A fixed-dose combination maintenance bronchodilator for people with moderate to severe COPD
Once-daily maintenance bronchodilator for people with moderate to severe COPD
Indacaterol 110 micrograms / glycopyrronium 50 micrograms (Ultibro Breezhaler 110/50) is a fixed-dose combination of these medicines. It provides maintenance bronchodilation for 24 hours after a once-daily dose in people with COPD.
Not PBS listed for first-line bronchodilation therapy in COPD
Patients must have been stabilised on a combination of a long-acting muscarinic receptor antagonist/anticholinergic (tiotropium, glycopyrronium, aclidinium or umeclidinium) and long-acting beta-2 receptor agonist (indacaterol, salmeterol or eformoterol).
- Not for use in asthma or mixed airways disease
Similar efficacy and safety to that of both ingredients delivered concurrently
Over 4 weeks, improvements in lung function, symptom reduction, use of rescue medication and rate of adverse events for indacaterol/glycopyrronium 110/50 micrograms FDC were comparable to those for both ingredients inhaled concurrently as single-agent formulations.
What is known about this combination drug
Indacaterol/glycopyrronium 110/50 FDC consists of a long-acting beta-2 agonist (LABA) and a long-acting muscarinic antagonist/anticholinergic (LAMA) in a single capsule taken via an inhaler device.
It is used as maintenance treatment for symptom control in patients with moderate to severe COPD who have previously been stabilised on both a LABA and a LAMA in separate inhalers.
It has a similar safety and tolerability profile to that of the components (indacaterol 150 micrograms and glycopyrronium 50 micrograms) delivered concurrently or as monotherapy.
Areas of uncertainty
The long-term clinical effects of indacaterol/glycopyrronium FDC are unknown, as there are no safety data beyond 64 weeks.
Comparative data are available on clinical efficacy and safety of indacaterol/glycopyrronium FDC compared with that of indacaterol or glycopyrronium delivered separately as monotherapy for up to 26 weeks and 64 weeks, respectively.
The comparison between indacaterol/glycopyrronium FDC and the component ingredients delivered concurrently was only a 4-week trial.
What does NPS MedicineWise say?
COPD stepwise management is complicated and requires patients to discontinue some previous medicines before undertaking new treatment.
The December 2014 NPS RADAR In Brief item Pharmacological therapies for COPD in Australia provides a list of currently available medicines and explains which medicines may be used in combination.
Indacaterol/glycopyrronium FDC is PBS listed for use in people with moderate to severe COPD who have been stabilised on combination therapy of a LABA and a LAMA taken with separate inhalers.
It should not be used concurrently with any other product containing a short-acting or long-acting muscarinic antagonist (SAMA or LAMA) or long-acting beta-2 agonist (LABA, or LABA with inhaled corticosteroids [LABA/ICS]). A short-acting beta-2 agonist (SABA) should be used for symptom relief as needed while taking this combination FDC.
Indacaterol/glycopyrronium FDC is as effective and safe as concurrent delivery of indacaterol 150 micrograms and glycopyrronium 50 micrograms in separate inhalers, and more effective at improving lung function than either ingredient delivered alone.
Long-acting bronchodilators are the mainstay of pharmacological management of COPD. When symptoms persist or are not controlled on a single long-acting bronchodilator, consult guidelines before considering stepping up to a combination product and to inform a choice of products suitable for combination use.
Consider that bronchodilators delivered in a fixed-dose combination may simplify treatment and may be preferred by patients.
Quality of the evidence
See new section: Quality of the evidence below.
Authority required (Streamlined)
Indacaterol/glycopyrronium FDC (Ultibro Breezhaler 110/50) delivered via the single inhaler device is PBS listed as Authority Required (Streamlined)* for chronic obstructive pulmonary disease (COPD).
* Authority Required (Streamlined) benefits do not require prior approval from Medicare Australia but require the recording of a streamlined authority code.
May be prescribed by nurse practitioners
Indacaterol/glycopyrronium FDC may be prescribed by nurse practitioners as continuing therapy only, when the treatment and prescribing of medicine for a patient has been initiated by a medical practitioner. See the PBS website for more information on nurse practitioner PBS prescribing.
What is it?
