New Medicines Committee Briefing July Glycopyrronium bromide/indacaterol (Ultibro ) for maintenance treatment of adults with stable COPD

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1 Ultibro is to be reviewed for use within: New Medicines Committee Briefing July 2017 Glycopyrronium bromide/indacaterol (Ultibro ) for maintenance treatment of adults with stable COPD Summary: Primary Care Secondary Care Ultibro Breezhaler is a dry-powder combination inhaler containing indacaterol (a long-acting beta agonist (LABA)) and glycopyrronium (a long acting muscarinic antagonist (LAMA)). 1 Ultibro Breezhaler is licensed as a once daily maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). 1 Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) Guidance recommends a LABA/LAMA combination inhaler in the management of stable COPD due to significant improvement of lung function, health status and reduction in exacerbations. 2 NICE evidence summary stated that despite the small statistically significant improvement in lung function seen with Ultibro Breezhaler, the clinical importance of the differences in lung function and patient-oriented outcomes is unclear in comparison to other active comparators hence its place in therapy is currently difficult to assess. 3 Scottish Medicines Consortium (SMC) accepted Ultibro Breezhaler to be used within NHS Scotland for maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. 4 Regional Drug and Therapeutics Centre (RDTC) stated that fixed-dose LAMA/LABA combination inhalers, including Ultibro Breezhaler, should be reserved for those patients who would otherwise be treated with both components given separately. 5 Midlands Therapeutics Review and Advisory Committee (MTRAC) recommend that the choice between the different LAMA/LABA combination inhalers should be based on patients ability to tolerate and use the inhaler device as well as cost. 6 RCTs have demonstrated a reduction in exacerbations with Ultibro Breezhaler in comparison to Seretide (FLAME trial) and glycopyrronium and tiotropium (SPARK trial) as well as improvement in dyspnoea in comparison to placebo and tiotropium (BLAZE trial). 7,8,9 Ultibro is a black triangle drug ( ) and is monitored intensively by the MHRA. 1 1 P a g e

2 Formulary application Consultant submitting application: Clinical Director supporting application: Dr Imran Hussain (Respiratory Consultant) Dr Anthony Cadwgan (Clinical Director) Dr Hussain has requested for Ultibro to be considered for inclusion in the North Staffordshire Joint Formulary for the maintenance treatment of adult patients with stable COPD. He intends that Ultibro will be initiated by both hospital and primary care prescribers. Dr Hussain states that Ultibro is the only LAMA/LABA combination inhaler where there is strong evidence to show that it reduces exacerbation frequency in all severity sub-groups of COPD, over and above the reduction in exacerbation frequency seen with Seretide alone (other combinations have shown similar and non-inferiority effects to Seretide, though no improvement). He also stated in the application form that there is no difference in cost between Ultibro and the other LAMA/LABA combination inhalers on the formulary but there is the added benefit that the Ultibro Breezhaler requires a lower inspiratory flow rate of the device in comparison to the Ellipta and the Genuair devices currently on formulary. Background COPD is characterised by airflow obstruction that is usually progressive and not fully reversible 10. The main symptoms of COPD include chronic and progressive dyspnoea, cough and sputum production. NICE clinical guideline on COPD defines COPD as an airflow obstruction - defined as an FEV 1 /FVC ratio less than 0.7 or the presence of respiratory symptoms, for example, breathlessness or cough, irrespective of the FEV GOLD reports that currently COPD is the 4th leading cause of death worldwide with a projection of increasing to 3rd by It is estimated that 3 million people have COPD in UK with around 900,000 diagnosed and 2 million people remaining undiagnosed. 10 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. 10 Smoking is a major risk factor for developing COPD and all patients diagnosed with COPD should be encouraged to stop smoking. 10 Exacerbations often occur, during which there is a rapid and sustained worsening of symptoms beyond normal day-to-day variations which leads to change in medication. NICE made recommendations for effective inhaled therapy in people with stable COPD (figure 1). 10 NICE recommends the use of LABA plus LAMA inhaler: - In patients with stable COPD who remain breathless or have exacerbations despite use of SABA if their FEV 1 is < 50% predicted and they decline or are not tolerating ICS. OR - In patients with stable COPD and an FEV 1 of 50% predicted or more who remain breathless or have exacerbations despite taking a LABA when ICS is declined or not tolerated. NICE recommends that the choice of drug treatment should take into account the person's symptomatic response and preference, and the drug's potential to reduce exacerbations, side effects and costs. When this guideline was developed, there were no LABA/LAMA combination inhalers available. 2 P a g e

