BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE

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1 BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE December 2014 Review date: December 2017 Bulletin 208 : Indacaterol + Glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler ) for the Treatment of Chronic Obstructive Pulmonary Disease (COPD) JPC Recommendation: The prescribing of Indacaterol + glycopyrronium bromide 85 micrograms/43 micrograms (Ultibro Breezhaler ) for COPD is not currently recommended. New Medicine Review Indacaterol + Glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler ) for the Treatment of Chronic Obstructive Pulmonary Disease (COPD). Medicine Indacaterol + Glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler ) Document status Final approved Date of last 10/12/2014 revision Proposed Sector Primary and Secondary Care of prescribing This review is mainly based on the NICE New Medicines Summary (ESNM33: Chronic obstructive pulmonary disease: Indacaterol/glycopyrronium (Ultibro Breezhaler ) issued February Additional significant information that has been published since the publication of the New Evidence Summary is included in the review. Introduction Summary Key points Evidence level Introduction/Background The NICE clinical guideline on chronic obstructive pulmonary disease (COPD), June states that COPD is characterised by airflow obstruction that is usually progressive and not fully reversible; it is predominantly caused by smoking. About 900,000 people in the UK have diagnosed COPD, and an estimated 2 million people have COPD that remains undiagnosed. 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. Exacerbations often occur, during which there is a rapid and sustained worsening of symptoms beyond normal day-today variations. The NICE clinical guideline on COPD defines COPD as follows: Airflow obstruction is defined as a reduced FEV1/FVC ratio (where FEV1 is forced expired volume in 1 second and FVC is forced vital capacity), such that FEV1/FVC is less than 0.7. If FEV1 is 80% predicted normal or more, a diagnosis of COPD should be made only in the presence of respiratory symptoms, for example, breathlessness or cough. Page 1 of 23

2 The JPC has endorsed Bedfordshire and Luton COPD guidelines (Original Sept 13, updated April 14) which are intended to support the local implementation of the NICE Clinical Guideline. These guidelines are available on the GP Ref Website New combination inhalers of long acting Beta 2 agonists (LABA) plus long acting muscarinic antagonists (LAMA) are being launched for use in COPD. The Bedfordshire and Luton COPD guidelines do not currently include a combination LABA/LAMA inhaler in the primary care pathway. The JPC reviewed whether a change in pathway was required at the September 2014 meeting alongside Anoro Ellipta 55/22 microgram inhalation powder (umeclidinium/vilanterol), the first LABA/LAMA licensed and launched in the UK. The following recommendations were agreed:- There is currently no place in therapy for a LABA/LAMA combination inhaler in the COPD guidelines. The use of umeclidinium/vilanterol (Anoro Ellipta 55 microgram/22 microgram) inhalation powder as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD is not supported (in line with the SMC assessment). The LABA/LAMA place in therapy review is included in appendix 2 while the umeclidinium/vilanterol (Anoro Ellipta 55 microgram/22 microgram) inhalation powder can be accessed from the GP ref website The Bedfordshire and Luton COPD Guidelines recommend the following LAMA and LABA monotherapy choices:- LAMA First line: - Tiotropium (Spiriva Handihaler ), One 18 microgram capsule inhaled once daily. 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 should be used with caution in patients with known cardiac rhythm disorders. Monitor patients for new onset cardiac rhythm disorders. Further safety information on Spiriva Respimat is available at: ( LABA First line:- Formoterol MDI +/- spacer Second Choice: Formoterol breath actuated Easyhaler Third Choice: Salmeterol MDI (+/- spacer) The JPC is asked to consider the following information and agree a place in therapy (or otherwise) for Indacaterol plus glycopyrronium for the treatment of COPD. (N.B. Indacaterol monotherapy has not been assessed by the JPC, while glycopyrronium monotherapy has been assessed and recommended as a second line LAMA treatment choice). Summary Indacaterol/glycopyrronium (Ultibro Breezhaler 85/43 micrograms) is one of the first long-acting beta2 agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination inhalers to be approved for chronic obstructive pulmonary disease (COPD). It is licensed as a maintenance bronchodilator treatment to relieve symptoms in adults with COPD and was launched in the UK in December ,3 Although some small statistically significant improvements in lung function, dyspnoea (breathlessness), health status and use of rescue medication were Page 2 of 23

3 seen with indacaterol/glycopyrronium compared with active comparators, the clinical importance of these differences is unclear and indacaterol/glycopyrronium's place in therapy is currently difficult to assess. The indacaterol/glycopyrronium combination inhaler is less expensive than the cost of single-component inhalers and may be more convenient for people. However, compared with established drugs such as formoterol, salmeterol and tiotropium, the comparative efficacy and long-term safety of indacaterol and glycopyrronium (alone or in combination) is unclear, particularly in terms of reducing exacerbations. Key Points:- Effectiveness Indacaterol/glycopyrronium statistically significantly reduced the rate of moderate or severe exacerbations compared with glycopyrronium alone in people with severe or very severe COPD. However, the European Medicines Agency considered that the reduction was insufficient to support an indication for reducing exacerbations. 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. Patient factors People who are prescribed a LABA and a LAMA may find it easier to use a combination inhaler, rather than 2 single-component inhalers. Indacaterol/glycopyrronium and the single component inhalers are administered once daily using the Breezhaler dry powder inhalation device. Other LABAs, LAMAs and ICS/LABA inhalers are administered using different devices and many are taken twice daily. NICE advises that treatment and care should take into account a person's needs and preferences. Safety The summary of product characteristics 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 LABA/LAMA 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. Resource implications Indacaterol/glycopyrronium combination inhaler is less expensive than the combined cost of the single component inhalers (indacaterol 29.26, glycopyrronium for 30-days' treatment). Page 3 of 23

