenditure of long acting bronchodilators in Secondary Care (UHNM) March 2016 – February 2017:

Current Price % Usage UHNM UHNM TOTAL Total EXPENDITURE UHNM (incl. Medicine Description Constituents Pack size Quantity (VAT applied as VAT) appropriate)

SEEBRI BREEZHALER GLYCOPYRRONIUM £30.70 310 £311.14 10.21% (30 doses) BROMIDE 30 caps EKLIRA GENUAIR (60 £28.80 148 £4,287.01 4.88% doses) ACLIDINIUM 1 inhaler INCRUSE ELLIPTA (30 £33.00 387 £13,351.35 12.75% UMECLIDINIUM doses) 1 inhaler SPIRIVA COMBOPACK £38.92 1666 £66,140.93 54.89% (30 doses) TIOTROPIUM 1 inhaler SPIRIVA REFILL (30 £38.20 387 £14,668.71 12.75% doses) TIOTROPIUM 1 inhaler SPIRIVA RESPIMAT 137 4.51% £26.22 £4,035.12 (cart +device) (60 doses) TIOTROPIUM 1 inhaler 0 NA £23.22 NA BRALTUS ZONDA TIOTROPIUM 1 inhaler TOTAL £102,794.26

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Comparative Costs and Expenditure of long acting bronchodilators in Primary Care (North Staffordshire CCGs) March 2016 – February 2017:

Current Price North Staffordshire Primary Number Medicine Pack CCGs Sum of NIC Constituents Care (excl. of Packs % Usage Description size VAT) SEEBRI BREEZHALER GLYCOPYRRONIUM £27.50 229 £5,500.01 (30 doses) BROMIDE 30 caps 0.34% EKLIRA GENUAIR (60 1 4904 £140,254.40 doses) ACLIDINIUM inhaler £28.60 7.18% INCRUSE ELLIPTA (30 1 UMECLIDINIUM £27.50 6901 £189,777.14 doses) inhaler 10.10% SPIRIVA COMBOPACK 1 £34.87 7406 £258,247.00 (30 doses) TIOTROPIUM inhaler 10.84% SPIRIVA REFILL (30 1 £33.50 45836 £1,535,497.05 doses) TIOTROPIUM inhaler 67.10% SPIRIVA RESPIMAT (cart +device) (60 1 £23.00 3012 £79,765.35 doses) TIOTROPIUM inhaler 4.41% BRALTUS ZONDA (30 1 doses) TIOTROPIUM inhaler £25.80 10 £258.00 0.01% £2,209,298.95 TOTAL

Other cost considerations: Seebri® is also available in a 6 capsule pack plus inhaler at a cost of one fifth of the 30 capsule pack.

Produced by Helen Wrightson Specialist Rotational Pharmacist - Medicines Management University Hospital of North Midlands Telephone: 01782 674541 e-mail: [email protected]

Produced for use within the NHS. Not to be reproduced for commercial purposes.

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New Medicines Committee Briefing July 2013

Glycopyrronium bromide (Seebri® Breezhaler) for maintenance treatment of airflow obstruction in adults with COPD

Seebri® Breezhaler is to be reviewed for use within:

Primary Care  Secondary Care 

Summary:

 Glycopyrronium (Seebri® Breezhaler) dry-powder inhaler is a once-daily, long-acting muscarinic antagonist (LAMA).

 Seebri® was launched in the UK in November 2012, as a maintenance bronchodilator for treatment of airflow obstruction in adult patients with chronic obstructive pulmonary disease (COPD).

 Two randomised-controlled, double-blind, Phase III trials (GLOW 1 and GLOW 2) showed glycopyrronium 1 to be statistically superior to placebo in improving lung function (FEV1) after 12 weeks.  NICE Evidence Summary recommends more robust evidence to compare patient-oriented outcomes for Seebri® with other active treatments for COPD to enable its place in therapy to be more clearly established.1  Midlands Therapeutics Review and Advisory Committee (MTRAC) recommended that glycopyrronium is suitable for prescribing in primary care.2  Regional Drug & Therapeutics Centre (RDTC) recognised Seebri® to be more cost effective option than the other available LAMAs but noted that longer safety data and direct comparator trials are still lacking.3

 SMC has accepted the use of Seebri® Breezhaler within NHS Scotland as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.4

