1. No category

COPD Drug Update
11/15/2014
I have had no financial relationship over
the last 12 months with any commercial
sponsor with a vested interest in this
presentation.
Identify vilanterol containing products
List the most common adverse effects of vilanterol
containing products
Summarize evidence regarding safety and efficacy
of vilanterol containing products in COPD
Describe the Ellipta™ delivery device
Jane Vipond, PharmD
PGY-1 Pharmacy Resident
Sanford USD Medical Center
November 15, 2014
Identify vilanterol containing products and their role in
chronic obstructive pulmonary disease (COPD)
management
Describe the pharmacologic properties of vilanterol
containing products including mechanism of action,
adverse effects, contraindications, and precautions
Evaluate evidence regarding safety and efficacy of
vilanterol containing products in COPD
Demonstrate proper use of the Ellipta™ delivery device
Effectively counsel patients on the use of vilanterol
containing products
Recognize patients who should receive counseling
by a pharmacist on vilanterol containing products
Group B = Gold Stages 1 & 2
First Line Therapy
▪ Long acting anticholinergic or long acting beta-2 agonist
Alternative Therapy
▪ Long acting anticholinergic + long acting beta-2 agonist
Groups C & D = Gold Stages 3 & 4
First Line Therapy
▪ Long acting beta-2 agonist + inhaled corticosteroid
Alternative Therapy
▪ Long acting beta-2 agonist + long acting anticholinergic
Global Initiative for Chronic Obstructive Lung Disease, GOLD Guidelines. 2014.
Jane Vipond, PharmD
1
COPD Drug Update
11/15/2014
Fluticasone furoate & vilanterol trifenatate
Approved May 2013
FDA indications
Umeclidinium bromide & vilanterol trifenatate
Approved December 2013
FDA indications
Reduce acute exacerbations of COPD
COPD
COPD
Dosing
One inhalation by mouth once daily
▪ Umeclidinium 62.5 mcg and vilanterol 25 mcg per
inhalation
One inhalation by mouth once daily
▪ Fluticasone 100 mcg and vilanterol 25 mcg per inhalation
Dosing
Dose adjustments
Dose adjustments
None
None
Fluticasone Furoate/Vilanterol Trifenatate, Micromedex®. 2014.
Umeclidinium Bromide/Vilanterol Trifenatate, Micromedex®. 2014.
Products
Breo™ (fluticasone furoate/vilanterol trifenatate)
Anoro™ (umeclidinium bromide/vilanterol trifenatate)
Mechanism of action
Long acting beta 2 agonist (LABA)
▪ Increases cAMP resulting in bronchial smooth muscle
relaxation
▪ Inhibits release of mediators for immediate
hypersensitivity from mast cells
Fluticasone Furoate/Vilanterol Trifenatate, Micromedex®. 2014.
Umeclidinium Bromide/Vilanterol Trifenatate, Micromedex®. 2014.
Absorption
Tmax: ~10 minutes
systemic
30% feces
Protein binding: ~94%
Half-life
11-21 hours
Fluticasone Furoate/Vilanterol Trifenatate, Micromedex®. 2014.
Umeclidinium Bromide/Vilanterol Trifenatate, Micromedex®. 2014.
Jane Vipond, PharmD
Contraindications
Hypersensitivity to vilanterol or any component in
the drug product
Hypersensitivity to milk proteins
Excretion
70% urine
Distribution
Vd: 165 L
Liver – CYP3A4
Bioavailability: <2%
Metabolism
Precautions
Increased risk of asthma related death with LABA
ECG changes (QTc prolongation, flattening of T
wave, ST depression) with beta agonists
Hypokalemia – increased risk of CV effects
Diabetes mellitus and ketoacidosis exacerbation
Paradoxical bronchospasm
Fluticasone Furoate/Vilanterol Trifenatate, Micromedex®. 2014.
Umeclidinium Bromide/Vilanterol Trifenatate, Micromedex®. 2014.