4 The intervention Mechanism of action* 3 Licensed indication* 3 Formulation/ Available Products* 3 Usual dosage* 3 Ultibro Breezhaler is a combination inhaler containing 2 active ingredients; indacaterol 85 micrograms (a long-acting beta2 agonist [LABA] and glycopyrronium 43 micrograms (a long-acting muscarinic antagonist [LAMA]). Indacaterol + Glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler ) is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Pharmaceutical Form Inhalation powder, hard capsule. Each capsule contains 143 micrograms of indacaterol maleate equivalent to 110 micrograms of indacaterol and 63 micrograms of glycopyrronium bromide equivalent to 50 micrograms of glycopyrronium. Each delivered dose (the dose that leaves the mouthpiece of the inhaler) contains 110 micrograms of Indacaterol maleate equivalent to 85 micrograms of indacaterol and 54 micrograms of glycopyrronium bromide equivalent to 43 micrograms of glycopyrronium. Excipient(s) with known effect: Each capsule contains 23.5 mg lactose (as monohydrate). The capsules for inhalation (containing the active ingredients) are administered via the Ultibro Breezhaler inhalation device. The recommended dose is the inhalation of the content of one capsule once daily using the Ultibro Breezhaler inhaler, administered at the same time of the day each day. If a dose is missed, it should be taken as soon as possible on the same day. Patients should be instructed not to take more than one dose in a day. Special populations Elderly population Indacaterol + glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler ) can be used at the recommended dose in elderly patients (75 years of age and older). Renal impairment Indacaterol + glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler ) can be used at the recommended dose in patients with mild to moderate renal 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. Hepatic impairment Indacaterol + glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler ) can be used at the recommended dose in patients with mild and moderate hepatic impairment. There are no data available use of in patients with severe hepatic impairment, therefore caution should be observed in these patients. Paediatric population There is no relevant use of indacaterol + glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler ) in the paediatric population (under 18 years) in the indication COPD. The safety and efficacy of indacaterol + glycopyrronium bromide 85/43 (Ultibro Breezhaler ) in children have not been established. No data are available. Method of administration For inhalation use only. The capsules must not be swallowed. Patients should be instructed on how to administer the product correctly. Patients who do not experience improvement in breathing should be asked if they are swallowing the medicine rather than inhaling it. Page 4 of 23

5 Contraindications & Precautions for use* 3 Drug Interactions* 3 Pregnancy and lactation* 3 Treatment alternatives/ place in therapy Contraindications Hypersensitivity to the active substances or any of the excipients. Special warnings and precautions for use Should not be administered concomitantly with medicinal products containing other LABAs or LAMAs Not to be used for the treatment of asthma Not to be used to treat acute episodes of bronchospasm Hypersensitivity related to Indacaterol - Immediate hypersensitivity reactions have been reported after administration of indacaterol, If signs suggesting allergic reactions (in particular, difficulties in breathing or swallowing, swelling of tongue, lips and face, urticaria, skin rash) occur, treatment should be discontinued immediately and alternative therapy instituted. Paradoxical bronchospasm was not observed in clinical studies but it has been observed with other inhalation therapy and be life-threatening. If it occurs, discontinue treatment immediately and institute alternative therapy. Use with caution in patients with narrow-angle glaucoma (discontinue treatment if it occurs) or urinary retention. Use with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension.) and in patients with known or suspected prolongation of the QT interval or treated with medicinal products affecting the QT interval. Use with caution in patients with unstable ischaemic heart disease, left ventricular failure, history of myocardial infarction, arrhythmia (excluding chronic stable atrial fibrillation), a history of long QT syndrome or whose QTc was prolonged (>450 ms) data lacking as patients excluded from trials. Hypokalaemia and hyperglycaemia have been noted in patients taking beta2 agonists. Patients should be monitored closely for changes in serum glucose and serum potassium. Use with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to beta2-adrenergic agonists. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. No specific interaction studies have been conducted with indacaterol + glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler. The Summary of Product Characteristics (SPC) advises either concomitant use not recommended or caution with the following medications, based on the properties of the individual components: Concomitant use not recommended Beta blockers including eye drops decrease the effects of beta agonists Anticholinergics not studied and therefore not recommended Other sympathomimetic agents may potentiate the adverse events of Indacaterol Caution required with concomitant use Drugs which cause hypokalaemia- e.g. methylxanthine derivatives, steroids, non-potassium sparing diuretics. Manufacturer advises use only if the expected benefit to the patient justifies the potential risk to the foetus/infant. There are a number of monotherapy treatment alternatives see above for details of currently recommended LABAs and LAMAs included in the Bedfordshire and Luton COPD Guidelines. Umeclidinium/vilanterol (Anoro Ellipta 55 microgram/22 microgram) inhalation powder is the only other combined LABA/LAMA inhaler that is currently licensed and launched in the UK as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. The JPC reviewed this product at the September 2014 meeting and use was not supported. Possible place in therapy for indacaterol/glycopyrronium combination inhaler:- Indacaterol + glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler ) could be used as an alternative option when combined corticosteroids inhalers with Page 5 of 23

