Drug Safety Evaluation
1.
Introduction
2.
Review of umeclidinium and vilanterol
3.
Efficacy of UM, VI and
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combination therapy 4.
Safety and tolerability
5.
Conclusion
6.
Expert opinion
Umeclidinium/vilanterol combination inhaler efficacy and potential impact on current chronic obstructive pulmonary disease management guidelines James F Davidson, James F Donohue & Jill A Ohar† †
Wake Forest School of Medicine, Medical Center Boulevard, Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunology, Winston-Salem, NC, USA
Introduction: Umeclidinium bromide (UM) with vilanterol (VI) is the first oncedaily long-acting muscarinic antagonist/long-acting b2 agonist (LAMA/LABA) combination approved for use in the treatment of chronic obstructive pulmonary disease (COPD) in the USA. Prior to this, only combinations of short-acting bronchodilators and short-acting muscarinic antagonists were available in the USA as a single inhaler and they required frequent dosing. LAMA or LABA therapy is the recommended first choice for moderate-tovery severe COPD with combination therapy added if monotherapy fails to control patients’ symptoms. This allows lower dosing of individual medications, which may limit adverse effects. It could also have the additional benefit of improving patient compliance by making medication regimens less laboring. Areas covered: A comprehensive literature search of journal articles and abstracts looking for trials that evaluated both the efficacy and the safety of UM/VI revealed that UM/VI improves patients’ lung function and overall health status, while maintaining excellent safety and tolerability profiles compared to placebo and other bronchodilators. Expert opinion: Given the clinical efficacy, favorable safety profile and ease of use, clinicians may recommend UM/VI to patients with moderate-to-very severe COPD -- a shift that could have significant impact on the management of COPD. Keywords: bronchodilator, chronic obstructive pulmonary disease, forced expiratory volume in 1 s, forced vital capacity, long-acting b agonists, long-acting muscarinic antagonist, umeclidinium, vilanterol Expert Opin. Drug Saf. (2015) 14(2):317-324
1.
Introduction
Chronic obstructive pulmonary disease (COPD) severity is based on lung function measurements and is defined by the Global Initiative for Chronic Obstructive Lung Disease criteria, with stage I being mild and stage IV being very severe [1]. Bronchodilators are the foundation of pharmacological management of COPD; unfortunately, patients’ response and adherence to different bronchodilators vary. To maximize medication efficacy and minimize unwanted effects, physicians have started combining bronchodilators of different classes. Data published recently show that combination bronchodilator therapy improves airway reversibility [2], lung function [3] and quality of life [4]. Since convenience plays a role in patient compliance, once-daily (q.d.) bronchodilators may lead to better adherence [5,6]. 10.1517/14740338.2015.983898 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug Summary.
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Drug name Phase Indication Mechanism of action Route of administration Chemical structure Pivotal trial(s) for umeclidinium bromide /VI National Institute of Health Clinical Trials, ClinicalTrials.gov
There has not been a pharmaceutical treatment proven to slow decline in lung function or improve mortality in COPD; therefore, other markers of disease modification have been targeted as outcomes in research trials. Minimal clinically important differences (MCIDs) are used to determine the clinical significance of changes from baseline or treatment differences from placebo. MCIDs correspond to significant outcomes in COPD intervention trials. MCIDs include lung function (trough forced expiratory volume in 1 s [FEV1] 100 -- 140 ml or 5 -- 10% from baseline), dyspnea (improvement of 1 unit in transition dyspnea index score, 5 units in the units in the University of California, San Diego Shortness of Breath Questionnaire) and health status (reduction of 4 units in the Saint George’s Respiratory Questionnaire total score) [7,8]. 2.
Review of umeclidinium and vilanterol
Evidence suggests that the long-acting muscarinic antagonist (LAMA) and long-acting b2 agonist (LABA) combination plays an important role in maximizing bronchodilation. Overview of the market Formoterol, in addition to tiotropium, has been shown to improve both FEV1 and forced vital capacity (FVC) and produces a more rapid onset of action than each bronchodilator individually [9]. In 2013, Wedzicha et al. [10] compared the efficacy of indacaterol/glycopyrronium in patients with severe and very severe COPD with glycopyrronium or tiotropium both as monotherapies with the primary outcome of COPD exacerbations. They found that the combination inhaler group experienced 15 and 14% fewer exacerbations, compared to the glycopyrronium and tiotropium groups, respectively. The complementary interaction(s) between the b2-agonist and muscarinic antagonist pathways is not completely understood; however, there appears to be enough evidence to recommend combining therapies that utilize both pathways to maximize bronchodilation in treatment of COPD. The purpose of this article is to review the efficacy and safety of q.d. dose of umeclidinium bromide (UM)/vilanterol (VI). 2.1
Introduction to the compound: UM and VI UM/VI (Box 1) is a dry powder for inhalation bronchodilator that is used for the treatment of COPD, including chronic 2.2
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Umeclidinium bromide/vilanterol Post-marketing surveillance Moderate-to-very severe chronic obstructive pulmonary disease Long-acting muscarinic antagonist/Long-acting b2 agonist Oral inhalation C29H34BrNO2/C24H33Cl2NO5 NCT01822899, NCT01879410, NCT01313650, NCT01636713, NCT01313637
bronchitis and emphysema. It was approved in December of 2013 by the FDA. Chemistry UM is a slightly water-soluble, 29-carbon, quaternary ammonium bromide containing molecule with a molecular weight of 428.6 (Figure 1) [11]. A LAMA acts as a competitive inhibitor to all muscarinic receptors but shows a greater affinity for the M3 acetylcholine receptor subtype, which is concentrated along airway smooth muscle [12]. 2.3
Pharmacokinetics and metabolism After inhalation of UM, Cmax occurs at 5 -- 15 min [12]. UM is mostly absorbed from the lung after inhalation with a minimum contribution from oral absorption. The bronchodilation following inhalation of UM is predominantly a sitespecific effect. A steady state is achieved within 14 days with up to 1.8-fold accumulation [13]. The mean volume of distribution was 86 L. In vitro plasma protein binding in human plasma was on an average 89% [13]. UM is primarily metabolized by the CYP2D6 enzyme and is a substrate for the Pglycoprotein (P-gp) transporter [13]. There are ranges of metabolites with either reduced or not-yet-established pharmacological activity. Systemic exposure to the metabolites is low. About 58% of UM is excreted in the feces and 22% is excreted in the urine when administered intravenously [13]. The effective half-life after q.d. dosing is 11 h [11]. UM has duration of bronchodilation of > 24 h (Table 1) [11]. 2.4
Introduction to VI VI is water-insoluble, 24-carbon containing triphenyl acetate salt, with a molecular weight of 774.8 (Figure 2) [14]. It is currently marketed in the USA in combination with the inhaled corticosteroid (ICS) fluticasone furoate and with UM. LABAs, like VI, activate adrenergic receptors found in bronchial smooth muscle which leads to increased levels of cAMP decreasing intracellular Ca2+ concentrations leading to bronchodilation [14]. After inhalation of VI, Cmax occurs at 5 -- 15 min [12]. VI is mostly absorbed from the lung after inhaled doses with negligible contribution from oral absorption. Steady state is reached within 14 days with up to 1.7-fold accumulation [14]. The mean volume of distribution at steady state was 165 L [13]. In vitro plasma protein binding in human plasma 2.5
Expert Opin. Drug Saf. (2015) 14(2)
Umeclidinium/vilanterol
Br H
N
+
O
OH
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Figure 1. Schematic representation of chemical structure of umeclidinium bromide.