 Seebri® is a black triangle drug ( ) and is monitored intensively by the CHM and MHRA.5

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Formulary application:

Respiratory: Consultant submitting application: Dr Ajit Thomas (Respiratory Consultant) Clinical Director supporting application: Dr Martin Allen (Clinical Director)

Dr Thomas has requested for Seebri® to be considered for inclusion in the North Staffordshire Joint Formulary as an alternative to tiotropium (Spiriva®) for the maintenance treatment of airflow obstruction in adult patients with COPD. Dr Thomas noted the cost difference between Seebri® (£330 per patient per year) and Spiriva® (£418 per patient per year). There was also the advantage of faster onset of action with Seebri® (5 minutes) compared to tiotropium (30 minutes). He intends that Seebri® be initiated by both hospital and primary care prescribers.

Background:

An estimated 3 million people have COPD in the UK.6 About 2 million people have COPD which remains undiagnosed. It is characterised by airflow obstruction that is not fully reversible and is usually progressive in the long term. The airflow obstruction is present because of a combination of airway and parenchymal damage. The damage is the result of chronic inflammation that differs from that seen in asthma and which usually is as a result of tobacco smoke. COPD is an irreversible lung disease which includes the conditions chronic bronchitis and emphysema that is usually brought on by airway irritants, such as smoking or inhaled dust. The symptoms include breathlessness and chronic cough. NICE6 stated that COPD should be defined based on:

 Airflow obstruction where the FEV1/FVC ration is less than 0.7

 If FEV1 is >80% predicted normal with respiratory symptoms, e.g. breathlessness or cough. COPD produces symptoms, disability and impaired quality of life which may respond to pharmacological and other therapies that have limited or no impact on the airflow obstruction. There is no single diagnostic test for COPD. Making a diagnosis relies on clinical judgement based on a combination of history, physical examination and confirmation of the presence of airflow obstruction using spirometer.1 Long-acting inhaled bronchodilators are recommended for the management of moderate and more severe COPD and are considered more effective and convenient than short-acting agents (, terbutaline, ipratropium) with adherence to long-term treatment being poor among COPD subjects. Currently available agents include the once daily (indacaterol) and twice daily ( and ) long acting beta agonists (LABAs), and the once daily (tiotropium and glycopyrronium) and twice daily (aclidinium) anti muscarinic antagonists (LAMA).5 According to NICE, the choice of drugs should be based on individual’s symptomatic response and preference, the drug’s potential to reduce exacerbations, its side effects and cost. Inhaled muscarinic antagonists work by binding to muscarinic receptor subtypes, M1 to M5 in varying affinities, and inhibiting the bronchoconstrictor action of acetylcholine, on airway smooth muscle cells, 8 | P a g e

thereby dilating the airways. Glycopyrronium has a greater selectivity for the human M3 receptors over M2 receptors and works by blocking the bronchoconstrictor action of acetylcholine on airway smooth muscle cells. The duration of action of both tiotropium and glycopyrronium are approximately 24 hours hence the once daily.7

Current formulary status:

The North Staffordshire Joint Formulary currently lists the following agents:

3.1.2 Antimuscarinic bronchodilators

Ipratropium

Tiotropium Restriction: See APC/NMC Advice APC/NMC

APC/NMC Advice: Tiotropium May 2005

Tiotropium should only be prescribed for patients with COPD who remain symptomatic despite treatment with short- acting bronchodilators and for patients who have two or more exacerbation per year, this recommendation is in line with NICE guidance. Tiotropium is not suitable for acute symptomatic relief. Tiotropium should be considered the second-line long-acting bronchodilator; salmeterol is to remain first-line. Salmeterol and tiotropium can be used in combination when a patient has responded to salmeterol alone. However, combination therapy should be discontinued after 4 weeks if there is no improvement in symptoms or lung function. If a patient has not shown improvement on salmeterol alone, salmeterol should be discontinued before tiotropium is prescribed

Within Secondary Care tiotropium should only be prescribed on recommendation of a respiratory physician (Consultant, SpR or Staff Grade)

Therapeutic class and mode of action:7 Seebri® is an inhaled long-acting muscarinic receptor antagonist () with greater selectivity for the human M3 receptors over M2 receptors. Parasympathetic nerves are the major bronchoconstrictive neural pathway in airways, and cholinergic tone is the key reversible component of airflow obstruction in COPD. Glycopyrronium works by blocking the bronchoconstrictor action of acetylcholine on airway smooth muscle cells, thereby dilating the airways. Seebri® has a rapid onset of action of about 5 minutes with sustained bronchodilation seen over 24 hours.