6 LABA are declined or not tolerated. However, comparative data with combined corticosteroids inhalers only exists for those patients with no history of exacerbations. There may be patients who are over treated (i.e. being treated with LABA/ICS but rarely exacerbating) in primary care who would benefit from indacaterol + glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler ). These patients will need to be carefully assessed before switching as withdrawal from treatment with inhaled corticosteroids may lead to exacerbations. Indacaterol + glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler ) is viewed by some Respiratory Specialists as an option in mild to moderate COPD patients who have a low risk of exacerbation but have significant symptoms despite single long-acting bronchodilator therapy. Indacaterol + glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler ) could also be used as a single inhaler to replace use of LAMA and LABA inhalers prescribed separately. Future Aclidinium + formoterol, may be available Q alternatives 4 Olodaterol + tiotropium. Estimated launch date Q Formoterol + glycopyrronium in development. Estimated launch date National guidance The NICE Clinical Guideline 1 (CG101) on chronic obstructive pulmonary disease combination therapy of a LABA and inhaled corticosteroid (ICS) can be used in patients with FEV1<50%, or those with FEV1 50% plus continued loss of control despite LABA therapy. A LABA and LAMA combination is recommended where inhaled corticosteroids in combination are declined or not tolerated. Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines classifies patients according to their degree of FEV1 severity, quality of life and exacerbation history. GOLD recommends the combined use of LAMA and LABA as an option in patients who have a low risk of exacerbation but have significant symptoms with monotherapy. GOLD also recommends a LABA+LAMA combination as an alternative option to combined ICS with LABA or LAMA, which are generally used in patients with symptoms but at a high risk of exacerbations, but acknowledge good clinical practice for combining long-acting bronchodilators in patients with high risk of exacerbations is lacking. Local Guidance 6 The JPC has endorsed the Bedfordshire and Luton COPD guidelines which are intended to support the local implementation of the NICE Clinical Guideline, updated April The guidelines do not currently include the option to use a LABA/LAMA combination inhaler (last reviewed September 2014). Evidence for use The NICE evidence summary 7 focuses on 2 published studies (SPARK [Wedzicha et al. 2013]) and BLAZE [Mahler et al. 2013]) that reported exacerbations and dyspnoea respectively (patient orientated outcomes), as their primary outcomes. Additional studies that reported lung function outcomes and longer-term assessments of safety are also discussed. See the full evidence summary for a detailed consideration of the evidence. In SPARK (n=2224), indacaterol/glycopyrronium statistically significantly reduced the annualised rate of moderate to severe exacerbations in people with severe or very severe COPD by 12% compared with glycopyrronium alone (relative risk [RR] 0.88, 95% confidence interval [CI] 0.77 to 0.99, p=0.038). A non-significant reduction of 10% was seen in this outcome between indacaterol/glycopyrronium and open-label tiotropium (RR 0.90, 95% CI 0.79 to 1.02, p=0.096). In the European public assessment report for indacaterol/glycopyrronium, the 12% reduction was considered to be 'very small' and not supportive of the manufacturer's requested indication of 'exacerbation reduction'. The full NICE guideline on COPD considers a relative reduction in the risk of exacerbations of 20% or more to be clinically important. The annualised rate of severe exacerbations (defined as worsening of symptoms needing admission to hospital or emergency treatment) was not statistically significantly reduced with Indacaterol/glycopyrronium compared with either glycopyrronium or tiotropium. Page 6 of 23

7 BLAZE (n=247) found that indacaterol/glycopyrronium statistically significantly improved dyspnoea scores (primary outcome) in people with moderate or severe COPD compared with placebo. The mean difference exceeded the 1 point improvement considered to be clinically important (least squares mean [LSM] difference 1.37, 95% CI 0.95 to 1.79; p<0.001). The dyspnoea score for indacaterol/glycopyrronium was also statistically significantly higher than for tiotropium (LSM difference 0.49, 95% CI 0.07 to 0.91; p=0.021). However, this difference is unlikely to be clinically important. Two studies have reported lung function measures (disease orientated outcomes) as primary outcomes: SHINE (Bateman et al. 2013; n=2144) and ILLUMINATE (Vogelmeier et al. 2012; n=523). In SHINE, indacaterol/glycopyrronium statistically significantly improved trough FEV1 compared with indacaterol, glycopyrronium, openlabel tiotropium and placebo (LSM differences 70 ml, 90 ml, 80 ml and 200 ml respectively; p<0.001 in all comparisons). For comparisons with active comparators, these changes in FEV1 are less than the 100 ml or more that the full NICE guideline on COPD considers to be clinically important. In the other study, ILLUMINATE, FEV1 standardised area under the curve from 0 to 12 hours (FEV1 AUC0-12h) at week 26 was significantly higher with indacaterol/glycopyrronium compared with salmeterol/fluticasone (LSM difference 138 ml, 95% CI 100 ml to 176 ml; p<0.0001). A Medicines Information search identified the following additional relevant information which has become available since the NICE New Evidence Review was published:- Beeh, K-M et al. Effect of QVA149 on lung volumes and exercise tolerance in COPD patients: The Bright Study, Respiratory Medicine (2014) 108, This study evaluated the effects of QVA149 on exercise tolerance, hyperinflation, lung function and lung volumes versus placebo and tiotropium. Methods: Patients with moderate-to-severe COPD were randomized to QVA /50 mg, placebo or tiotropium 18 mg once daily in a blinded, 3-period crossover study for 3 weeks. The primary endpoint was exercise endurance time at Day 21 for QVA149 versus placebo. Results: Eighty-five patients were randomized; 86% completed the study. QVA149 significantly improved exercise endurance time at Day 21 compared with placebo (least squares mean treatment difference 60 s [p Z 0.006]). No significant improvements in exercise endurance time at Day 21 between QVA149 and tiotropium were found. (N.B. The study was powered for comparison of QVA149 and placebo only).dynamic inspiratory capacity (IC) at exercise isotime, trough forced expiratory volume in 1 s, residual volume and functional residual capacity showed significant improvements with QVA149 from Day 1 of treatment that were maintained throughout the study. The safety profiles were similar across groups. Dahl R et al. Efficacy and safety of QVA149 compared to the concurrent administration of its monocomponents indacaterol and glycopyrronium: the BEACON study. Int J Chron Obstruct Pulmon Dis. 2013;8: Introduction: The BEACON study evaluated the efficacy and safety of QVA149, a once-daily dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist (LABA) indacaterol and long-acting muscarinic antagonist (LAMA) glycopyrronium (NVA237), in development for the treatment of patients with chronic obstructive pulmonary disease (COPD), compared with the free-dose concurrent administration of indacaterol plus glycopyrronium (IND+GLY). Methods: In this multicenter, double-blind, parallel group study, patients with stage II or stage III COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] 2010) were randomized (1:1) to once-daily QVA149 (110 μg indacaterol/50 μg glycopyrronium) or concurrent administration of indacaterol (150 μg) and glycopyrronium (50 μg) via the Breezhaler device (Novartis AG, Basel, Switzerland) for 4 weeks. The primary endpoint was to evaluate the noninferiority of QVA149 as compared with concurrent administration of IND+GLY, for trough forced Page 7 of 23