Table 1. Properties of umeclidinium and vilanterol [11-14]. Umeclidinium Drug class
Vilanterol
Long-acting muscarinic antagonist Oral inhalation 5 -- 15 min CYP2D6 11 h Feces 92%, urine < 1% (oral dosing)
Route Tmax Metabolism Half-life Elimination
Long-acting b2-adrenergic agonist Oral inhalation 5 -- 15 min CYP3A4 11 h Urine 70%, feces 30% (oral dosing)
.
OH
OH
CI H N
O
O CI
HO
Vilanterol
Figure 2. Schematic representation of chemical structure of vilanterol.
was 94% [13]. VI is metabolized principally by CYP3A4 and is a substrate for the P-gp transporter [14]. There are a range of metabolites with reduced b1- and b2-agonist activity [12]. About 70% of VI is excreted in the urine and 30% is excreted in the feces [13]. The effective half-life for VI is 11 h (Table 1) [13]. The drug is administered as a dry powder inhaler at a dosage of 25 µg q.d. in combination with an ICS and LAMA but is not currently available as monotherapy [13].
Efficacy of UM, VI and combination therapy
3.
Recent trials have demonstrated that UM and VI deliver superior bronchodilation both individually and in
combination when compared with placebo. Decramer et al. [15] performed a randomized, placebo-controlled, parallelgroup study to evaluate three different doses of UM -- 125, 250 and 500 µg compared to placebo (Table 2). Patients between 40 and 80 years of age with COPD and ‡ 10 pack-years of smoking were randomized to receive either placebo or one of the three concentrations of UM daily for a total of 28 days. Serial spirometry was performed and the patients’ change from baseline trough FEV1 was measured on day 29 as the primary outcome. They also looked at use of rescue inhalers, change in FVC and adverse events (AEs). The patients randomized into the UM groups showed a statistically significant increase in their trough FEV1 compared to those in the placebo group. Interestingly, there was no dose-dependent difference between the three treatment groups noted. This is important because this allows for maximal bronchodilator effect at a lower dosage, which should in turn limit side effects. Donohue et al. [16] studied five q.d. doses, three twicedaily (b.i.d.) doses of UM in a three-way incomplete block crossover study with q.d. tiotropium as an open-label active control. There was no benefit in b.i.d. dosing over q.d. dosing. To further characterize the dose response, Donohue et al. [17] performed a pooled analysis of two randomized, double-blind, placebo-controlled studies of UM administered q.d or b.i.d. in patients with COPD. Doses of 15.6 -- 1000 µg/day of UM and 15.6 -- 250 µg b.i.d. were evaluated. UM doses of ‡ 62.5 µg were differentiated from the lower doses and b.i.d. dosing had no additional benefit. Hence, UM 62.5 and 125 µg q.d. dosages were investigated further. Hanania et al. [18] performed a randomized, placebocontrolled trial comparing VI at multiple doses: 3, 6.25, 12.5, 25 and 50 µg with placebo (Table 2). Their study population included men and woman aged 40 -- 80 with COPD and ‡ 10 pack-years of smoking. The primary outcome measured was change from baseline trough FEV1 at the end of 28 days. They found that treatment with 25 and 50 µg doses of VI resulted in a 100 ml increase in FEV1 for 90% of the participants. The medication was shown to be well tolerated with adverse effects like headache being more prominent in the treatment groups but no difference in serious AEs. After these successful trials, comparing individual bronchodilators against placebo, attention turned to evaluating the efficacy and safety of q.d. dual UM/VI therapy. Donohue et al. [19] studied the efficacy and safety of UM/ VI 62.5/25 µg q.d. in patients ‡ 40 years who carried a diagnosis of COPD, had a ‡ 10 pack-year history of smoking and had a score of ‡ 2 on the modified Medical Research Counsel Dyspnea Score (Table 2). This was a randomized, double-blinded, placebo-controlled study. Eligible patients were randomized to one of four groups: UM/VI 62.5/25 µg, UM 62.5 µg, VI 25 µg and placebo in a
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Table 2. Statistically significant benefits of UM, VI and UM/VI combination therapy in chronic obstructive pulmonary disease.