Licensed indication:7

Seebri Breezhaler is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. It is not indicated for the initial treatment of acute episodes of , i.e. as a rescue therapy.

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Dosage and administration:7

The recommended dose is the inhalation of the content of one capsule once daily using the Seebri Breezhaler inhaler. Seebri Breezhaler is recommended to be administered, at the same time of the day each day. If a dose is missed, the next dose should be taken as soon as possible. Presentation:7

Inhalation powder, hard capsule Transparent orange capsules containing a white powder, with the product code “GPL50” printed in black above and the company logo printed in black below a black bar.

Guidance:

Nice Guidance published Yes Management of chronic obstructive pulmonary disease in adults in primary and secondary care (Partial update) (2010)

NICE Guidance: 1016 Made recommendations for effective inhaled therapy in people with stable COPD who remain breathless or have exacerbations despite use of SABA as required to offer as maintenance therapy:

 If FEV1 > 50% predicted; either LABA or LAMA

 If FEV1 <50% predicted; either LABA with ICS in combination or LAMA.

If the exacerbation and breathlessness continues despite combination of LABA and ICS, offer addition of

LAMA irrespective of their FEV1

NICE , in an Evidence Summary1 published in January 2013, stated that evidence from the 2 phase III placebo-controlled studies showed a statistically significant improvement in the disease-oriented primary endpoint, 12 week trough FEV1 with glycopyrronium bromide compared with placebo. It stated that the differences are around the level considered to be clinically relevant. It also noted that both studies showed a statistically significant difference for the key secondary patient-oriented outcomes, breathlessness and health status. However the difference in health status was not clinically significant while the difference for breathlessness was clinically significant in GLOW 1 but not in GLOW 2.

NICE ESNM9 indicated that there is need for more robust evidence comparing patient-oriented outcomes for Seebri® with other active treatments for COPD to enable its place in therapy to be more clearly established. It did highlight the uncertainty of long term safety issues and the effects of glycopyrronium being maintained beyond 1 year. 10 | P a g e

Scottish Medicines Consortium:

SMC recommended use within NHS Scotland:4 Yes

SMC accepted Seebri® Breezhaler for use within NHS Scotland as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD this was based on evidence from two phase III studies were glycopyrronium was statistically superior to placebo in improving FEV1 after 12 weeks. They noted that Seebri® is preferable to tiotropium on cost-minimisation grounds and would offer an alternative inhaled LAMA to tiotropium and aclidinium for COPD patients.

Regional Drug and Therapeutics Centre:3 Yes

RDTC stated that trials have demonstrated that glycopyrronium had a greater effect on lung function, exercise endurance and disease-specific patient reported outcomes than placebo. Glycopyrronium was well tolerated, with anticholinergic effects being the most frequently reported. RDTC noted that the available data so far suggest glycopyrronium may provide more rapid bronchodilation than tiotropium, whilst reducing the rate of moderate and severe exacerbations. Glycopyrronium may offer a more cost-effective option than the other two available LAMAs, tiotropium and aclidinium; however, long-term safety data and direct comparator trials are still lacking. RDTC highlighted that all three GLOW trials were designed and funded by the manufacturer and excluded patients with cardiovascular risk factors. The populations enrolled in the studies were younger and healthier patients, on average, than the UK population with COPD. Glycopyrronium has not been compared to other long-acting bronchodilators in appropriately powered trials.

Midlands Therapeutics Review and Advisory Committee (MTRAC):2 Yes

MTRAC stated that commissioners may wish to bear the following in mind when considering the commissioning of glycopyrronium:  Based on the published evidence, glycopyrronium bromide appears to be of similar efficacy to tiotropium but longer term data are lacking.  Based on current prices, glycopyrronium bromide is less expensive than tiotropium.  Glycopyrronium bromide could be considered as an option when initiating treatment for a new patient.  There is insufficient evidence to support a switching in prescribing from tiotropium to glycopyrronium in patients already receiving treatment for COPD.  The patent for tiotropium is expected to expire in 2015. MTRAC stated that glycopyrronium is suitable for prescribing in primary care for maintenance treatment of COPD. The evidence for the efficacy of glycopyrronium was considered to be relatively strong based on two

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randomised controlled trials (GLOW 1 and 2) which found glycopyrronium to be more effective than placebo in improving lung function, breathlessness and lowering exacerbations.