8 Page 8 of 23 expiratory volume in 1 second (FEV1) after 4 weeks of treatment. The other assessments included FEV1 area under the curve from 0 to 4 hours (AUC0 4 hours) at day 1 and week 4, symptom scores, rescue medication use, safety, and tolerability over the 4-week study period. Results: Of 193 patients randomized, 187 (96.9%) completed the study. Trough FEV1 at week 4 for QVA149 and IND+GLY was 1.46 L ± 0.02 and 1.46 L ± 0.18, respectively. The FEV1 AUC0 4 hours at day 1 and week 4 were similar between the two treatment groups. Both treatment groups had a similar reduction in symptom scores and rescue medication use for the 4-week treatment period. Overall, 25.6% of patients in QVA149 group and 25.2% in the IND+GLY group experienced an adverse event, with the majority being mild-to-moderate in severity. No deaths were reported during the study or during the 30 days follow-up period. Conclusion: The BEACON study demonstrated that once-daily QVA149 provides an efficacy and safety profile similar to the concurrent administration of its monocomponents indacaterol and glycopyrronium. Information from New Drugs Online 4 Sept 14: Data from LANTERN study (n=744) presented at European Respiratory Society Congress. Ultibro was superior to Seretide accuhaler in reducing exacerbations and improving lung function. Rate of moderate-to-severe exacerbations was reduced with Ultibro by 31% vs. Seretide. 08/09/ May 14: Novartis announces positive data from the QUANTIFY study, which met its primary endpoint of showing non-inferiority of Ultibro Breezhaler compared to tiotropium 18mcg once daily/formoterol 12mcg twice daily in improving health-related quality of life outcomes. Ultibro Breezhaler induced superior improvements in lung function at 26 weeks vs. tiotropium plus formoterol, & patients taking Ultibro were more likely to demonstrate a clinically meaningful improvement in shortness of breath and health-related quality of life. 22/05/ :21:08. Safety *3,7 The summary of product characteristics for Ultibro Breezhaler 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. The safety profile of indacaterol/glycopyrronium is characterised by typical anticholinergic and beta-adrenergic symptoms. Overall, the most frequently reported adverse effects were upper respiratory tract infections (incidence 1/10 patients), nasopharingitis, urinary tract infections, sinusitis, rhinitis, dizziness, headache, cough, oropharyngeal pain including throat irritation, dyspepsia, dental caries, gastroenteritis, musculoskeletal pain, pyrexia and chest pain (incidence common, 1/100 to < 1/10 patients). In the 52-week safety study, ENLIGHTEN, statistical analyses of the primary outcome (incidence of all adverse events) in the indacaterol/glycopyrronium and placebo groups were not presented, although the overall incidence does appear to be similar (130/225 [57.8%] and 64/113 [56.6%] respectively). Thirteen people receiving indacaterol/glycopyrronium (5.8%) had an adverse event leading to discontinuation of the study drug compared with 7 people receiving placebo (6.2%; p value not reported). In ENLIGHTEN, some respiratory-related adverse events occurred in greater numbers of people in the indacaterol/glycopyrronium treatment group compared with the placebo group, including cough (8.0% compared with 6.2%) and lower respiratory tract infections (6.7% compared with 3.5%; p values not reported). Significantly more people in the indacaterol/glycopyrronium group experienced pneumonia (8 compared with 0; p=0.074). In additional post-hoc analyses to investigate these differences, rates of pneumonia and respiratory-related serious adverse events were found not to be statistically significantly different. The authors suggest that the numerical difference for some adverse events may, in part, be explained by demographic imbalances at baseline, with greater numbers of people in the indacaterol/glycopyrronium group with severe COPD and using ICS. The European public assessment report for indacaterol/glycopyrronium indicates this imbalance relates to stratification of people based only on their smoking status, in accordance with regulatory guidance on clinical trials for COPD treatments. Also, a higher