Indacaterol/glycopyrronium 110/50 micrograms FDC (Ultibro Breezhaler 110/50) is an inhaled powder containing two bronchodilators with different modes of action:1
- indacaterol, a long-acting beta-2 agonist producing bronchodilation by stimulation of intracellular adenyl cyclase
- glycopyrronium, a long-acting muscarinic antagonist/anticholinergic that provides bronchodilation by blocking the action of acetylcholine on the muscarinic receptors of airway smooth muscle cells.
Both bronchodilators are long acting, with an onset of action within 5 minutes after inhalation and a duration of effect that is sustained over 24 hours.1
Indacaterol/glycopyrronium FDC capsules are for inhalation only and are supplied with an inhalation device.1
Who is it for?
Use indacaterol/glycopyrronium FDC for maintenance bronchodilation treatment in patients with moderate to severe COPD.1
Do not use as first-line bronchodilation therapy in COPD
For PBS-listed use, patients must have been stabilised on a combination of a LAMA (tiotropium, glycopyrronium, aclidinium or umeclidinium) and a LABA (indacaterol, salmeterol or eformoterol), in separate devices.
Not for asthma, mixed airways disease or acute episodes of bronchospasm
Indacaterol/glycopyrronium FDC is not for people with asthma, as there are insufficient data to support its use for this indication.
Exclude a diagnosis of asthma or mixed airways disease before starting indacaterol/glycopyrronium FDC.
Do not use as rescue therapy for treatment of acute episodes of bronchospasm.1
Not for people under 18 years of age
COPD affects adults only, and indacaterol/glycopyrronium FDC is not for use in patients aged under 18 years.1
Where does it fit?
Indacaterol/glycopyrronium FDC is a once-daily LABA/LAMA combination bronchodilator that provides a single-inhaler alternative to a LABA and LAMA in two separate inhaler devices.
Combination products such as indacaterol/glycopyrronium FDC can simplify treatment regimens in COPD when used in line with a stepwise approach to management.4
Use for maintenance treatment in moderate to severe COPD
Current recommendations for stepwise management support using a LABA and a LAMA for symptom control in patients with moderate (40–59% FEV1 predicted) or severe (< 40% FEV1 predicted) COPD.3
Indacaterol/glycopyrronium FDC is an option for patients who have been previously stabilised on a combination of a LABA and LAMA taken in two separate inhalers.3
Indacaterol/glycopyrronium FDC can only be used with a SABA
It should not be used concomitantly with any other inhaler containing a short-acting or long-acting muscarinic antagonist (SAMA or LAMA) or long acting beta-2 agonist (LABA or LABA/ICS). It may be used with a short-acting beta-2 agonist as needed for symptom relief (SABA).2, 3, 5
Medicines that are replaced by this FDC should be returned to a pharmacy for safe destruction.
How does it compare?
Combination therapy involving the bronchodilator action of a LABA and a LAMA for moderate to severe COPD has been shown to be more effective than single bronchodilator monotherapy (either a LABA or LAMA in a single inhaler) due to the complementary mechanism of action of the individual components.1, 6-9
To date, all trials assessing efficacy for indacaterol/glycopyrronium FDC have recruited people aged over 40 with moderate or severe COPD2 who were current or ex-smokers with a smoking history of at least 10 pack–years†.7, 10, 11
† Pack–years is calculated by pack smoked per day × number of years as a smoker.
Comparable efficacy to that of both drugs delivered concurrently
In the 4-week BEACON trial of people with moderate to severe COPD (n = 193), indacaterol/glycopyrronium 110/50 micrograms FDC delivered via a single inhaler (Breezhaler) improved lung function to a degree comparable with concurrent indacaterol 150 micrograms and glycopyrronium 50 micrograms delivered via separate inhalers (both Breezhalers).
Lung function was primarily determined by trough FEV1 at 4 weeks and did not differ between the two groups. Other measures of lung function such as FEV1 AUC(0–4 h)‡ were also similar between groups at day 1 and week 4.11
A similar reduction in self-reported symptoms (eg, coughing, wheezing, sputum production, breathlessness) and use of rescue medicine was seen between the two groups. Exacerbations and quality-of-life measures were not reported.11
‡ FEV1 AUC (hours) is the area under the curve post bronchodilation divided by the number of hours and subtracting baseline FEV1
Greater efficacy than for monotherapy with either drug
Compared with monotherapy with either indacaterol 150 micrograms or glycopyrronium 50 micrograms taken for 26 weeks in the SHINE trial (n = 2144), people taking indacaterol 110 micrograms / glycopyrronium 50 micrograms FDC showed significantly greater improvements in lung function throughout the trial period.