3 Figure 1: NICE Algorithm for Use of Inhaled Therapies in COPD 10 Ultibro Breezhaler was the first LABA/LAMA combination inhaler to be approved for COPD and was launched in the UK in It is licensed as a maintenance bronchodilator treatment to relieve symptoms in adults with COPD. When indacaterol and glycopyrronium are administered together in Ultibro Breezhaler, they provide additive efficacy due to their different mode of action targeting different receptors and pathways to achieve smooth muscle relaxation. When inhaled, indacaterol acts locally in the lung as a bronchodilator while glycopyrronium bromide is a high affinity muscarinic receptor antagonist. Ultibro Breezhaler showed a rapid onset of action within 5 minutes after dosing with the effect remaining constant over the whole 24 hour dosing interval. 1 Current formulary status The North Staffordshire Joint Formulary currently lists the following agents: Compound bronchodilator preparations Anoro Ellipta (Umeclidinium & vilanterol) Duaklir Genuair (Aclidinium & formoterol) For use in COPD only For use in COPD with end of day deterioration At a glance guide: Stable COPD At a glance guide: Stable COPD 3 P a g e

4 Therapeutic class and mode of action 1 Ultibro Breezhaler is a combination product containing indacaterol and glycopyrronium. Indacaterol is a long-acting beta 2 -adrenergic agonist (LABA). The pharmacological effects of beta 2 - adrenoceptor agonists, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'- adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. When inhaled, indacaterol acts locally in the lung as a bronchodilator. Glycopyrronium is an inhaled long-acting muscarinic receptor antagonist (LAMA). 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. When indacaterol and glycopyrronium are administered together, they provide additive efficacy due to their different mode of action targeting different receptors and pathways to achieve smooth muscle relaxation. Due to the differential density of beta 2 -adrenoceptors and M3-receptors in central versus peripheral airways, beta 2 -agonists should be more effective in relaxing peripheral airways, whilst an anticholinergic compound may be more effective in central airways. Thus, for bronchodilation in both peripheral and central airways a combination of a beta 2 -adrenergic agonist and a muscarinic antagonist may be beneficial. Licensed indication 1 Ultibro Breezhaler is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage and administration 1 The recommended dose is the inhalation of the content of one capsule once daily using the Ultibro Breezhaler inhaler. Each delivered dose contains 110 µg of indacaterol maleate equivalent to 85 µg of indacaterol and 54 µg of glycopyrronium bromide equivalent to 43 µg of glycopyrronium. Safety and adverse effects 12 Contraindications: Hypersensitivity to the active substances or to any of the excipients lactose monohydrate or magnesium stearate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not use Ultibro. Cautions: 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: Ultibro Breezhaler can be used at the recommended dose in patients with mild and moderate hepatic impairment. There are no data available for the use of Ultibro Breezhaler in patients with severe hepatic impairment, therefore caution should be observed in these patients. 4 P a g e

5 Pregnancy and Lactation: There are no data from the use of Ultibro Breezhaler in pregnant women available. It is not known whether indacaterol, glycopyrronium and their metabolites are excreted in human milk. Therefore, Ultibro Breezhaler should only be used during pregnancy and lactation if the expected benefit to the patient justifies the potential risk. Paradoxical bronchospasm: Administration of Ultibro Breezhaler may result in paradoxical bronchospasm which can be lifethreatening. If this occurs, treatment should be discontinued immediately and alternative therapy instituted. Anticholinergic effect: Ultibro Breezhaler should be used with caution in patients with narrow-angle glaucoma or urinary retention. Cardiovascular effects: Ultibro Breezhaler should be used 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. Hyperglycaemia: Inhalation of high doses of beta 2 -adrenergic agonists may produce increases in plasma glucose. Upon initiation of treatment with Ultibro Breezhaler plasma glucose should be monitored more closely in diabetic patients. General disorders: Ultibro Breezhaler should be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to beta 2 -adrenergic agonists. Undesireable Effects: Ultibro Breezhaler showed similar adverse reactions to the individual components. The safety profile is characterised by typical anticholinergic and beta-adrenergic symptoms related to the individual components. Other most common adverse were cough, nasopharyngitis and headache. Refer to the Summary of Product Characteristics for a full list of adverse effects. Drug Interactions 1 Ultibro Breezhaler should not be administered concomitantly with medicinal products containing other LABAs or LAMAs. No specific interaction studies were conducted with Ultibro Breezhaler. Information on the potential for interactions is based on the potential for each of its two components. Presentation 1 Inhalation powder, hard capsule Capsules with transparent yellow cap and natural transparent body containing a white to almost white powder, with the product code IGP printed in blue under two blue bars on the body and the company logo printed in black on the cap. Other Considerations 1 The capsules must be stored below 25 C and in the original blister to protect from moisture. A new inhaler is provided with each new prescription and should be disposed of after 30 days of use. It has a shelf life of 2 years. 5 P a g e