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Author
Study design
Intervention
Decramer et al. (2013) [15]
Randomized, double-blinded, placebo-controlled, parallel group
UM 125 µg; UM 250 µg; UM 500 µg; Placebo
Hanania et al. (2012) [18]
Randomized, double-blinded, placebo-controlled
VI 3.00 µg; VI 6.25 µg; VI 12.5 µg; VI 25.0 µg; VI 50.0 µg; Placebo
Donohue et al. (2013) [19]
Randomized, double-blinded, placebo-controlled, parallel group
UM 62.5 µg; VI 25.0 µg; UM/VI 62.5/25 µg; Placebo
Celli et al. (2014) [34]
Randomized, double-blinded, placebo-controlled, parallel group
UM 125 µg; VI 25 µg; UM/VI 125/25 µg; Placebo
*Decramer et al. (2014) (study 1) [26]
Randomized, blinded, active-controlled, parallel group
UM/VI 125/25 µg versus TI 18 µg versus VI 25 µg UM/VI 62.5/25 µg versus TI 18 µg versus VI 25 µg
*Decramer et al. (2014) (study 2) [26]
Randomized, blinded, active-controlled, parallel group
UM/VI 125/25 µg versus TIO 18 µg versus UM 125 µg UM/VI 62.5/25 µg versus TIO 18 µg versus VI 25 µg
Donohue et al. (2014) [17]
Randomized, double-blinded, meta-analysis
Once-daily UM (15.6 -- 1000 µg); Twice-daily UM (15.6 -- 250 µg)
1 Outcome (compared to placebo) Day 29 Trough FEV1 +159 ml (p < 0.001) +168 ml (p < 0.001) +150 ml (p < 0.001) Day 29 Trough FEV1 +92 ml (p < 0.001) +98 ml (p < 0.001) +110 ml (p < 0.001) +137 ml (p < 0.001) +165 ml (p < 0.001) Day 169 Trough FEV1 +72 ml (p < 0.001) +115 ml (p < 0.001) +167 ml (p < 0.001) Day 169 Trough FEV1 +160 ml (p < 0.001) +124 ml (p < 0.001) +238 ml (p < 0.001) Day 169 Trough FEV1 compared to monotherapy +88 ml (p = 0.001) +88 ml (p = 0.001) +90 ml (p = 0.0006) +90 ml (p = 0.006) Day 169 Trough FEV1 compared to monotherapy +74 ml (p = 0.0031) +37 ml (p = 0.14) +60 ml (p = 0.0182) +22 ml (p = 0.38) Day 8 Trough FEV1 compared to placebo over dosing range +97 -- 189 ml; Day 15 Trough FEV1 compared to placebo over dosing range +83 -- 187 ml
*Study 1 compared UM/VI 125/25 and 62.5/25 µg to monotherapy TI or VI. Study 2 compared UM/VI 125/25 and 62.5/25 µg to monotherapy TI or UM. FEV1: Forced expiratory volume in 1 s; SGRQ: Saint George’s Respiratory Questionnaire; TI: Tiotropium; UM: Umeclidinium; VI: Vilanterol.
3:3:3:2 ratio. The primary outcome was change in pre-dose trough FEV1 on day 169. They also evaluated trough FVC values, rescue inhaler use and a variety of quality of life questionnaires. They found that the UM/VI, UM and VI groups had statistically significant improvements in trough FEV1, FVC and reduced rescue inhaler use compared to placebo. The combination inhaler UM/VI was better than either drug alone, thus supporting the idea that bronchodilators 320
that affect multiple physiological pathways improve lung function to a greater degree than those that affect only one pathway. The improvement in lung function experienced by the treatment arm translated into improved dyspnea scores and health-related quality of life measurements indicate the positive change in lung function translated into positive change in patients’ subjective symptoms of dyspnea and disease control.
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Umeclidinium/vilanterol
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4.
Safety and tolerability
There have been a number of retrospective observational studies that have shown an association between LAMA use, allcause and cardiovascular deaths. However, showing causality between LAMA use and increased mortality is challenging because the event rate(s) are low and the needed follow-up time is long. Lee et al. [20] performed a nested case--control study that revealed that people who are diagnosed with COPD and on an anticholinergic had an adjusted odds ratio for all-cause mortality and cardiovascular death of 1.11 and 1.34, respectively. Sensitivity analysis went on to demonstrate that these outcomes occurred in a dose-dependent manner with amplified risk in those on higher dose anticholinergic compared to lower dose. A systematic review and metaanalysis also published in 2008 with 17 randomized controlled trials showed that anticholinergics, both tiotropium and ipratropium, were associated with an increased relative risk in all-cause mortality (1.26), myocardial infarction (1.53) and cardiovascular deaths (1.8) [21]. For the past decade, there has been concern that a link exists between LABA use as monotherapy and sudden death from severe asthma attacks [22]. These data have met significant criticism since publication; however, salmeterol and all other LABAs carry a black box warning for increased risk of asthma-related deaths when used as monotherapy. Similarly, observational studies comparing AEs in COPD patients taking LABA have shown an increase in AEs, in particular, cardiovascular event in elderly patients that was similar to that of LAMA [23]. However, a Cochrane review released in 2013 showed there was no increase in mortality or AEs noted in COPD patients taking LABAs compared to placebo. This review included 26 randomized controlled trials that showed, in addition to a favorable safety profile, fewer hospitalizations in LABA users for COPD and improved quality of life metrics [24]. At this time, there is no black box warning linking LABA use to increased COPD-related death or cardiovascular events but current studies are ongoing. Because of this literature, there has been a great deal of effort placed on finding bronchodilator therapy that can be both effective at low doses and have unique mechanisms of action. A number of studies have assessed the safety of the UM/VI combination inhaler compared to placebo. Prior to approval, UM/VI was evaluated for safety and efficacy in > 2400 patients with COPD [25]. The effect of UM/VI on cardiac rhythm in subjects diagnosed with COPD was assessed in trials ranging in duration from 28 days to 12 months. No clinically meaningful effects on cardiac rhythm were observed. There has been no statistically significant or clinically meaningful difference in cardiovascular variables including pulse rate or QTc measurement, or change in hematological, clinical chemistry and urinalysis assessments in UM/VI users compared with placebo groups [18,19,26-31]. The recently published 1-year safety and tolerability study
by Donohue et al. shows that the incidences of serious AEs, drug-related AEs were similar across treatment and placebo groups. The incidence of atrial arrhythmias was the same as placebo. Few deaths occurred and none on UMEC/VI [27]. Beyond published data there are data printed in abstract form that have assessed the safety and tolerability of UM, VI and UM/VI. A number of these are illustrated in Table 3, along with previously reported trial data.
Special populations UM/VI is a category C medication. It is unknown whether UM/VI is excreted into breast milk or not [13]. No overall differences in safety or effectiveness were observed between older subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects [13]. Patients with moderate hepatic impairment (Child--Pugh score of 7 -- 9) showed no relevant increases in Cmax or AUC nor did protein binding differ between subjects with moderate hepatic impairment and their healthy controls [13]. There were no significant increases in either UM or VI exposure in subjects with severe renal impairment (creatinine clearance < 30 ml /min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [13]. 4.1
Drug interactions Caution should be exercised when considering the coadministration of UM/VI with long-term ketoconazole and other known CYP3A4 inhibitors like ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin and voriconazole, because increased cardiovascular adverse effects may occur [13]. 4.2
5.
Conclusion
The worldwide prevalence of COPD is challenging to attain because of variability in diagnostic criteria, both subjective and objective diagnoses, and varying use of spirometry; however, available data suggest its prevalence in people aged ‡ 40 to be 9 -- 10% [1]. By 2030, COPD is projected to be the fourth-leading cause of death and the seventhleading cause of disability worldwide [32]. In the USA, the estimated direct and indirect cost of COPD each year is ~ $50 billion [33]. Bronchodilator therapy is the widely accepted treatment strategy for moderate-to-very severe COPD. Therapy that utilizes more than one physiological pathway has additional benefits of improved objective and subjective outcomes. The development of q.d. LABA and its addition to q.d. LAMA therapy will improve COPD management through better bronchodilation and improved patient compliance.