9 discontinuation rate was seen in the placebo group leading to a healthier population in that group. In ILLUMINATE, the overall incidences of adverse events and serious adverse events were similar for indacaterol/glycopyrronium and fluticasone/salmeterol treatment groups (55.4% compared with 60.2%, and 5.0% compared with 5.3%, respectively; p values not reported). Reports of pneumonia, an adverse event associated with long-term ICS, were numerically higher in the fluticasone/salmeterol treatment group (4/159 compared with 0/143), although no statistical comparisons were provided. Costs Tariff status Activity costs The indacaterol/glycopyrronium combination inhaler 30 day cost is which is less expensive than the combined cost of the single-component inhalers (indacaterol 29.26, glycopyrronium for 30-days' treatment). Drug Usual dosage 30-day cost excluding VAT Single-component LABAs Formoterol fumarate 12 micrograms/dose inhaler CFC (Atimos Modulite ) 1 puff twice daily Formoterol fumarate 12 micrograms/dose dry powder inhaler (Easyhaler {Formoterol} ) 1 puff twice daily Indacaterol maleate 150 micrograms/dose 1 puff and 300 micrograms/dose (Onbrez daily Breezhaler) Salmeterol 25 micrograms/dose CFC free inhaler 2 puffs twice daily Single-component LAMAs Aclidinium bromide 322 micrograms/dose (Eklira Genuair ) 1 puff twice daily Glycopyrronium bromide 1 puff 44 micrograms/dose (Seebri Breezhaler ) daily Tiotropium bromide 18 micrograms/dose, dry powder (Spiriva Handihaler) 1 puff daily Page 9 of 23

10 Tiotropium bromide 2.5 micrograms/dose, aerosol (Spiriva Respimat) 2 puffs daily Combination LABA/LAMA inhalers Umeclidinium/vilanterol 55/22 micrograms/dose (Anoro Ellipta ) 1 puff daily Combination ICS/LABA inhalers Beclometasone dipropionate/formoterol fumarate 100/6 micrograms (Fostair ) Budesonide/formoterol fumarate 200/6 micrograms (Symbicort Turbohaler 200/6) 2 puffs twice daily 2 puffs twice daily Budesonide/formoterol fumarate 1 puff /12 micrograms (Symbicort Turbohaler twice daily 400/12) Fluticasone propionate/salmeterol xinafoate 500/50 micrograms/dose (Seretide 500 Accuhaler ) 1 puff twice daily Abbreviations: ICS, inhaled corticosteroid; LABA, long-acting beta2 agonist; LAMA, long-acting muscarinic antagonist. All prices have been taken from the Chemist and Druggist/Drug Tariff, November Cost effectiveness (if available) 5 Potential number of patients in Bedfordshire and Luton Impact per 100,000 population Affordability considerations N.B. Doses are for general comparison and do not imply therapeutic equivalence Health economic analyses are not available for indacaterol/glycopyrronium (Ultibro Breezhaler 85/43 micrograms). Cost per QALY costs for other COPD drug treatments were estimated ( ): tiotropium ( 7,000/QALY), LABA ( 8,000/QALY), and triple therapy ( 35, ,000). 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 An average GP practice of 6,600 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. An audit of GP practice of COPD prescribing in 2013 (BCCG) 9 provides the following information (see appendix 2 for more details): 53 out of 55 practices (96.4%) took part in the COPD audit. A total of 1828 patients were audited, which makes up 21% of all the COPD patients in BCCG. The number COPD patients audited per practice ranged from 16 patients to 69 patients. The data presented in this report are based on the Page 10 of 23

11 audit returns from these 53 practices. Hence, the results are not a complete audit of all patients with COPD within Bedfordshire, but they do provide a good representative sample. 1.4 % of patients in BCCG (6,090 / 423,998) are on the practices COPD register (53 out of 55 practices). 2% of patients were prescribed LABA monotherapy; 9% LAMA monotherapy and 2% on both a LABA and a LAMA The cost impact to the Health Economy is dependent on where the product is placed in the COPD pathway. When the JPC reviewed Umeclidinium/vilanterol 55/22 micrograms inhalation powder (Anoro Ellipta ), September 2014, the following cost assumptions were included 10 :- 1. Should clinicians use a LABA / LAMA combination inhaler after a LAMA has been found to be partially effective or ineffective in our local pathway, this would represent an increase of 250 per patient per year. Just making this change in prescribing for 10% of our Bedfordshire COPD population would result in an increased expenditure of 159,570 per year. 2. Should clinicians use a LABA / LAMA combination inhaler instead of separate LABA and LAMA inhalers, for example, in place of a LABA / ICS combination inhaler as per NICE CG 101 in patients with FEV1 <50% predicted, but the ICS component is declined, contra-indicated or not tolerated, this would represent a saving of 156 per patient per year. If a LABA / LAMA combination inhaler were used instead of separate LABA and LAMA inhalers in 2% of our local COPD population this would result in a saving of 19,937 per year and may improve patient adherence. Decisions from other bodies Comments sought from All Wales Medicines Strategy Group, Feb 2014 recommended as an option for use within NHS Wales as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD (based on a limited submission). Scottish Medicines Consortium forthcoming submission (Dec 14) Norfolk CCGs not yet reviewed Hertfordshire Medicines Management Committee due for review 18 November 2014 Cambridgeshire and Peterborough Joint Prescribing Group (September 2014) not recommended. Respiratory Consultants/Respiratory Specialist Nurses, Bedford Hospital and Luton and Dunstable Hospital. Respiratory Leads, BCCG and LCCG. Additional Points for consideration Indacaterol/glycopyrronium (Ultibro Breezhaler 85/43 micrograms) is a dual bronchodilator, given via one single inhaler and is once daily dosing. Currently only a small number of inhalers are licensed to be used once daily for COPD. It could be postulated that using this combination inhaler is advantageous, but currently there is no evidence to show that using once daily dosing is better than twice daily dosing or that one combination inhaler is better than using two separate inhalers. The Breezhaler device is known to have a lower inspiratory resistance than the Accuhaler, Handihaler and Turbohaler devices. Replacing LABA/ICS with Indacaterol/glycopyrronium (Ultibro Breezhaler 85/43 micrograms), in those patients inappropriately prescribed steroids, can avoid adverse effects associated with long term use of inhaled steroids. The long term safety of indacaterol and glycopyrronium is unknown. For indacaterol/glycopyrronium, 18 month data are available but with more established therapies e.g. tiotropium, 4 year data are published. Data for indacaterol/glycopyrronium were collected on exacerbation rates but not on hospitalisation rates. Current evidence does not support the use of indacaterol/glycopyrronium to reduce exacerbations in people with COPD, either as an intermediate step between LAMA monotherapy and LAMA plus LABA/ICS triple therapy, or as an alternative to LABA/ICS Page 11 of 23