Cochrane Review No

Efficacy:

GLOW 1 Study:8 D’Urzo et al in a double-blind, randomised control trial of 822 patients compared the efficacy and safety of glycopyrronium 50 micrograms once daily with placebo in a ratio of 2:1 for 26 weeks, with lung function (trough FEV1) at week 12 as the primary outcome measure, and breathlessness [Transition Dyspnoea Index (TDI)] and quality of life [St. George’s Respiratory Questionnare (SGRQ)] as the key secondary outcome measures at week 26. The enrolled patients were aged ≥ 40 years with stable moderate to severe COPD (post-bronchodilator FEV1 30-79% predicted and FEV1/FVC < 0.7) and a smoking history of at least 10 pack-years. Patients with a history of asthma were excluded. Long-acting bronchodilators were stopped but inhaled corticosteroids (ICS) and short-acting β2-agonists could be continued throughout the study. Approximately half of the patients in each group were using ICS at baseline, 59.6% were ex-smokers and overall mean smoking history was 47.6 pack-years.

FEV1 (Lung function): After 12 weeks treatment, trough FEV1 values were higher with glycopyrronium treatment than placebo with a treatment difference of 108mls (p < 0.001). The value of 100mls is considered to be the minimum clinically important improvement in trough FEV1. Breathlessness (TDI focal score): At week 26, glycopyrronium showed both a statistically and clinically significant improvement in breathlessness compared to placebo (1.84 vs. 0.8) with an absolute TDI focal score difference of 1.04. (1 point difference is considered clinically meaningful). Quality of life (SGRQ): Although glycopyrronium was statistically superior to placebo in the SGRQ score at week 26 with a mean improvement over placebo of -2.8 points (p = 0.004), the difference was below the threshold of clinical relevance (≥ 4 points). Exacerbations: During the 26-weeks trial, 17.5% of glycopyrronium-treated patients has one or more moderate to severe exacerbations, compared to 24.2% placebo-treated patients. There was a significant reduction in the risk of severe COPD exacerbations leading to hospitalisation in the glycopyrronium-treated patients compared to placebo (HR 0.35, 95% CI 0.141-0.857; p = 0.22) a significant reduction in the percentage of hospitalizations due to exacerbations (4.2% vs. 1.7%, OR 0.34, 95% CI 0.129-0868; p = 0.024). Improvements were also seen with glycopyrronium in terms of less use of rescue medications compared to placebo (p = 0.005) (between-group difference of 0.46 puffs per day). Safety The incidence of adverse events was lower in glycopyrronium patients compared to placebo (57.5% vs. 65.2%). Patients reporting serious adverse events were more in placebo compared to glycopyrronium (9% vs. 8.4%). The rate of discontinuation due to adverse events was also higher in the placebo group (7.1% vs. 5.8).

GLOW 2 Study:9 Kerwin et al conducted a randomised, double blind, placebo-controlled study to evaluate the efficacy and safety of glycopyrronium in moderate to severe COPD over 52 weeks. 1066 patients were 12 | P a g e

randomised in a ratio of 2:1:1 to glycopyrronium 50 microgram, open-label tiotropium 18 microgram or placebo. The study was not designed to compare glycopyrronium directly to tiotropium. The primary efficacy end-point was trough (24 h post-dose) FEV1 after 12 weeks. Secondary end-points were TDI and SGRQ scores at week 26 and 52 respectively.

Glycopyrronium and tiotropium increased trough FEV1 at week 12 by 97 mL and by 83ml over placebo respectively (p<0.001). There was no significant difference between glycopyrronium and tiotropium. During week 26, the improvements seen in TDI scores for the active comparators glycopyrronium and tiotropium were significant compared to placebo (treatment difference 0.81 and 0.94; p=0.002), though it was not recognised as being clinically significant. Note: Minimally clinically important difference is ≥ 1 point. Both active treatments produced better (lower) SGRQ scores compared to placebo at week 52, but did not reach the threshold for clinical significance (treatment difference for glycopyrronium vs. placebo -3.32; tiotropium vs. placebo – 2.84). The minimum clinically important improvement in SGRQ total score is - 4 on a 100-point scale. There was no statistically significant difference between tiotropium and glycopyrronium for any of the outcomes. Over 52 weeks, The European Medicines Agency (EMA) assessment report showed that 33% and 30% of glycopyrronium and tiotropium-treated patients, respectively, had a moderate to severe exacerbation, compared with 40% of placebo-treated patients. Glycopyrronium provided rapid bronchodilation following the first dose on day 1, with significantly higher