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Table 3. Safety and tolerability data for UM, VI and UM/VI.
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Author
Study design
Hanania et al. (2012) [18]
Randomized, double-blinded, placebo-controlled study
*Feldman (2012) [28]
Double-blinded, placebo-controlled, parallel group study
Kelleher et al. (2012) [29]
Double-blinded, placebo-controlled, randomized four-way crossover study
Donohue et al. (2013) [19]
Randomized, double-blinded, placebo-controlled study
Donohue et al. (2014) [27]
Randomized, double-blind, placebo-controlled study
Kelleher et al. (2014) [30]
Randomized, placebo-and moxifloxacin-controlled fourperiod incomplete block crossover study
Nakahara (2012) [31]
Randomized, double-blind, placebo-controlled doseascending study
Feldman (2012) [28]
Randomized, double-blind, placebo-controlled, parallelgroup study
Intervention VI 3 µg VI 6.25 µg VI 12.5 µg VI 25 µg VI 50 µg Placebo UM/VI 500/ 25 µg Placebo VI 50 µg/ Placebo UM 500 µg/ Placebo UM 500/VI 50 µg Placebo/Placebo UM 62.5 µg VI 25.0 µg UM/VI 62.5/ 25 µg Placebo UM/VI 125/ 25 µg UM 125 µg Placebo UM/VI 125/ 25 µg UM/VI 500/ 100 µg UM 500 µg PlaceboMoxifloxacin UM 1000 µg UM 500 µg UM 250 µg Placebo UM/VI 500/ 25 µg Placebo
Safety outcome
Study length
AE Vital signs ECG assessment Laboratory values
28 days
AEs Pulse rate Blood pressure QTc Vital signs ECG assessment Laboratory values Holter monitoring QTc
28 days
Vital signs ECG assessment laboratory values
24 weeks
AEs, serious AEs, drug-related AEs, supraventricular tachycardia, ectopic beats and ectopic rhythm, mortality QTc interval
52 weeks
10 days
AEs
10 days
Pulse rate blood pressure ECG 24-h Holter
28 days
10 days
AE: Adverse event; ECG: Electrocardiogram; QTc: Corrected QT interval; UM: Umeclidinium; VI: Vilanterol.
6.
Expert opinion
The ability of combination inhalers to decrease the dose of an individual medication could make the AE rates smaller and lessen the known side effects of both LAMAs and LABAs. Anticholinergic agents can cause urinary retention, gastrointestinal symptoms, and may worsen closed-angle glaucoma. Beyond that, recent observational data has shown an increase in allcause and cardiovascular mortality in patients on anticholinergics. Again, there is not enough evidence to prove causality, but the mounting association is difficult to ignore. Adverse reactions to LABAs are well documented and include arrhythmia, electrolyte imbalance and paradoxical bronchospasm leading 322
to increased risk of death (in asthmatics). Small studies have shown a correlation between increased cardiovascular death and LABA use but the most recent data showed that there was no increase in cardiovascular or all-cause mortality in patients using LABAs for COPD. With improved patient compliance and a decrease in AEs, physicians should feel more comfortable prescribing q.d. LAMA/LABA combinations. This shift could alter the landscape of COPD management with a focus away from laborious, multiple-daily dosing of inhalers and toward q.d. dosing regimens of all classes of bronchodilators. The long-term effects of q.d. LAMA/ LABAs do require further investigation considering the safety data available that is measured in days-to-weeks as opposed
Expert Opin. Drug Saf. (2015) 14(2)
Umeclidinium/vilanterol
to years and decades. In the absence of safety concerns that may develop during the post-marketing surveillance period, the UM/VI inhaler could become the mainstay of moderate-tovery severe COPD treatment.
Declaration of interest JA Ohar received editorial assistance from Glaxo SmithKline for a manuscript published within the past year and
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Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Jama 2008;300(12):1439-50
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23.
Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129(1):15-26 Gershon A, Croxford R, Calzavara A, et al. Cardiovascular safety of inhaled long-acting bronchodilators in individuals with chronic obstructive pulmonary disease. JAMA Intern Med 2013;173(13):1175-85
24.
Kew KM, Mavergames C, Walters JA. Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013;10:Cd010177
25.
Goldenberg MM. Pharmaceutical approval update. P T 2014;39(2):112-18
26.
Decramer M, Anzueto A, Kerwin E, et al. Efficacy and safety of umeclidinium
324
..
27.
..
28.
plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med 2014;2(6):472-86 This paper compared combination UM/VI with tiotropium and found that the combination inhaler improved lung function to a greater degree than tiotropium monotherapy. Both treatments had similar safety profiles. Donohue JF, Niewoehner D, Brooks J, et al. Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study. Respir Res 2014;15(1):78 This paper assessed the efficacy and safety of UM/VI for a period of 12 months. It showed similar efficacy measures as previous studies. The evaluation of safety showed an increase in atrial arrhythmias but no increase in AEs or changes in laboratory parameters. Feldman G. Safety and tolerability of the GSK573719/vilanterol combination in patients with COPD. Am J Respir Crit Care Med 2012;185(meeting abstracts):A2938
29.
Kelleher DL, Mehta RS, Jean-Francois BM, et al. Safety, tolerability, pharmacodynamics and pharmacokinetics of umeclidinium and vilanterol alone and in combination: a randomized crossover trial. PLoS One 2012;7(12):e50716
30.
Kelleher D, Tombs L, Preece A, et al. A randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects. Pulm Pharmacol Ther 2014;29(1):49-57
31.
Nakahara N. Safety, tolerability and pharmacokinetics (pk) of single and repeat doses of Gsk573719 in healthy japanese subjects. Am J Respir Crit
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Care Med 2012;185(meeting abstracts):A2915 32.
Mathers CD, Loncar D. Projections of global mortality and burden of disease from. 2002 to 2030. PLoS Med 2006;3(11):e442
33.
Lopez AD, Shibuya K, Rao C, et al. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J 2006;27(2):397-412 This paper outlines the current and future trends in COPD morbidity and mortality. It also discusses the future economic burden that COPD will have.
.
34.