12 Evidence strengths and limitations 5, 7 Page 12 of 23 From the current published evidence, it is not possible to determine whether the use of indacaterol/glycopyrronium in COPD patients would reduce the burden on healthcare resources compared to using a single long-acting bronchodilator. 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. (N.B. While 100mL trough FEV1 is generally considered as a clinically significant improvement when active components are compared to placebo, unfortunately no standard definition of accepted clinical improvement when comparing active treatments is known). 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 inhaled corticosteroid (ICS). This meant that many people in the indacaterol/glycopyrronium group received triple therapy (LAMA/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 (postbronchodilator 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). The study did not evaluate exacerbation risk, because low risk non-exacerbating patients were recruited. The advantage of the BLAZE study was that it used blinded tiotropium, but the study is limited by a short duration (6 weeks). In addition, changes in trough FEV1, or exacerbation rates were not assessed. 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 longerterm comparative safety data for the 2 treatments. N:\Medicines Management\JPC\Approved Bulletins and Papers\from Aug 13 )\Dec 14 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.

13 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. CG 101, Chronic Obstructive Pulmonary Disease (update), National Institute for Health and Care Excellence, June Personal Communication, Ipswich Medicines Information Department, November EPAR for Ultibro Breezhaler (which includes the Summary of Product Characteristics) man_med_ jsp&mid=wc0b01ac058001d New Drugs Online Accessed 11/11/ Ultibro Breezhaler (Indacaterol/glycopyrronium) Maintenance bronchodilator treatment to relieve symptoms in adults with COPD, London Medicines Evaluation Network Review, issued February England/LNDG/London-Wide-Reviews/Ultibro-Breezhaler-indacaterolglycopyrronium/ 6. Bedfordshire and Luton COPD Guidelines, updated April New Medicines Summary (ESNM33: Chronic obstructive pulmonary disease: Indacaterol/glycopyrronium (Ultibro Breezhaler ), NICE, issued February Prescribing Outlook New Medicines, UKMi, September 2012, updated October Report on the BCCG Practice Audit of COPD Prescribing Bulletin 202: Umeclidinium/ vilanterol (Anoro Ellipta 55/22 micrograms) inhalation powder, Bedfordshire and Luton Joint Prescribing Committee, September Appendix 1 :Search Strategy The main source of evidence is the NICE New Medicines Summary (ESNM33: Chronic obstructive pulmonary disease: Indacaterol/glycopyrronium (Ultibro Breezhaler ) issued February Medicines information has undertaken a literature search to update the information provided by the NICE New Evidence Review. Page 13 of 23

14 Appendix 2 Bedfordshire and Luton Joint Prescribing Committee 17 th September 2014 Review Date: September 2017 Bulletin 201 LABA / LAMA combination inhalers in COPD Place in Therapy? JPC Recommendations: There is currently no place in therapy for LABA / LAMA combination inhalers in the Bedfordshire and Luton COPD guidelines. Current pathway (Appendix 1 below) The Bedfordshire and Luton COPD guidelines do not currently place a LABA / LAMA combination inhaler within the primary care pathway. A LAMA inhaler is the recommended option when maintenance bronchodilator treatment is required when a short acting bronchodilator (SABA) alone does not control symptoms regardless of FEV1. If treatment with a LAMA inhaler is ineffective after 4 weeks, then inhaler technique and compliance with medication are checked before changing to either a LABA inhaler alone (if FEV1 50%) or a LABA / ICS combination inhaler (if FEV1 <50%). Referral to the integrated COPD service (ICOPDS) is recommended if patients remain symptomatic or become symptomatic at this stage. This is so that all other measures to manage COPD are fully explored with the patient, e.g. smoking cessation advice, inhaler technique and compliance with treatment, pulmonary rehabilitation, flu vaccination, pneumococcal vaccination, and medicines optimisation. NICE CG101 -Management of COPD in adults in primary and secondary care As illustrated in Figure 1, NICE CG101 recommends combined LABA / LAMA inhalers in patients where an inhaled corticosteroid is declined, contra-indicated or not tolerated and have: 1. FEV1 <50% predicted with exacerbations or persistent breathlessness despite as required use of a SABA or short acting muscarinic antagonist (SAMA) OR 2. FEV1 50% with persistent exacerbations or breathlessness despite maintenance treatment with a LABA. Page 14 of 23