The primary endpoint at 26 weeks, trough FEV1, was 70 mL and 90 mL higher (p < 0.001) than for indacaterol and glycopyrronium, respectively, taken as monotherapy.7
The clinical relevance of such differences is unclear given most trials consider an improvement of ≥ 100 mL to be a clinically relevant change in lung function in COPD.12
FEV1 AUC(0–4 h), peak FEV1 and FEV1 AUC(0–12 h) were all significantly improved over the trial period in patients taking indacaterol/glycopyrronium FDC compared with those taking indacaterol or glycopyrronium alone.7
People assigned to the FDC did not report a reduction in breathlessness, as measured by total dyspnoea index focal scores,§ or improvement in health status, as measured by St George's respiratory questionnaire (SGRQ), which were secondary outcomes, compared with those taking indacaterol or glycopyrronium alone.7
Use of rescue medication was significantly lower for people taking indacaterol/glycopyrronium FDC compared with those taking indacaterol (p < 0.05) or glycopyrronium (p < 0.001) alone.7
People who had experienced a recent exacerbation requiring antibiotics, systemic steroids (oral or intravenous) or hospitalisation, within 6 weeks of enrolment, were excluded from the trial. The authors noted that this study did not provide useful information on the effect of indacaterol/glycopyrronium FDC on exacerbations.7
In the SPARK trial (n = 2224) comparing indacaterol/glycopyrronium FDC with glycopyrronium alone, people taking the FDC experienced greater improvements in lung function at 64 weeks.
Trough FEV1 was significantly higher (70–80 mL difference, p < 0.0001) in people using indacaterol/glycopyrronium FDC after the 64-week trial than those taking glycopyrronium alone.10
People taking the FDC also reported greater improvements in health status (SGRQ) and less use of rescue medication compared with those taking glycopyrronium alone.10
The primary endpoint of the SPARK trial was number of exacerbations. Patients who had experienced a recent exacerbation requiring antibiotics, systemic steroids (oral or intravenous) or hospitalisation, within 6 weeks of enrolment, were excluded.
Ninety-eight per cent of patients had experienced one or more exacerbations in the previous year, while 22% experienced two or more exacerbations. Seventy-five per cent of patients were taking an ICS with their assigned treatment.
Patients taking indacaterol/glycopyrronium FDC experienced 12% fewer moderate or severe exacerbations‖ than patients taking glycopyrronium alone (1.11 vs 1.22 events per year, p < 0.05).10
§ The transition dyspnoea index (TDI) evaluates changes in dyspnoea over time and incorporates three components: functional impairment, magnitude of effort, and magnitude of task. The TDI focal score is the addition of scores from the three categories.13
‖ Moderate COPD exacerbation defined as requirement for treatment with systemic corticosteroids and/or antibiotics. Severe exacerbation defined as hospital admission, including emergency department visit > 24 hours.10
The longest trial was the SPARK trial, with safety and efficacy data up to 64 weeks' follow-up.10 There are no published safety data beyond 64 weeks.
For information about reporting adverse reactions to the Therapeutic Goods Administration, or to report suspected adverse reactions online, see the TGA website.
Comparable safety to that of both drugs delivered concurrently
In the BEACON trial, safety and tolerability of indacaterol/glycopyrronium FDC were equivalent to the profile for concurrent indacaterol 150 micrograms and glycopyrronium 50 micrograms delivered in separate inhalers over a 4-week period, with a similar percentage of people reporting adverse events (25.6% vs 25.2%).11
Nasopharyngitis, worsening COPD and a cough were the most common adverse events across both groups. The level of serious adverse events was equivalent between groups, and no deaths or cardiovascular or cerebrovascular events were reported in either group.11
Safety of the FDC over concurrent delivery of both ingredients beyond 4 weeks has not been established.
No additive adverse effects from using this FDC bronchodilator
Safety and tolerability of indacaterol/glycopyrronium delivered as an FDC were comparable to that experienced in people using either component as a single agent,7 indicating there was no evidence of additive adverse effects when the two bronchodilators were delivered in a single inhaler.
COPD exacerbations, nasopharyngitis, cough and URTIs were the most common adverse events.7 However, because under the current PBS restriction patients must have been stabilised on the concomitant use of a LABA and a LAMA before being eligible for the FDC, if additive effects were experienced these would be addressed before starting on the FDC.