6 Guidance and Evidence Summary NICE Guidance published Yes NICE Clinical Guideline 101: Chronic obstructive pulmonary disease in over 16s: diagnosis and management 10 NICE recommends the use of LABA plus LAMA inhaler: - In patients with stable COPD who remain breathless or have exacerbations despite use of SABA if their FEV 1 is < 50% predicted and they decline or are not tolerating ICS. OR - In patients with stable COPD and an FEV 1 of 50% predicted or more who remain breathless or have exacerbations despite taking a LABA when ICS is declined or not tolerated. This recommendation was based on use of separate LABA and LAMA inhalers as there were no LABA/LAMA combination inhalers when this guideline was developed. NICE Evidence Summary 3 : NICE published an evidence summary (ESNM33) in February This evidence summary focuses on 2 randomised controlled trials (SPARK [Wedzicha et al. 2013] 8 ) and BLAZE [Mahler et al. 2013] 9 ) that reported exacerbations and dyspnoea respectively, as their primary outcomes. It stated that although some small statistically significant improvements in lung function, dyspnoea, health status and use of rescue medication were seen with Ultibro compared with active comparators (indacaterol, glycopyrronium, tiotropium and Seretide ), the clinical importance of these differences is unclear and Ultibro s place in therapy is currently difficult to assess. Global Initiative for COPD (GOLD) Guidance 2 The 2017 GOLD report s advice on the treatment of stable COPD recommends stepping up to a combination LAMA/LABA inhaler as first-choice fixed-dose combination therapy when initial treatment with a single long-acting bronchodilator is insufficient for patients graded as B, C or D (high risk of exacerbations or high symptoms impact scores). GOLD recommend the use of a LABA/LAMA combination inhaler before the use of a LABA+ICS. ICS increases the risk of developing pneumonia in some patients. GOLD noted that a LABA/LAMA combination significantly improves lung function, dyspnoea, health status and reduced exacerbations. There is evidence to show LABA/LAMA combination to be superior to monotherapy or LABA+ICS combination in reducing exacerbations. GOLD recommends de-escalation of treatment where the introduction of additional inhaler did not improve symptoms. SMC recommended use within NHS Scotland 4 : Yes Ultibro Breezhaler is accepted for use within NHS Scotland for maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. SMC noted that Ultibro Breezhaler provides the two 6 P a g e