15 Figure 1 The first scenario could be incorporated into the Bedfordshire and Luton COPD pathway and a LABA / LAMA combination inhaler recommended in patients in whom a LAMA inhaler is partially effective after 4 weeks and their FEV1 <50% predicted and would normally be offered a LABA / ICS combination inhaler, but the ICS component is declined, contra-indicated or not tolerated. However, our COPD guidelines recommend referral to the ICOPDS at this stage. If the LAMA inhaler was ineffective previously, it would not be logical to add it back in. In the second scenario, patients with FEV1 50% will have already tried a LAMA inhaler for 4 weeks and found to be ineffective, and so changed to a LABA. Adding a LAMA inhaler back in again at this stage is not logical as the LAMA inhaler was previously found to be ineffective. In addition, our COPD guidelines recommend referring patients to the ICOPDS for a full review before considering adding in other therapies. If the patient had a partial response to the LAMA inhaler before it was stopped and a LABA inhaler commenced, the ICOPDS might consider a LABA / LAMA combination inhaler. LABA / LAMA inhalers prescribed separately The Bedfordshire COPD audit 2013 found that 2% of COPD patients were prescribed a LABA inhaler plus a LAMA inhaler. At the time of the audit a LABA / LAMA combination inhaler was not available and so it can be assumed that the inhalers were prescribed separately. The LABA / LAMA combination inhaler is less costly per year than prescribing two separate LABA and LAMA inhalers as illustrated in table 1 below. If a LABA / LAMA combination inhaler were used instead of separate LABA and LAMA inhalers in 2% of our local COPD population this could result in a saving of 19,937 per year and may improve patient adherence. Table 1: Cost comparison of separate LABA and LAMA inhalers versus a LABA / LAMA combination inhaler. Page 15 of 23

16 Drug Dose Regimen Cost per year ( ) Umeclidinium/vilanterol 55/22 micrograms once daily 394 Long acting beta2 agonists (LABA) Indacaterol 150 to 300 micrograms once daily 355 Salmeterol 50 micrograms twice daily 337 Formoterol 12 micrograms twice daily* 144 Long acting muscarinic antagonists (LAMA) Tiotropium (Spiriva HandiHaler ) 18 micrograms once daily 406 Tiotropium (Spiriva Respimat ) 5 micrograms once daily 406 Aclidinium 322 micrograms twice daily 347 Glycopyrronium 44 micrograms once daily 334 LABA plus LAMA prescribed together as separate inhalers Formoterol plus Tiotropium (Spiriva HandiHaler ) 550 Indacaterol plus Tiotropium (Spiriva HandiHaler ) 761 N.B. Doses are for general comparison and do not imply therapeutic equivalence *There is some dose variation among different formulations of formoterol. For cost of LABA plus LAMA comparators, the costs of individual treatments should be added. Costs are from the SMC assessment and Chemist & Druggist August Triple therapy The Bedfordshire and Luton COPD guidelines recommend referral to the ICOPDS before triple therapy with LABA, ICS and LAMA is considered so that all other measures can be optimised for the patient. In NICE CG101, triple therapy features only in patients who are on a LABA / ICS inhaler and the LAMA inhaler is added in. It is unlikely that patients would want to change to a LABA / LAMA combination inhaler plus separate ICS monotherapy inhaler when they are currently on a LABA / ICS inhaler. The ICS inhaler component would also represent an off-license use as Clenil modulite is not licensed for use in COPD, but is licensed for use in asthma. This may be a less costly, but unlicensed way of providing triple therapy as illustrated in table 2. Table 2 Cost comparison for triple therapy using LABA/LAMA combination inhaler plus ICS inhaler compared to LABA / ICS inhaler plus LAMA inhaler Drug Cost per year ( ) LABA / LAMA combination inhaler plus separate ICS inhaler Umeclidinium/vilanterol inhaler (one inhalation daily) plus beclometasone inhaler (Clenil modulite 250 micrograms (2 puffs twice daily) LABA / ICS Combination Inhaler plus separate LAMA inhaler 511 Fostair 100/6 inhaler (2 puffs twice daily) plus Tiotropium (Spiriva HandiHaler ) (one inhalation daily) 758 JPC considerations on LABA / LAMA combination inhalers place in therapy within the Bedfordshire and Luton COPD guidelines (17 September 2014 meeting) Two main potential places in therapy for LABA/LAMA combination inhalers were proposed (see figure 1 below) and debated by the Committee:- Page 16 of 23