FEV1 at all time-points (from 5 minutes to 4 hours post dosing), compared with placebo (p<0.001) and tiotropium (p<0.01). However, this was not a pre-specified endpoint. The GLOW 2 study included an open-label tiotropium control arm and although the study was not designed to compare the two active agents, their efficacy appeared similar. However unblinded use of tiotropium may have introduced bias. Safety: The overall incidence of adverse events was similar across the three treatment groups (glycopyrronium 76.6%, placebo 76.5%, tiotropium 74.2%). This was similar to patients reporting severe adverse events. The rate of discontinuations due to adverse events were similar between glycopyrronium and tiotropium (8% vs. 7.5%) compared to placebo (11.6%). Atrial fibrillation occurred more frequently in the glycopyrronium group compared to placebo (4 vs. 0) respectively; 2 of the 4 patients had a co-existing history of AF and a third patient had a history of cardiac morbidity.

GLOW 3 Study:10 Beeh et al. conducted a short, 21-day placebo-controlled crossover trial that evaluated the efficacy of glycopyrronium (50 micrograms once daily) in improving exercise tolerance in patients with moderate to severe COPD compared to placebo in 108 patients. The primary outcome measure was the effect of glycopyrronium on exercise tolerance. On days 1 and 21, exercise tolerance was measured by tolerance time during submaximal exercise testing (SMET). SMET was performed at 80% of a patients’ maximum working capacity evaluated at screening. Glycopyrronium was significantly superior to placebo with respect to exercise tolerance time at day 21. The least square means (LSM) treatment difference on Day 21 between treatment groups was 88.9 seconds, corresponding to an approximately 21% difference (P < 0.001). On Day 1, the LSM treatment difference between groups was 43.1 seconds, corresponding to an approximately 10% difference (P < 0.001). After 21 days treatment, the mean exercise endurance was 8.5 minutes in glycopyrronium-treated patients compared with 7 minutes in placebo-treated patients. (~21%

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difference, p< 0.001). The minimal important difference is 1.25 minutes, so this change was considered to be clinically important.11

Safety and adverse effects:Error! Reference source not found.

Contraindications: Hypersensitivity to the active substance, and/or to the excipients lactose monohydrate and magnesium stearate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Caution: Paradoxical bronchospasm: In clinical studies with Seebri Breezhaler, paradoxical bronchospasm was not observed. However, paradoxical bronchospasm has been observed with other inhalation therapy and can be life-threatening. If this occurs, Seebri Breezhaler should be discontinued Anticholinergic effects: Seebri Breezhaler should be used with caution in patients with narrow-angle glaucoma or urinary retention. Should these signs or symptoms develop, patients should stop using Seebri® and contact their doctor immediately. Renal impairment: Renal impairment has an impact on the systemic exposure to glycopyrronium bromide. A moderate mean increase in total system exposure (AUC) of up to 1.4-fold was seen in subjects with mild and moderate renal impairment and up to 2.2-fold in subjects with severe renal impairment and end-stage renal disease. In patients with severe renal impairment (eGFR <30 ml/min/1.73 m2), including those with end-stage renal disease requiring dialysis, Seebri® should only be used if the expected benefit outweighs the potential risk Hepatic impairment: No dose adjustment is required as clinical studies have not been conducted in patients with hepatic impairment and glycopyrronium is cleared predominantly from the systemic circulation by renal excretion. Pregnancy and Lactation: No data available. Glycopyrronium should only be used if the expected benefit to the patient justifies the potential risk to the foetus or infant. Cardiovascular disease: These patient groups were excluded from the studies; hence Seebri® is to be used with caution in these populations. Undesirable effects: The most common anticholinergic adverse reaction was dry mouth (2.4%). Other common adverse effects included nasopharyngitis, insomnia (1.1%), gastroenteritis (1.4%), and urinary tract infection. Uncommon side-effects include rhinitis, cystitis, hyperglycaemia, hypoaesthesia, atrial fibrillation, palpitations etc. Refer to the Summary of Product Characteristics for a full list of adverse effects.