7 ingredients in a single hard capsule at a lower cost than the individual components for patients in whom the combination of indacaterol maleate and glycopyrronium bromide is an appropriate choice of therapy. Regional Drug and Therapeutics Centre (RDTC) 5 : Yes RDTC reviewed Ultibro Breezhaler in December 2014 based on five RCTs. Four of the trials evaluated the effects of Ultibro on lung function or symptoms on moderate to severe COPD patients while the fifth trial evaluated its effect on exacerbation rates among high risk patients with severe COPD. The combination of glycopyrronium/indacaterol improved lung function more than placebo, the individual components and fluticasone/salmeterol. It also reduced the rate of moderate to severe COPD exacerbations compared with glycopyrronium alone. The frequency and character of adverse events reported in the efficacy studies was similar across treatment groups. RDTC noted that the limitation to ILLUMINATE study was that very few of the patients enrolled met the current guideline criteria for treatment with fluticasone/salmeterol as most of them had FEV 1 >50% predicted with no exacerbations in the previous year. More than 50% of patients in the SHINE, SPARK and BLAZE trails were using ICS at baseline and continued throughout the trials. RDTC stated that until there are longer-term data on safety and evidence of clear patient-oriented advantages over alternatives, fixed-dose LAMA/LABA combination inhalers, including Ultibro, should be reserved for those patients who would otherwise be treated with both components given separately. Midlands Therapeutics Review and Advisory Committee (MTRAC) 6 : Yes MTRAC reviewed the evidence for all 4 available LAMA/LABA combination inhalers (Ultibro Breezhaler, Anoro Ellipta, Duaklir Genuair and Spiolto Respimat ). A meta-analysis including 27 trials comparing the efficacy of the different LAMA/LABA inhalers in COPD was reviewed. MTRAC stated there were no significant differences between the different LAMA/LABA inhalers for any outcomes, with the exception of trough FEV 1 for Anoro Ellipta vs Duaklir Genuair. MTRAC recommended that CCGs who wish to rationalise the number of products on the formulary when considering the choice between LAMA/LABA inhalers should base it on patients ability to tolerate and use the inhaler device as well as cost. All Wales Medicines Strategy Group (AWMSG) 11 : Yes Ultibro Breezhaler is recommended as an option for use within NHS Wales as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic COPD. AWMSG reviewed the BEACON study that evaluated non-inferiority of Ultibro versus treatment with individual components in the efficacy and safety of treatment in COPD patients. The trial data indicated similarity in both clinical efficacy and safety profile of Ultibro in comparison to administering the two individual components. Cochrane Review No 7 P a g e

8 Efficacy: FLAME Trial 7 : Indacaterol-Glycopyrronium versus Salmeterol Fluticasone for COPD The FLAME trial - a 52 week randomised, double blinded, non-inferiority trial - compared Ultibro Breezhaler to Seretide 500 Accuhaler (n=3362) in adult patients over 40 years with COPD (postbronchodilator FEV % predicted and post-bronchodilator FEV 1 /FVC less than 0.70 and a modified Medical Research Council (mmrc) of at least 2) and at least one COPD exacerbation in the previous year. The primary outcome was to demonstrate non-inferiority of Ultibro to Seretide with respect to the rate of COPD exacerbations. A key secondary objective was to demonstrate superiority of Ultibro compared to Seretide if the primary objective was met. Other secondary objectives included the time to the first COPD exacerbation (all exacerbations, and by severity), trough FEV 1, FEV 1 area under the curve from 0-12h, health status according to the St George s Respiratory questionnaire (SGRQ) total score and the use of rescue medication. Exacerbations: There was a significantly lower annual rate of all exacerbations (primary outcome) (RR 0.89; 95% CI 0.83 to 0.96; p=0.003) and moderate to severe exacerbations requiring hospitalisation with Ultibro Breezhaler compared to Seretide (RR 0.83; 95% CI 0.75 to 0.91; p<0.001). The time to the first exacerbation (71 days vs 51 days, p<0.001) and first moderate or severe exacerbation (127 days vs 87 days, p<0.001) was longer in the Ultibro group. Lung function: At week 52, the change from baseline in trough FEV 1 was statistically significantly improved in the Ultibro group compared to Seretide (difference 62ml; p<0.001). NICE considers a value of 100ml to be clinically significant. Quality of life (SGRQ): Health status, as measured by the St. George's Respiratory Questionnaire (SGRQ) scores were statistically significantly lower (improved) with Ultibro compared to Seretide - differences ranged from 1.2 points at week 12 to 1.8 points at week 52 (p<0.01), however this was below the difference considered to be clinically significant by NICE ( 4 points). At week 52, the percentage of patients who had a decrease of at least 4 points was significantly higher in the Ultibro group compared to the Seretide group (49.2% vs 43.7%, p<0.001). Safety: The incidence of adverse events and deaths was similar in the two groups. The incidence of pneumonia was 3.2% in the Ultibro group and 4.8% in the Seretide group (P=0.02). SPARK Trial 8 : Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study The SPARK trial is a multicentre trial that compared Ultibro Breezhaler with blinded glycopyrronium or open-label tiotropium monotherapy (n=2224) over 64 weeks, with an optional extension to 76 weeks. This was conducted in adult patients aged 40 or over, at GOLD stages III IV, and with one or more moderate COPD exacerbation in the past year. Long-acting bronchodilators were discontinued before screening but continued use of ICS was permitted during the study. The primary objective was to demonstrate superiority of Ultibro compared to glycopyrronium for the annualised rate of moderate or severe COPD exacerbations (requiring treatment with oral steroids or antibiotics, emergency treatment or hospital admission) during the treatment period. The main secondary 8 P a g e