Caution in people with urinary retention, angle-closure glaucoma or renal failure
Due to the known risks of anticholinergics in people with angle-closure glaucoma or urinary retention, use caution if prescribing indacaterol/glycopyrronium FDC in these people.15
Glycopyrronium is primarily eliminated by renal excretion.1 No dose adjustment is required for people with mild to moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2) but use with caution in people with severe renal impairment (eGFR < 30 mL/min/1.73 m2).1
Patients with urinary infections, angle-closure glaucoma or severe renal failure were excluded from clinical trials.1
Be aware of paradoxical bronchospasm
As with any inhalation therapy, discontinue indacaterol/glycopyrronium FDC and switch to an alternative if the patient experiences paradoxical bronchospasm after inhalation.1
Use with caution in people with cardiovascular disorders
As with all beta-2 agonists, use indacaterol/glycopyrronium FDC with caution in people with cardiovascular disorders (eg, coronary artery disease, acute MI, cardiac arrhythmias, hypertension), convulsive disorders or thyrotoxicosis, and those who are unusually responsive to beta-2 agonists, as these patients were excluded from clinical trials.1
Use with caution in people with type 1 or uncontrolled type 2 diabetes
Plasma glucose level has been shown to increase after inhalation of beta-2 agonists, and people with type 1 or uncontrolled type 2 diabetes were excluded from the clinical trials.1
Reason for PBS listing
The Pharmaceutical Benefits Advisory Committee accepted that indacaterol/glycopyrronium FDC has a place in COPD therapy for patients already stabilised on individual components.
The PBAC noted concerns that the incremental benefit of the combination product on improving lung function could not be translated into clinically relevant measures of effect such as exacerbations and hospitalisations, but accepted that the combination may be more convenient and improve management of COPD while providing cost-savings for patients who are already using an individual LAMA and LABA in separate devices.
The Authority required (Streamlined) listing was imposed to address inappropriate prescribing of the product, particularly in the first-line setting.5
Administer indacaterol/glycopyrronium FDC capsules by oral inhalation using the Breezhaler device.1
Dose once daily, preferably at the same time each day. If a dose is missed it may be inhaled as soon as possible but a double-dose is not required. Advise people taking indacaterol/glycopyrronium FDC not to take more than one dose per day.1
Correct use of the inhaler is imperative. If patients do not report symptom improvement check inhaler technique before considering other options.1 The correct inhaler technique is available online at NPS MedicineWise.
Information for patients
Explain to patients that, as maintenance treatment, the contents of one capsule of indacaterol/glycopyrronium FDC should be inhaled daily, even if the patient feels well.
Ensure the patient understands the difference between their maintenance treatment and reliever medicine and remind them to carry their reliever inhaler at all times.
Explain that indacaterol/glycopyrronium FDC capsules must be inhaled only with the Breezhaler device included with their medicines. Capsules are not to be swallowed.
Check the patient's inhaler technique and ensure they understand how to use the device correctly (there are instructions on the inside of the packaging for Ultibro Breezhaler 110/50).
Medicines that are replaced by this FDC should be returned to a pharmacy for safe destruction.
Advise patients to store capsules in the blister pack to protect from moisture, and only remove immediately before use.
Arrange a follow-up appointment to occur 4 weeks after the patient starts indacaterol/glycopyrronium FDC to review control of their COPD.
Tell them to contact you if they find the usual dose of indacaterol/glycopyrronium FDC is not providing as much relief as their previous medications.
Tell the patient to stop taking Ultibro Breezhaler 110/50 and seek urgent medical attention if they experience:
- tightness in the chest, coughing, wheezing or breathlessness immediately after using the inhaler (signs of bronchospasm)
- difficulties breathing or swallowing, swelling of the tongue, lips or face, urticaria, skin rash (signs of hypersensitivity reaction)
- eye-pain or discomfort, temporary blurring of vision, visual halos or coloured images in association with red eyes (signs of an acute attack of angle-closure glaucoma)
- pain or difficulty passing urine (signs of urinary retention).
Discuss the Ultibro Breezhaler 110/50 Consumer Medicine Information (CMI) leaflet with the patient.