2
COPD Drug Update
COMMON
Headache
Diarrhea
Respiratory tract
infection
Pharyngitis
Sinusitis
Tachycardia
Arthralgia
Back pain
11/15/2014
Paradoxical
bronchospasm
Electrocardiogram
abnormalities
QTc prolonging medications
Monoamine oxidase inhibitors (MAOIs)
Tricyclic antidepressants (TCAs)
QTc prolongation
Beta blockers
SERIOUS
Increased risk of cardiovascular adverse effects
Increased risk of cardiovascular adverse effects
Severe bronchospasm and decreased effectiveness of
T wave flattening
vilanterol
ST depression
Atrial flutter/fibrillation
Potassium sparing diuretics
Strong CYP 3A4 inducers/inhibitors
Hypokalemia and/or ECG changes
Hypersensitivity reaction
Fluticasone Furoate/Vilanterol Trifenatate, Micromedex®. 2014.
Umeclidinium Bromide/Vilanterol Trifenatate, Micromedex®. 2014.
Martinez FJ, Boscia J, Feldman G, Scott-Wilson C, Kilbride
S, Fabbri L, et al. Fluticasone furoate/vilanterol (100/25;
200/25 ug) improves lung function in COPD: A randomised
trial. Respiratory Medicine. 2013; 107:550-559.
Fluticasone Furoate/Vilanterol Trifenatate, Micromedex®. 2014.
Umeclidinium Bromide/Vilanterol Trifenatate, Micromedex®. 2014.
24 week, multi-center, randomized, stratified,
placebo-controlled, double-blind, parallelgroup study (Oct 2009 – Mar 2011)
2 week single-blind run-in period with placebo
6 double-blind groups (1:1:1:1:1:1 ratio)
Fluticasone/Vilanterol (200/25 mcg; 100/25 mcg)
Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg
C, Church A. Efficacy and safety of once-daily
umeclidinium/vilanterol 62.5/25 mcg in COPD. Respiratory
Medicine. 2013; 107:1538-1546.
Fluticasone (200 mcg; 100 mcg)
Vilanterol 25 mcg
Placebo
Martinez FJ et al., Respiratory Medicine. 2013.
Evaluate effect of adding fluticasone to vilanterol
and the dose effects of fluticasone; confirm oncedaily dosing of vilanterol and evaluate safety and
efficacy of all treatments in patients with COPD
INCLUSION CRITERIA
Primary Efficacy Endpoints
Weighted mean FEV1 (0-4 hours post dose) on day 168
Change from baseline in trough FEV1 (23-24 hours post
dose) on day 169
Safety Endpoints
Adverse effects, COPD exacerbations, and pneumonias
Clinical diagnosis of COPD
≥40 years of age
≥10 pack-year smoking history
Post-bronchodilator
FEV1/FVC ratio ≤0.70
Post-bronchodilator FEV1
≤70% predicted (NHANES III)
Score of ≥2 on the Modified
Medical Research Council
Dyspnoea Scale (mMRC)
EXCLUSION CRITERIA
Respiratory disorder other than
COPD
Lung volume reduction surgery
within 12 months of screening
Acute worsening of COPD
within 6 weeks of screening
Hospitalization for COPD within
12 weeks of screening
Lower respiratory tract infection
requiring antibiotics within 6
weeks of screening
Need for long-term oxygen
therapy or nocturnal oxygen
therapy (≥12 hours/day)
Martinez FJ et al., Respiratory Medicine. 2013.
Martinez FJ et al., Respiratory Medicine. 2013.
Jane Vipond, PharmD
3
COPD Drug Update
11/15/2014
wm FEV1 Day 168
Trough FEV1 Day 169
CRQ-SAS Day 168
Peak FEV1 Day 1
50%
VI 25 vs.
Placebo
0.185
(0.133-0.237)
0.100
(0.048-0.151)
0.07
(-0.14-0.28)
0.147
(0.117-0.177)
45%
FF/VI 200/25
vs. Placebo
0.209
(0.157-0.261)
0.131
(0.080-0.183)
0.1
(-0.12-0.31)
0.141
(0.111-0.171)
40%
FF/VI 200/25
vs. VI 25
0.024
(-0.027-0.075)
0.032
(-0.019-0.083)
0.03
(-0.18-0.23)
-0.006
(-0.036-0.024)
FF/VI 200/25
vs. FF 200
0.168
(0.117-0.219)
0.123
(0.072-0.174)
0.1
(-0.11-0.31)
0.134
(0.104-0.164)
25%
FF 200 vs.