9 objective was to demonstrate superiority of Ultibro in comparison to tiotropium for the rate of moderate or severe COPD exacerbations during the treatment period. Other secondary end points included annualised rates of exacerbations by degree of severity, use of rescue salbutamol and adverse events. Measures of lung function, health status scores (as measured by the St. George's Respiratory Questionnaire [SGRQ]) and adverse events were also assessed. Exacerbations: The study reported a 12% reduction in the rate of annualised moderate to severe exacerbations (primary outcome) for Ultibro Breezhaler compared with glycopyrronium monotherapy (relative risk [RR] 0.88, 95% confidence interval [CI] , p=0.038); and a non-statistically significant reduction in this outcome compared to open-label tiotropium (RR 0.90, 95% CI 0.79 to 1.02, p=0.096). The NICE clinical guideline on COPD considers a relative reduction in the risk of exacerbations of 20% or more to be clinically important. The trial also demonstrated a significantly lower rate of all exacerbations with Ultibro Breezhaler compared with glycopyrronium alone (RR 0.85, 95% CI , p<0.0012) and with open-label tiotropium (RR 0.86, 95% CI , p<0.0017). Quality of life (SGRQ): Health status, as measured by the St. George's Respiratory Questionnaire [SGRQ] scores were statistically significantly lower (improved) with indacaterol/glycopyrronium at all time points assessed (12, 24, 38, 52 and 64 weeks): differences ranged from 1.7 to 3.1 compared with glycopyrronium and open-label tiotropium (p<0.05 in all comparisons), however this was below the difference considered to be clinically significant by NICE ( 4 points). Lung function: The trough FEV 1 was statistically significantly higher with Ultibro at all assessments (continued to 64 weeks) compared with glycopyrronium (differences 70 to 80 ml; p<0.0001) and open-label tiotropium (differences 60 to 80 ml; p<0.0001). Safety: Serious adverse events were reported in similar proportions across the treatment groups with no statistically significant differences between groups for any event (23% - Ultibro, 24% - glycopyrronium and 22% - tiotropium). Fewer patients discontinued Ultibro due to unsatisfactory clinical effect (2.5%) compared to glycopyrronium (4.3%) and tiotropium (5.2%). Statistical significance was not reported. Limitations: 75% of the participants in the trial used ICS. Therefore, a significant number of patients in the Ultibro group received triple therapy (LAMA/LABA plus ICS), and were compared with a LAMA treatment arm in which a significant number of people received dual therapy with a LAMA and an ICS. LAMA/ICS is not recommended in the NICE clinical guideline on COPD. BLAZE Trial 9 : Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: BLAZE study. The BLAZE trial compared the effects of Ultibro with placebo (primary objective) and tiotropium (secondary objective) on patient-reported dyspnoea over 6 weeks in a randomised double-blind, doubledummy, placebo-controlled 3-period crossover study. The patients enrolled were adults aged 40 years or over (n=247) with moderate or severe stable COPD (post-bronchodilator FEV % of predicted; postbronchodilator FEV 1 /FVC less than 0.70; and a modified Medical Research Council (mmrc) dyspnoea scale grade of at least 2), who were current or ex-smokers with a smoking history of at least 10 pack-years. Use of long-acting bronchodilators or short-acting muscarinic antagonists (SAMAs) was not permitted during the study, but treatment with ICS was continued. Patients were randomised to one of six treatment sequences and received each treatment (Ultibro, tiotropium and placebo) for 6 weeks, followed by a 2 week washout period. The primary objective was to demonstrate superiority of Ultibro compared to placebo in patient-reported dyspnoea scores after 6 weeks' treatment, as assessed using a computerised version of the Baseline and Transition Dyspnoea Indices (BDI/TDI). A key secondary objective was to demonstrate superiority of Ultibro in comparison to tiotropium for the same outcome. Other secondary outcomes included 9 P a g e