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Celli B, Crater G, Kilbride S, et al. Once-daily umeclidinium/vilanterol 125/ 25 mcg in COPD: a randomized, controlled study. Chest 2014;145(5):981-91 This was a long-term study that showed UM/VI improved patients’ lung function and patients reported dyspnea and health-related quality of life status compared with placebo. It also demonstrated similar adverse event (AE) profiles with UM/VI compared to placebo.
Affiliation James F Davidson1 MD, James F Donohue2 MD & Jill A Ohar†3 MD † Author for correspondence 1 Fellow, Wake Forest School of Medicine, Medical Center Boulevard, Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunology, Winston-Salem, NC 27157-1054, USA 2 Professor of Medicine, University of North Carolina College of Medicine, Department of Medicine, Chapel Hill, NC 27599, USA 3 Professor of Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunology, Winston-Salem, NC 27157-1054, USA Tel: +1 336 716 8426; Fax: +1 336 716 7277; E-mail: [email protected]
1.
Introduction
2.
Review of umeclidinium and vilanterol
3.
Efficacy of UM, VI and
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combination therapy 4.
Safety and tolerability
5.
Conclusion
6.
Expert opinion
Umeclidinium/vilanterol combination inhaler efficacy and potential impact on current chronic obstructive pulmonary disease management guidelines James F Davidson, James F Donohue & Jill A Ohar† †
Wake Forest School of Medicine, Medical Center Boulevard, Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunology, Winston-Salem, NC, USA
Introduction: Umeclidinium bromide (UM) with vilanterol (VI) is the first oncedaily long-acting muscarinic antagonist/long-acting b2 agonist (LAMA/LABA) combination approved for use in the treatment of chronic obstructive pulmonary disease (COPD) in the USA. Prior to this, only combinations of short-acting bronchodilators and short-acting muscarinic antagonists were available in the USA as a single inhaler and they required frequent dosing. LAMA or LABA therapy is the recommended first choice for moderate-tovery severe COPD with combination therapy added if monotherapy fails to control patients’ symptoms. This allows lower dosing of individual medications, which may limit adverse effects. It could also have the additional benefit of improving patient compliance by making medication regimens less laboring. Areas covered: A comprehensive literature search of journal articles and abstracts looking for trials that evaluated both the efficacy and the safety of UM/VI revealed that UM/VI improves patients’ lung function and overall health status, while maintaining excellent safety and tolerability profiles compared to placebo and other bronchodilators. Expert opinion: Given the clinical efficacy, favorable safety profile and ease of use, clinicians may recommend UM/VI to patients with moderate-to-very severe COPD -- a shift that could have significant impact on the management of COPD. Keywords: bronchodilator, chronic obstructive pulmonary disease, forced expiratory volume in 1 s, forced vital capacity, long-acting b agonists, long-acting muscarinic antagonist, umeclidinium, vilanterol Expert Opin. Drug Saf. (2015) 14(2):317-324
1.
Introduction
Chronic obstructive pulmonary disease (COPD) severity is based on lung function measurements and is defined by the Global Initiative for Chronic Obstructive Lung Disease criteria, with stage I being mild and stage IV being very severe [1]. Bronchodilators are the foundation of pharmacological management of COPD; unfortunately, patients’ response and adherence to different bronchodilators vary. To maximize medication efficacy and minimize unwanted effects, physicians have started combining bronchodilators of different classes. Data published recently show that combination bronchodilator therapy improves airway reversibility [2], lung function [3] and quality of life [4]. Since convenience plays a role in patient compliance, once-daily (q.d.) bronchodilators may lead to better adherence [5,6]. 10.1517/14740338.2015.983898 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug Summary.
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Drug name Phase Indication Mechanism of action Route of administration Chemical structure Pivotal trial(s) for umeclidinium bromide /VI National Institute of Health Clinical Trials, ClinicalTrials.gov
There has not been a pharmaceutical treatment proven to slow decline in lung function or improve mortality in COPD; therefore, other markers of disease modification have been targeted as outcomes in research trials. Minimal clinically important differences (MCIDs) are used to determine the clinical significance of changes from baseline or treatment differences from placebo. MCIDs correspond to significant outcomes in COPD intervention trials. MCIDs include lung function (trough forced expiratory volume in 1 s [FEV1] 100 -- 140 ml or 5 -- 10% from baseline), dyspnea (improvement of 1 unit in transition dyspnea index score, 5 units in the units in the University of California, San Diego Shortness of Breath Questionnaire) and health status (reduction of 4 units in the Saint George’s Respiratory Questionnaire total score) [7,8]. 2.
Review of umeclidinium and vilanterol
Evidence suggests that the long-acting muscarinic antagonist (LAMA) and long-acting b2 agonist (LABA) combination plays an important role in maximizing bronchodilation. Overview of the market Formoterol, in addition to tiotropium, has been shown to improve both FEV1 and forced vital capacity (FVC) and produces a more rapid onset of action than each bronchodilator individually [9]. In 2013, Wedzicha et al. [10] compared the efficacy of indacaterol/glycopyrronium in patients with severe and very severe COPD with glycopyrronium or tiotropium both as monotherapies with the primary outcome of COPD exacerbations. They found that the combination inhaler group experienced 15 and 14% fewer exacerbations, compared to the glycopyrronium and tiotropium groups, respectively. The complementary interaction(s) between the b2-agonist and muscarinic antagonist pathways is not completely understood; however, there appears to be enough evidence to recommend combining therapies that utilize both pathways to maximize bronchodilation in treatment of COPD. The purpose of this article is to review the efficacy and safety of q.d. dose of umeclidinium bromide (UM)/vilanterol (VI). 2.1
Introduction to the compound: UM and VI UM/VI (Box 1) is a dry powder for inhalation bronchodilator that is used for the treatment of COPD, including chronic 2.2
318
Umeclidinium bromide/vilanterol Post-marketing surveillance Moderate-to-very severe chronic obstructive pulmonary disease Long-acting muscarinic antagonist/Long-acting b2 agonist Oral inhalation C29H34BrNO2/C24H33Cl2NO5 NCT01822899, NCT01879410, NCT01313650, NCT01636713, NCT01313637
bronchitis and emphysema. It was approved in December of 2013 by the FDA. Chemistry UM is a slightly water-soluble, 29-carbon, quaternary ammonium bromide containing molecule with a molecular weight of 428.6 (Figure 1) [11]. A LAMA acts as a competitive inhibitor to all muscarinic receptors but shows a greater affinity for the M3 acetylcholine receptor subtype, which is concentrated along airway smooth muscle [12]. 2.3
Pharmacokinetics and metabolism After inhalation of UM, Cmax occurs at 5 -- 15 min [12]. UM is mostly absorbed from the lung after inhalation with a minimum contribution from oral absorption. The bronchodilation following inhalation of UM is predominantly a sitespecific effect. A steady state is achieved within 14 days with up to 1.8-fold accumulation [13]. The mean volume of distribution was 86 L. In vitro plasma protein binding in human plasma was on an average 89% [13]. UM is primarily metabolized by the CYP2D6 enzyme and is a substrate for the Pglycoprotein (P-gp) transporter [13]. There are ranges of metabolites with either reduced or not-yet-established pharmacological activity. Systemic exposure to the metabolites is low. About 58% of UM is excreted in the feces and 22% is excreted in the urine when administered intravenously [13]. The effective half-life after q.d. dosing is 11 h [11]. UM has duration of bronchodilation of > 24 h (Table 1) [11]. 2.4
Introduction to VI VI is water-insoluble, 24-carbon containing triphenyl acetate salt, with a molecular weight of 774.8 (Figure 2) [14]. It is currently marketed in the USA in combination with the inhaled corticosteroid (ICS) fluticasone furoate and with UM. LABAs, like VI, activate adrenergic receptors found in bronchial smooth muscle which leads to increased levels of cAMP decreasing intracellular Ca2+ concentrations leading to bronchodilation [14]. After inhalation of VI, Cmax occurs at 5 -- 15 min [12]. VI is mostly absorbed from the lung after inhaled doses with negligible contribution from oral absorption. Steady state is reached within 14 days with up to 1.7-fold accumulation [14]. The mean volume of distribution at steady state was 165 L [13]. In vitro plasma protein binding in human plasma 2.5
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Umeclidinium/vilanterol
Br H
N
+
O
OH
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Figure 1. Schematic representation of chemical structure of umeclidinium bromide.