Drug Interactions:7

The co-administration of Seebri Breezhaler with other anticholinergic-containing medicinal products has not been studied.

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Other considerations:7

Storage: The capsules must always be stored in the blister to protect from moisture and only removed immediately before use. It should not be stored above 25OC and an inhaler is provided with each new prescription and disposed after 30 days of use. It has a shelf life of 2 years.

Cost analysis:12, 13

Costs of Seebri ® in Primary and Secondary care: Product Pack size Primary care Secondary care (Exc. VAT) (Inc. VAT) Seebri® 30-cap pack with Breezhaler £27.50 Seebri® 6-cap pack with Breezhaler £5.60

Comparative costs with other long acting antimuscarinic bronchodilators:12, 13 Product Strength Dose Pack size Formulary Primary Care Secondary Care (micrograms) status (Exc. VAT) (Inc. VAT) Seebri® Breezhaler 44 1 puff OD 30-cap pack No £27.50 Spiriva® 18 1 puff OD 30-cap pack Yes £34.87/ handihaler/Refill £33.50 Respimat® 2.5 2 puffs OD 60-dose unit Yes £35.50 Eklira Genuair® 322 1 dose BD 60-dose unit No £28.60

Expenditure of long acting bronchodilators across the Health Economy from November 2012 – May 201314 Product UHNS STOKE CCG NORTH STAFF CCG Seebri® Breezhaler (glycopyrronium) £0 £0 £315.10 Respimat® (tiotropium) £2,076.14 £44,474.23 £24,677.99 Spiriva® (tiotropium) capsule and handihaler £28,083.03 £61,781.80 £26,334.94 Spiriva® (tiotropium) capsule refill ££8,660.41 £350,029.00 £214,966.89 Eklira Genuair® (aclidinium) £0 £686.94 £264.41

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References

1 National Institute for Health and Clinical Excellence (NICE). Evidence summary: new medicine ESNM9: Chronic obstructive pulmonary disease: glycopyrronium bromide. January 2013. Accessed via: http://publications.nice.org.uk 2 Midlands Therapeutic Review and Advisory Committee (MTRAC) Commissioning Support: glycopyrronium bromide (Seebri Breezhaler®) for maintenance treatment of COPD. November 2012. Accessed via: http://www.keele.ac.uk/media/keeleuniversity 3 Regional Drug and Therapeutics Centre (RDTC) New Drug Evaluation. Glycopyrronium bromide for chronic obstructive pulmonary disease. Nov 2012. Accessed via: http://www.nyrdtc.nhs.uk 4 Scottish Medicines Consortium. Glycopyrronium 44 micrograms hard capsules of inhalation powder (Seebri Breezhaler®). No. 829/12.7thDecember 2012. Accessed via http://www.scottishmedicines.org.uk 5 British National Formulary (BNF) 65 March 2013. Accessed via www.bnf.org 6 NICE. Clinical guideline 101: Chronic obstructive pulmonary disease Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update). June 2010. Accessed via http://www.nice.org.uk/nicemedia/live/13029/49397/49397.pdf 7 Summary of Product Characteristics. Seebri Breezhaler® Inhalation Powder, Hard Capsules 44 micrograms. Novartis Pharmaceuticals. Last updated on 02/11/2012..Accessed via: http://www.medicines.org.uk/emc 8 D'Urzo A, Ferguson GT, van Noord JA et al. (2011) Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respiratory Research 12: 156 9 Kerwin E, Hébert J, Gallagher N et al. (2012) Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study. European Respiratory Journal 40:1106–14 10 Beeh KM et al. Once-daily NVA237 improves exercise tolerance from the first dose in patients with COPD: the GLOW3 trial. Int J Chron Obstruct Pulmon Dis 2012;7: 503-13. 11 Cazzola M et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J 2008; 31:416-68. 12 Drug Tariff May 2013 13 Chemist & Druggist Monthly pricelist May 2013.

Produced by Susheela Sumelingam Specialist Rotational Pharmacist Medicines Management University Hospital of North Staffordshire Telephone: 01782 674542 e-mail: [email protected] Produced for use within the NHS. Not to be reproduced for commercial purposes.

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