10 measures of lung function, use of rescue medications, night-time awakenings due to symptoms, and symptom scores. Breathlessness: The study reported that Ultibro statistically significantly improved dyspnoea scores in people with moderate or severe COPD compared with placebo (least squares mean [LSM] difference 1.37, 95% CI 0.95 to 1.79; p<0.001) and tiotropium (LSM difference 0.49, 95% CI 0.07 to 0.91; p=0.021). The study reported that a difference of 1 point improvement is considered to be clinically important compared to placebo. The study also reported a significant reduction in the use of rescue medication in the Ultibro group and a significantly higher percentage of days with no rescue medication use compared with those taking placebo (p<0.001 for both) or tiotropium (p=0.002 and p<0.001 respectively). A statistically significant reduction in night time awakening, and daytime symptoms was seen with Ultibro compared to placebo, but no statistical difference was reported compared to tiotropium. Lung function: The Ultibro group demonstrated statistically significant improvements in lung function, with higher post-dose FEV 1, standardised area under the curve from 0 to 4 hours (FEV 1 AUC 0-4h ) compared with placebo and tiotropium at day 1 and week 6 (all p<0.001) Safety: The incidence of adverse events was similar across all treatment groups (35.0% for Ultibro versus 35.5% and 39.4% for tiotropium and placebo respectively). The incidence of serious adverse events (2.7% for both active treatment groups and 2.3% for placebo), and adverse events leading to discontinuation (4.9% for Ultibro versus 5.5%, 4.1% for tiotropium and placebo respectively) was similar in each treatment group. SHINE Trial 12 : Dual bronchodilation with QVA149 versus single bronchodilator therapy The SHINE trial (n=2144) compared Ultibro with indacaterol, glycopyrronium and placebo (all doubleblind) and open-label tiotropium on trough FEV 1. The patients enrolled were aged 40 years or over (mean age 64 years) who had moderate or severe stable COPD (stage II or III according to GOLD 2008 criteria). Patients using fixed-dose ICS/LABA at study entry were switched to an equivalent dose of ICS monotherapy. The primary outcome was trough FEV 1 at week 26 for Ultibro compared with its individual components. Secondary outcomes included trough FEV 1 compared with placebo and tiotropium, changes in dyspnoea and health status scores, use of rescue medication, patient reported symptoms and adverse events. Efficacy: The trial demonstrated a statistically significant improvement in trough FEV 1 with Ultibro compared with indacaterol, glycopyrronium, open-label tiotropium and placebo (LSM differences 70 ml, 90 ml, 80 ml and 200 ml respectively; p<0.001 in all comparisons) Limitations: The trial compared dual therapy with a LAMA/LABA, to monotherapy with either a LABA or a LAMA. More than half of patients were using ICS at baseline, therefore a significant number of patients in the Ultibro group received triple therapy (LAMA/LABA plus ICS), and were compared with a LAMA treatment arm in which a significant number of people received dual therapy with a LAMA and an ICS. ILLUMINATE Trial: 13 Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol/fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study The ILLUMINATE study compared Ultibro with Seretide in patients with moderate to severe COPD (stage II or III according to GOLD 2009 criteria) over 26 weeks (n=523) in a randomised double-blinded study. 10 P a g e

11 The primary outcome was the standardised area under the curve from 0 to 12 hours post-dose for FEV 1 (FEV 1 AUC 0-12h ) at week 26. Secondary outcomes included other measures of lung function, changes in dyspnoea and health status scores, use of rescue medication and adverse events. Efficacy: The study reported at significantly higher FEV 1 AUC 0-12h at week 26 with Ultibro compared to Seretide (difference 138ml, 95% CI , p<0.0001). BEACON Trial 14 : Efficacy and safety of QVA149 compared to the concurrent administration of its monocomponents indacaterol and glycopyrronium The four week BEACON study (n = 193) evaluated the efficacy and safety of Ultibro compared to the concurrent administration of its separate components indacaterol and gylcopyrronium. The primary endpoint was to evaluate the non-inferiority of Ultibro for trough FEV 1. Efficacy: The trial demonstrated that effects on lung function with the Ultibro combination are equivalent to those seen with concurrent use of the individual components. Safety: Adverse effects were reported in similar proportions in each treatment arm, with the majority being mild-to-moderate in severity. Inspiratory flow rate 15 : A review by Dal Negro reported the required inspiratory flow rate for Ultibro Breezhaler was higher than the Ellipta and Genuair devices (the alternative LAMA/LABA inhalers available) (111L/min vs 74L/min and 64L/min respectively). The review stated that although Ultibro had the lowest intrinsic resistance, this corresponded to the highest inspiratory flow rate required. When using a low resistance DPI, the only driving force for the disaggregation and microdispersion of the drug to inhale is represented by the patient s inhalation airflow rate (the role of the resistance-induced turbulence is negligible in these cases) which depends on the patient s airflow limitation and disease severity. 11 P a g e