Quality of the evidence
NPS MedicineWise is trialling the inclusion of a new section where we discuss the quality of evidence used in developing our conclusions about a new medicine's efficacy and safety. NPS used the GRADE criteria for assessing evidence quality.16, 17
Risk of bias
Is there evidence of bias in the study design and approach?
Participants in all three published trials were appropriately randomised with adequate allocation concealment.
Both the BEACON and SHINE studies may have introduced some bias in the data analysis through use of a per-protocol analysis (BEACON) and rejecting data from patients who did not adhere to treatment (SHINE).
The SPARK study had > 20% loss to follow-up in both groups and closed one site that did not adhere to protocol standards, which would have introduced selection bias through attrition.
Are the data consistent between trials?
Several efficacy outcomes were considered by the trials, including rate of exacerbation and lung function measured as trough FEV1.
The SHINE and SPARK studies, comparing the FDC to monotherapy, did not designate the same primary outcomes although both studies reported a similar improvement in lung function with the FDC that did not meet clinical significance.
The 4-week BEACON trial was the only trial conducted to establish non-inferiority of the FDC against concurrent delivery of both products in separate devices.
Are the trial data applicable to the wider population that will be prescribed this medicine?
Most trials included people with moderate to severe COPD; however, some trials (SHINE and SPARK) excluded people with comorbidities, which may limit applicability to the general patient population.
One study selected patients with a history of exacerbations, which may limit applicability in people with less severe COPD.
Also, most trials allowed concurrent use of ICS, which may limit applicability in people not treated with ICS.
Are the confidence intervals around the estimate of effect wide?
The effect size was small for all three trials, with tight 95% confidence intervals, and there were no clinically relevant differences between the FDC over monotherapy.
Is there evidence that trials have been selectively published?
NPS could find no evidence of selective publication.
The quality of the evidence for the efficacy of this FDC across these three trials is considered to be moderate. This is because of a risk of bias due to attrition, lack of consistency, and not all study findings being directly applicable to the population who will receive the FDC in an Australian context under existing guidelines and PBS restrictions.
- Novartis Pharmaceuticals Australia Pty Ltd. Ultibro Breezhaler 110/50 Product Information. 2014. [TGA PI repository] (accessed 13 August, 2014).
- Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2013. [Online PDF] (accessed 16 August 2014).
- Abramson M, Crockett AJ, Dabscheck E, et al. The COPD-X Plan: Australian and New Zealand Guidelines for the management of Chronic Obstructive Pulmonary Disease V2.36, 2013 (accessed 28\u00a0August, 2014). .
- Therapeutic Guidelines: Respiratory. Chronic obstructive pulmonary disease. 2013. [Online] (accessed 16 August 2014).
- Australian Government Department of Health, Pharmaceutical Benefits Scheme. Public Summary Document: Indacaterol 110 micrograms / glycopyrronium 50 micrograms (Ultibro Breezhaler 110/50) for chronic obstructive pulmonary disease. 2014. [Public Summary Document] (accessed 22 October 2014).
- Mahler DA, D&Urzo A, Bateman ED, et al. Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison. Thorax 2012;67:781\u20138. [PubMed] .
- Bateman ED, Ferguson GT, Barnes N, et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J 2013;42:1484\u201394. [PubMed] .
- Karner C, Cates CJ. Long-acting beta(2)-agonist in addition to tiotropium versus either tiotropium or long-acting beta(2)-agonist alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012;4:CD008989. [PubMed] .
- van Noord JA, Buhl R, Laforce C, et al. QVA149 demonstrates superior bronchodilation compared with indacaterol or placebo in patients with chronic obstructive pulmonary disease. Thorax 2010;65:1086\u201391. [PubMed] .
- 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. Lancet Respir Med 2013;1:199\u2013209. [PubMed] .
- Dahl R, Jadayel D, Alagappan VK, 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;8:501\u20138. [PubMed]
- Donohue JF. Minimal clinically important differences in COPD lung function. COPD 2005;2:111\u201324. [PubMed] .
- Witek TJ Jr, Mahler DA. Meaningful effect size and patterns of response of the transition dyspnea index. J Clin Epidemiol 2003;56:248\u201355. [PubMed] .
- Vogelmeier CF, Bateman ED, Pallante J, 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;1:51\u201360. [PubMed] .
- Australian Medicines Handbook. Anticholinergics (inhaled). [Online] (accessed 21 January 2014).
- Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations. BMJ 2004;328:1490. [PubMed] .
- Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924\u20136. [PubMed]