17 Figure 1 The first scenario could be incorporated into the Bedfordshire and Luton COPD pathway and a LABA / LAMA combination inhaler recommended in patients in whom a LAMA inhaler is partially effective after 4 weeks and their FEV1 <50% predicted and would normally be offered a LABA / ICS combination inhaler, but the ICS component is declined, contra-indicated or not tolerated. However, our COPD guidelines recommend referral to the ICOPDS at this stage. If the LAMA inhaler was ineffective previously, it would not be logical to add it back in. In the second scenario, patients with FEV1 50% will have already tried a LAMA inhaler for 4 weeks and found to be ineffective, and so changed to a LABA. Adding a LAMA inhaler back in again at this stage is not logical as the LAMA inhaler was previously found to be ineffective. In addition, our COPD guidelines recommend referring patients to the ICOPDS for a full review before considering adding in other therapies. If the patient had a partial response to the LAMA inhaler before it was stopped and a LABA inhaler commenced, the ICOPDS might consider a LABA / LAMA combination inhaler. Other potential places in therapy were:- In patients currently receiving a LABA and LAMA inhalers separately as this could be a cost saving. The major disadvantage to this proposal was that only combination inhaler available was not yet available as monotherapy components. It was suggested that potentially that it could be an advantage to change both inhalers (particularly if there had been a partial response), however this was not a strategy which was well supported by the Committee as when changing therapy, it is good practice to change one component at a time. In patients receiving triple therapy, patients could be changed to receive a LABA/LAMA combination inhaler plus an inhaled corticosteroid (as a monotherapy inhaler). This was not considered to be a sensible option as although potentially a less costly method of providing Page 17 of 23

18 triple therapy, it would involve the off licensed use of the inhaled corticosteroid (Clenil modulite is licensed for use in asthma but not COPD). After considering all of the above information the JPC decided that there was not as yet enough evidence to warrant changing the Bedfordshire and Luton COPD guidelines and therefore the briefing paper, bulletin and following recommendations were supported:- There is currently no place in therapy for LABA/LAMA combination inhaler in the COPD guidelines. N:\Medicines Management\JPC\Approved Bulletins and Papers\Approved bulletins & papers (from Aug 13 )\Sept 14\Bulletin 201 LABA_LAMA place in therapy COPD.docx References / Sources of Review 1. Scottish Medicines Consortium. Umeclidinium / vilanterol, 55/22 micrograms, inhalation powder (Anoro ) SMC No. (978/14) 4 July Summary of Product Characteristics. Anoro Ellipta. GlaxoSmithKline UK. EMC last updated 6 June Accessed 20/8/14 and available at 3. UKMI New Drugs On-Line. New Drugs Online Report for umeclidinium + vilanterol. Accessed 20/8/14 and available at (user registration required for additional content): 4. GSK. Anoro Ellipta 55/22mcg (umeclidinium and vilanterol) for the treatment of chronic obstructive pulmonary disease (COPD). Medicines evidence pack to support formulary and guidelines decision making. May Zinc code: UK/UCV/0009/ National Institute for Health and Care Excellence. Clinical Guideline 101- Chronic obstructive pulmonary disease: Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) Bedfordshire and Luton COPD Guidelines. Updated April Available at: 7. Bedford Borough Council. Respiratory Disease. working_well /respiratory_disease.aspx Accessed 20/8/14. Central Bedfordshire Council. Respiratory Health. Accessed 20/8/14. Page 18 of 23

19 Appendix 1 (as referenced in Bulletin 201) Bedfordshire and Luton COPD Guidelines- Diagnosis and management of chronic obstructive pulmonary disease in Bedfordshire and Luton Updated April 2014 COPD Guidelines Revised April 2014 v1 Page 19 of 23

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22 Bedfordshire and Luton Joint Prescribing Committee (JPC) Assessment against Ethical and Commissioning Principles Treatment assessed (December 2014): Indacaterol + Glycopyrronium bromide 85/43 micrograms (Ultibro Breezhaler ) for the Treatment of Chronic Obstructive Pulmonary Disease (COPD) JPC Recommendation The prescribing of Indacaterol + glycopyrronium bromide 85 micrograms/43 micrograms (Ultibro Breezhaler ) for COPD is not currently recommended. 1) Clinical Effectiveness Indacaterol/glycopyrronium statistically significantly reduced the rate of moderate or severe exacerbations compared with glycopyrronium alone in people with severe or very severe COPD. However, the European Medicines Agency considered that the reduction was insufficient to support an indication for reducing exacerbations. 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. 2) Cost Effectiveness Health economic analyses are not available for indacaterol/glycopyrronium (Ultibro Breezhaler 85/43 micrograms). Cost per QALY costs for other COPD drug treatments were estimated ( ): tiotropium ( 7,000/QALY), LABA ( 8,000/QALY), and triple therapy ( 35, ,000). The cost of the indacaterol/glycopyrronium combination inhaler is for 30 days treatment which is less expensive than the combined cost of the single component inhalers (indacaterol 29.26, glycopyrronium for 30-days treatment). The cost impact to the Health Economy is dependent on where the product is placed in the COPD pathway. 3) Equity No impact on equity in envisaged. 4) Needs of the community COPD prevalence locally is increasing and underdiagnosed. 5) Need for healthcare (incorporates patient choice and exceptional need) A number of alternative treatment options are available. 6) Policy drivers NICE Clinical Guideline 101. Management of COPD in adults in primary and secondary care. Bedfordshire and Luton COPD Guidelines (Original September 2013, updated April 2014) 7) Disinvestment Should clinicians use a LABA / LAMA combination inhaler instead of separate LABA and LAMA inhalers, for example, in place of a LABA / ICS combination inhaler as per NICE CG 101 in patients with FEV1 <50% predicted, but the ICS component is declined, contraindicated or not tolerated, this would represent a saving of 156 per patient per year. If a LABA / LAMA combination inhaler were used instead of separate LABA and LAMA inhalers in 2% of our local COPD population this would result in a saving of 19,937 per year and may improve patient adherence. 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 22 of 23

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