Table 1. Properties of umeclidinium and vilanterol [11-14]. Umeclidinium Drug class
Vilanterol
Long-acting muscarinic antagonist Oral inhalation 5 -- 15 min CYP2D6 11 h Feces 92%, urine < 1% (oral dosing)
Route Tmax Metabolism Half-life Elimination
Long-acting b2-adrenergic agonist Oral inhalation 5 -- 15 min CYP3A4 11 h Urine 70%, feces 30% (oral dosing)
.
OH
OH
CI H N
O
O CI
HO
Vilanterol
Figure 2. Schematic representation of chemical structure of vilanterol.
was 94% [13]. VI is metabolized principally by CYP3A4 and is a substrate for the P-gp transporter [14]. There are a range of metabolites with reduced b1- and b2-agonist activity [12]. About 70% of VI is excreted in the urine and 30% is excreted in the feces [13]. The effective half-life for VI is 11 h (Table 1) [13]. The drug is administered as a dry powder inhaler at a dosage of 25 µg q.d. in combination with an ICS and LAMA but is not currently available as monotherapy [13].
Efficacy of UM, VI and combination therapy
3.
Recent trials have demonstrated that UM and VI deliver superior bronchodilation both individually and in
combination when compared with placebo. Decramer et al. [15] performed a randomized, placebo-controlled, parallelgroup study to evaluate three different doses of UM -- 125, 250 and 500 µg compared to placebo (Table 2). Patients between 40 and 80 years of age with COPD and ‡ 10 pack-years of smoking were randomized to receive either placebo or one of the three concentrations of UM daily for a total of 28 days. Serial spirometry was performed and the patients’ change from baseline trough FEV1 was measured on day 29 as the primary outcome. They also looked at use of rescue inhalers, change in FVC and adverse events (AEs). The patients randomized into the UM groups showed a statistically significant increase in their trough FEV1 compared to those in the placebo group. Interestingly, there was no dose-dependent difference between the three treatment groups noted. This is important because this allows for maximal bronchodilator effect at a lower dosage, which should in turn limit side effects. Donohue et al. [16] studied five q.d. doses, three twicedaily (b.i.d.) doses of UM in a three-way incomplete block crossover study with q.d. tiotropium as an open-label active control. There was no benefit in b.i.d. dosing over q.d. dosing. To further characterize the dose response, Donohue et al. [17] performed a pooled analysis of two randomized, double-blind, placebo-controlled studies of UM administered q.d or b.i.d. in patients with COPD. Doses of 15.6 -- 1000 µg/day of UM and 15.6 -- 250 µg b.i.d. were evaluated. UM doses of ‡ 62.5 µg were differentiated from the lower doses and b.i.d. dosing had no additional benefit. Hence, UM 62.5 and 125 µg q.d. dosages were investigated further. Hanania et al. [18] performed a randomized, placebocontrolled trial comparing VI at multiple doses: 3, 6.25, 12.5, 25 and 50 µg with placebo (Table 2). Their study population included men and woman aged 40 -- 80 with COPD and ‡ 10 pack-years of smoking. The primary outcome measured was change from baseline trough FEV1 at the end of 28 days. They found that treatment with 25 and 50 µg doses of VI resulted in a 100 ml increase in FEV1 for 90% of the participants. The medication was shown to be well tolerated with adverse effects like headache being more prominent in the treatment groups but no difference in serious AEs. After these successful trials, comparing individual bronchodilators against placebo, attention turned to evaluating the efficacy and safety of q.d. dual UM/VI therapy. Donohue et al. [19] studied the efficacy and safety of UM/ VI 62.5/25 µg q.d. in patients ‡ 40 years who carried a diagnosis of COPD, had a ‡ 10 pack-year history of smoking and had a score of ‡ 2 on the modified Medical Research Counsel Dyspnea Score (Table 2). This was a randomized, double-blinded, placebo-controlled study. Eligible patients were randomized to one of four groups: UM/VI 62.5/25 µg, UM 62.5 µg, VI 25 µg and placebo in a
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Table 2. Statistically significant benefits of UM, VI and UM/VI combination therapy in chronic obstructive pulmonary disease.