12 Cost Analysis Comparative Costs and Expenditure of LAMA/LABA combination inhalers in Secondary Care (UHNM) March 2016 February 2017: Medicine Description ULTIBRO BREEZHALER ANORO ELLIPTA (30 doses) DUAKLIR GENUAIR (60 doses) Constituents Pack size Current Price UHNM (incl. VAT) Number of Packs UHNM TOTAL EXPENDITURE (VAT applied as appropriate) % Usage GLYCOPYRRONIUM BROMIDE and INDACATEROL MALEATE 30 caps % UMECLIDINIUM and VILANTEROL ACLIDINIUM and FORMOTEROL 1 inhaler % 1 inhaler % TOTAL Comparative Costs and Expenditure of LAMA/LABA combination inhalers in Primary Care (North Staffordshire CCGs) March 2016 February 2017: Medicine Description ULTIBRO BREEZHALER ANORO ELLIPTA (30 doses) DUAKLIR GENUAIR (60 doses) Constituents Pack size Current Price Primary Care (excl. VAT) Number of Packs North Staffordshire CCGs Sum of NIC % Usage GLYCOPYRRONIUM BROMIDE and INDACATEROL MALEATE 30 caps , % UMECLIDINIUM and VILANTEROL ACLIDINIUM and FORMOTEROL 1 inhaler , % 1 inhaler , % TOTAL 90, Other cost considerations: Ultibro is also available in a 12 capsule pack plus inhaler at an equivalent cost per dose compared to the 30 capsule pack. 12 P a g e

13 References 1 Summary of Product Characteristics. Ultibro Breezhaler. Novartis Pharmaceuticals. Last updated on 14 th December Accessed via: 2 Global initiative for Chronic Obstructive Pulmonary Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease: 2017 Report. Accessed online via: 3 National Institute for Health and Clinical Excellence. Evidence summary ESNM33: Chronic obstructive pulmonary disease: indacaterol/glycopyrronium (Ultibro Breezhaler). February Scottish Medicines Consortium. Indacaterol maleate 143micrograms (equivalent to 110microgram indacaterol) with glycopyrronium bromide 63micrograms (equivalent to 50microgram glycopyrronium) inhalation powder hard capsules (Ultibro Breezhaler 85microgram/43microgram [delivered dose]) SMC No. 922/13. November Regional Drug and Therapeutics Centre (RDTC) New Drug Evaluation. Indacaterol and glycopyrronium for the treatment of COPD. December 2014 RDTC No Accessed online via: 6 Midlands Therapeutic Review and Advisory Committee (MTRAC) Commissioning Support Fixed-dose LABA/LAMA Inhalers: Ultibro Breezhaler, Anoro Ellipta, Duaklir Genuair, Spiolto Respimat For the treatment of Chronic Obstructive pulmonary Disease (COPD). Midlands Therapeutics Review & Advisory Committee. September Accessed online via 7 Wedzicha JA, Benerji D, Chapman KR et al. Indacaterol Glycopyrronium versus Salmeterol Fluticasone for COPD (FLAME). New England Journal of Medicine 2016; 374: Wedzicha JA, Decramer M, Ficker JH et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. The Lancet Respiratory Medicine 2013; 1: Mahler DA, Decramer M, D'Urzo A et al. Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: BLAZE study. European Respiratory Journal 2014; 43: National Institute for Health and Clinical Excellence (NICE) clinical guideline 101. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. June Access online via: 11 All Wales Medicines Strategy Group (2014). Final Appraisal Recommendation 0814: Indacaterol/glycopyrronium (Ultibro Breezhaler ) 85 micrograms/43 micrograms inhalation powder as hard capsules. 12 Bateman ED et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J Vogelmeier CF et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol/fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir Med 2013; 1: 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 2013; 8: Dal Negro RW. Dry powder inhalers and the right things to remember: a concept review. Multidisciplinary Respiratory medicine 2015; 10: 13 Produced by Helen Wrightson Specialist Rotational Pharmacist - Medicines Management University Hospital of North Midlands Telephone: helen.wrightson@uhnm.nhs.uk Produced for use within the NHS. Not to be reproduced for commercial purposes. 13 P a g e