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Author
Study design
Intervention
Decramer et al. (2013) [15]
Randomized, double-blinded, placebo-controlled, parallel group
UM 125 µg; UM 250 µg; UM 500 µg; Placebo
Hanania et al. (2012) [18]
Randomized, double-blinded, placebo-controlled
VI 3.00 µg; VI 6.25 µg; VI 12.5 µg; VI 25.0 µg; VI 50.0 µg; Placebo
Donohue et al. (2013) [19]
Randomized, double-blinded, placebo-controlled, parallel group
UM 62.5 µg; VI 25.0 µg; UM/VI 62.5/25 µg; Placebo
Celli et al. (2014) [34]
Randomized, double-blinded, placebo-controlled, parallel group
UM 125 µg; VI 25 µg; UM/VI 125/25 µg; Placebo
*Decramer et al. (2014) (study 1) [26]
Randomized, blinded, active-controlled, parallel group
UM/VI 125/25 µg versus TI 18 µg versus VI 25 µg UM/VI 62.5/25 µg versus TI 18 µg versus VI 25 µg
*Decramer et al. (2014) (study 2) [26]
Randomized, blinded, active-controlled, parallel group
UM/VI 125/25 µg versus TIO 18 µg versus UM 125 µg UM/VI 62.5/25 µg versus TIO 18 µg versus VI 25 µg
Donohue et al. (2014) [17]
Randomized, double-blinded, meta-analysis
Once-daily UM (15.6 -- 1000 µg); Twice-daily UM (15.6 -- 250 µg)
1 Outcome (compared to placebo) Day 29 Trough FEV1 +159 ml (p < 0.001) +168 ml (p < 0.001) +150 ml (p < 0.001) Day 29 Trough FEV1 +92 ml (p < 0.001) +98 ml (p < 0.001) +110 ml (p < 0.001) +137 ml (p < 0.001) +165 ml (p < 0.001) Day 169 Trough FEV1 +72 ml (p < 0.001) +115 ml (p < 0.001) +167 ml (p < 0.001) Day 169 Trough FEV1 +160 ml (p < 0.001) +124 ml (p < 0.001) +238 ml (p < 0.001) Day 169 Trough FEV1 compared to monotherapy +88 ml (p = 0.001) +88 ml (p = 0.001) +90 ml (p = 0.0006) +90 ml (p = 0.006) Day 169 Trough FEV1 compared to monotherapy +74 ml (p = 0.0031) +37 ml (p = 0.14) +60 ml (p = 0.0182) +22 ml (p = 0.38) Day 8 Trough FEV1 compared to placebo over dosing range +97 -- 189 ml; Day 15 Trough FEV1 compared to placebo over dosing range +83 -- 187 ml
*Study 1 compared UM/VI 125/25 and 62.5/25 µg to monotherapy TI or VI. Study 2 compared UM/VI 125/25 and 62.5/25 µg to monotherapy TI or UM. FEV1: Forced expiratory volume in 1 s; SGRQ: Saint George’s Respiratory Questionnaire; TI: Tiotropium; UM: Umeclidinium; VI: Vilanterol.
3:3:3:2 ratio. The primary outcome was change in pre-dose trough FEV1 on day 169. They also evaluated trough FVC values, rescue inhaler use and a variety of quality of life questionnaires. They found that the UM/VI, UM and VI groups had statistically significant improvements in trough FEV1, FVC and reduced rescue inhaler use compared to placebo. The combination inhaler UM/VI was better than either drug alone, thus supporting the idea that bronchodilators 320
that affect multiple physiological pathways improve lung function to a greater degree than those that affect only one pathway. The improvement in lung function experienced by the treatment arm translated into improved dyspnea scores and health-related quality of life measurements indicate the positive change in lung function translated into positive change in patients’ subjective symptoms of dyspnea and disease control.
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4.
Safety and tolerability
There have been a number of retrospective observational studies that have shown an association between LAMA use, allcause and cardiovascular deaths. However, showing causality between LAMA use and increased mortality is challenging because the event rate(s) are low and the needed follow-up time is long. Lee et al. [20] performed a nested case--control study that revealed that people who are diagnosed with COPD and on an anticholinergic had an adjusted odds ratio for all-cause mortality and cardiovascular death of 1.11 and 1.34, respectively. Sensitivity analysis went on to demonstrate that these outcomes occurred in a dose-dependent manner with amplified risk in those on higher dose anticholinergic compared to lower dose. A systematic review and metaanalysis also published in 2008 with 17 randomized controlled trials showed that anticholinergics, both tiotropium and ipratropium, were associated with an increased relative risk in all-cause mortality (1.26), myocardial infarction (1.53) and cardiovascular deaths (1.8) [21]. For the past decade, there has been concern that a link exists between LABA use as monotherapy and sudden death from severe asthma attacks [22]. These data have met significant criticism since publication; however, salmeterol and all other LABAs carry a black box warning for increased risk of asthma-related deaths when used as monotherapy. Similarly, observational studies comparing AEs in COPD patients taking LABA have shown an increase in AEs, in particular, cardiovascular event in elderly patients that was similar to that of LAMA [23]. However, a Cochrane review released in 2013 showed there was no increase in mortality or AEs noted in COPD patients taking LABAs compared to placebo. This review included 26 randomized controlled trials that showed, in addition to a favorable safety profile, fewer hospitalizations in LABA users for COPD and improved quality of life metrics [24]. At this time, there is no black box warning linking LABA use to increased COPD-related death or cardiovascular events but current studies are ongoing. Because of this literature, there has been a great deal of effort placed on finding bronchodilator therapy that can be both effective at low doses and have unique mechanisms of action. A number of studies have assessed the safety of the UM/VI combination inhaler compared to placebo. Prior to approval, UM/VI was evaluated for safety and efficacy in > 2400 patients with COPD [25]. The effect of UM/VI on cardiac rhythm in subjects diagnosed with COPD was assessed in trials ranging in duration from 28 days to 12 months. No clinically meaningful effects on cardiac rhythm were observed. There has been no statistically significant or clinically meaningful difference in cardiovascular variables including pulse rate or QTc measurement, or change in hematological, clinical chemistry and urinalysis assessments in UM/VI users compared with placebo groups [18,19,26-31]. The recently published 1-year safety and tolerability study
by Donohue et al. shows that the incidences of serious AEs, drug-related AEs were similar across treatment and placebo groups. The incidence of atrial arrhythmias was the same as placebo. Few deaths occurred and none on UMEC/VI [27]. Beyond published data there are data printed in abstract form that have assessed the safety and tolerability of UM, VI and UM/VI. A number of these are illustrated in Table 3, along with previously reported trial data.
Special populations UM/VI is a category C medication. It is unknown whether UM/VI is excreted into breast milk or not [13]. No overall differences in safety or effectiveness were observed between older subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects [13]. Patients with moderate hepatic impairment (Child--Pugh score of 7 -- 9) showed no relevant increases in Cmax or AUC nor did protein binding differ between subjects with moderate hepatic impairment and their healthy controls [13]. There were no significant increases in either UM or VI exposure in subjects with severe renal impairment (creatinine clearance < 30 ml /min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [13]. 4.1
Drug interactions Caution should be exercised when considering the coadministration of UM/VI with long-term ketoconazole and other known CYP3A4 inhibitors like ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin and voriconazole, because increased cardiovascular adverse effects may occur [13]. 4.2
5.
Conclusion
The worldwide prevalence of COPD is challenging to attain because of variability in diagnostic criteria, both subjective and objective diagnoses, and varying use of spirometry; however, available data suggest its prevalence in people aged ‡ 40 to be 9 -- 10% [1]. By 2030, COPD is projected to be the fourth-leading cause of death and the seventhleading cause of disability worldwide [32]. In the USA, the estimated direct and indirect cost of COPD each year is ~ $50 billion [33]. Bronchodilator therapy is the widely accepted treatment strategy for moderate-to-very severe COPD. Therapy that utilizes more than one physiological pathway has additional benefits of improved objective and subjective outcomes. The development of q.d. LABA and its addition to q.d. LAMA therapy will improve COPD management through better bronchodilation and improved patient compliance.
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Table 3. Safety and tolerability data for UM, VI and UM/VI.
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Author
Study design
Hanania et al. (2012) [18]
Randomized, double-blinded, placebo-controlled study
*Feldman (2012) [28]
Double-blinded, placebo-controlled, parallel group study
Kelleher et al. (2012) [29]
Double-blinded, placebo-controlled, randomized four-way crossover study
Donohue et al. (2013) [19]
Randomized, double-blinded, placebo-controlled study
Donohue et al. (2014) [27]
Randomized, double-blind, placebo-controlled study
Kelleher et al. (2014) [30]
Randomized, placebo-and moxifloxacin-controlled fourperiod incomplete block crossover study
Nakahara (2012) [31]
Randomized, double-blind, placebo-controlled doseascending study
Feldman (2012) [28]
Randomized, double-blind, placebo-controlled, parallelgroup study
Intervention VI 3 µg VI 6.25 µg VI 12.5 µg VI 25 µg VI 50 µg Placebo UM/VI 500/ 25 µg Placebo VI 50 µg/ Placebo UM 500 µg/ Placebo UM 500/VI 50 µg Placebo/Placebo UM 62.5 µg VI 25.0 µg UM/VI 62.5/ 25 µg Placebo UM/VI 125/ 25 µg UM 125 µg Placebo UM/VI 125/ 25 µg UM/VI 500/ 100 µg UM 500 µg PlaceboMoxifloxacin UM 1000 µg UM 500 µg UM 250 µg Placebo UM/VI 500/ 25 µg Placebo
Safety outcome
Study length
AE Vital signs ECG assessment Laboratory values
28 days
AEs Pulse rate Blood pressure QTc Vital signs ECG assessment Laboratory values Holter monitoring QTc
28 days
Vital signs ECG assessment laboratory values
24 weeks
AEs, serious AEs, drug-related AEs, supraventricular tachycardia, ectopic beats and ectopic rhythm, mortality QTc interval
52 weeks
10 days
AEs
10 days
Pulse rate blood pressure ECG 24-h Holter
28 days
10 days
AE: Adverse event; ECG: Electrocardiogram; QTc: Corrected QT interval; UM: Umeclidinium; VI: Vilanterol.
6.
Expert opinion
The ability of combination inhalers to decrease the dose of an individual medication could make the AE rates smaller and lessen the known side effects of both LAMAs and LABAs. Anticholinergic agents can cause urinary retention, gastrointestinal symptoms, and may worsen closed-angle glaucoma. Beyond that, recent observational data has shown an increase in allcause and cardiovascular mortality in patients on anticholinergics. Again, there is not enough evidence to prove causality, but the mounting association is difficult to ignore. Adverse reactions to LABAs are well documented and include arrhythmia, electrolyte imbalance and paradoxical bronchospasm leading 322
to increased risk of death (in asthmatics). Small studies have shown a correlation between increased cardiovascular death and LABA use but the most recent data showed that there was no increase in cardiovascular or all-cause mortality in patients using LABAs for COPD. With improved patient compliance and a decrease in AEs, physicians should feel more comfortable prescribing q.d. LAMA/LABA combinations. This shift could alter the landscape of COPD management with a focus away from laborious, multiple-daily dosing of inhalers and toward q.d. dosing regimens of all classes of bronchodilators. The long-term effects of q.d. LAMA/ LABAs do require further investigation considering the safety data available that is measured in days-to-weeks as opposed
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Umeclidinium/vilanterol
to years and decades. In the absence of safety concerns that may develop during the post-marketing surveillance period, the UM/VI inhaler could become the mainstay of moderate-tovery severe COPD treatment.
Declaration of interest JA Ohar received editorial assistance from Glaxo SmithKline for a manuscript published within the past year and
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consultancy fees from Astra Zeneca and CSL Behring. JF Donohue is a consultant and advisor to Sunovian. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents, received or pending, or royalties.
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plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med 2014;2(6):472-86 This paper compared combination UM/VI with tiotropium and found that the combination inhaler improved lung function to a greater degree than tiotropium monotherapy. Both treatments had similar safety profiles. Donohue JF, Niewoehner D, Brooks J, et al. Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study. Respir Res 2014;15(1):78 This paper assessed the efficacy and safety of UM/VI for a period of 12 months. It showed similar efficacy measures as previous studies. The evaluation of safety showed an increase in atrial arrhythmias but no increase in AEs or changes in laboratory parameters. Feldman G. Safety and tolerability of the GSK573719/vilanterol combination in patients with COPD. Am J Respir Crit Care Med 2012;185(meeting abstracts):A2938
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Celli B, Crater G, Kilbride S, et al. Once-daily umeclidinium/vilanterol 125/ 25 mcg in COPD: a randomized, controlled study. Chest 2014;145(5):981-91 This was a long-term study that showed UM/VI improved patients’ lung function and patients reported dyspnea and health-related quality of life status compared with placebo. It also demonstrated similar adverse event (AE) profiles with UM/VI compared to placebo.
Affiliation James F Davidson1 MD, James F Donohue2 MD & Jill A Ohar†3 MD † Author for correspondence 1 Fellow, Wake Forest School of Medicine, Medical Center Boulevard, Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunology, Winston-Salem, NC 27157-1054, USA 2 Professor of Medicine, University of North Carolina College of Medicine, Department of Medicine, Chapel Hill, NC 27599, USA 3 Professor of Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunology, Winston-Salem, NC 27157-1054, USA Tel: +1 336 716 8426; Fax: +1 336 716 7277; E-mail: [email protected]