Placebo
0.041
(-0.011-0.093)
0.008
(-0.044-0.060)
-0.01
(-0.22-0.21)
0.007
(-0.023-0.037)
20%
FF/VI 100/25
vs. Placebo
0.214
(0.161-0.266)
0.144
(0.091-0.197)
0.24
(0.02-0.46)
0.152
(0.122-0.182)
15%
FF/VI 100/25
vs. VI 25
0.029
(-0.023-0.081)
0.045
(-0.008-0.097)
0.17
(-0.04-0.38)
0.005
(-0.025-0.036)
10%
FF/VI 100/25
vs. FF 100
0.168
(0.116-0.220)
0.1
(0.047-0.152)
0.36
(0.14-0.57)
0.128
(0.098-0.158)
FF 100 vs.
Placebo
0.046
(-0.006-0.098)
0.044
(-0.008-0.097)
-0.12
(-0.33-0.10)
0.024
(-0.006-0.055)
Comparison
Red denotes p<0.001 Blue denotes p=0.224
35%
5%
0%
On treatment
AEs
On treatment
SAEs
Martinez FJ et al., Respiratory Medicine. 2013.
The combination of fluticasone/vilanterol
provides sustained improvement in FEV1
over 24 weeks in patients with COPD
Primary benefits related to vilanterol
component
No additional benefit observed with higher
doses of fluticasone
Findings confirm once-daily dosing for
combination product with long-acting
bronchodilator vilanterol and inhaled
corticosteroid fluticasone in COPD patients
Evaluate the safety and efficacy of the oncedaily, combination long-acting muscarinic
antagonist and long-acting beta-2 agonist
product umeclidinium/vilanterol compared to
monotherapy of each in patients with COPD
Primary Efficacy Endpoint
4 double-blind groups (3:3:3:2 ratio)
UMEC/Vilanterol 62.5/25 mcg
UMEC 62.5 mcg
Vilanterol 25 mcg
Placebo
INCLUSION CRITERIA
Adverse effects, vital signs, 12 lead ECG in all
patients, 24 hour Holter ECG in subset of patients,
and clinical chemistry and hematology
Fatal SAEs
Martinez FJ et al., Respiratory Medicine. 2013.
24 week, multi-center randomized, doubleblind, placebo-controlled, parallel-group
study conducted in 163 centers in 13
countries (March 30, 2011 - April 5, 2012)
Pre-dose trough FEV1 on day 169
Safety Endpoints
AEs leading
to withdrawal/
discontinuation
Martinez FJ et al., Respiratory Medicine. 2013.
Placebo
FF 100 mcg
FF 200 mcg
VI 25 mcg
FF/VI 100/25 mcg
FF/VI 200/25 mcg
30%
Current or former smokers
≥40 years of age
Clinically established history of
COPD characterized by airflow
limitation that is not fully
reversible and documented
based on smoking history of
≥10 pack-years
Post-salbutamol FEV1/FVC
ratio of <0.70
Post-salbutamol FEV1 of <70%
of predicted (NHANES III)
Score of ≥2 on mMRC
Donohue JF et al., Respiratory Medicine. 2013.
EXCLUSION CRITERIA
Current diagnosis of asthma
or other respiratory disorder
Abnormal and clinically
significant ECG or 24 hour
holter ECG
Significantly abnormal clinical
laboratory findings
Donohue JF et al., Respiratory Medicine. 2013.
Donohue JF et al., Respiratory Medicine. 2013.
Jane Vipond, PharmD
4
COPD Drug Update
11/15/2014
Placebo
(N=280)
UMEC
62.5 mcg
(N=418)
Vilanterol
25 mcg
(N=421)
UMEC/Vilanterol
62.5/25 mcg
(N=413)
Trough FEV1 at Day 169
LSMC from baseline
Difference vs. placebo
UMEC/VI vs. monotherapy
0.004 (0.0158)
-
0.119 (0.0126)
0.115 (0.076-0.155)
0.052 (0.017-0.087)
0.076 (0.0127)
0.072 (0.032-0.112)
0.095 (0.0601-0.130)
0.171 (0.0126)
0.167 (0.128-0.207)
-
0-6 h wm FEV1 at Day 168
LSMC from baseline
Difference vs. placebo
UMEC/VI vs. monotherapy
0.001 (0.0158)
-
0.151 (0.0128)
0.150 (0.110-0.190)
0.092 (0.056-0.127)
0.123 (0.0128)
0.122 (0.082-0.162)
0.120 (0.084-0.155)
0.243 (0.0127)
0.242 (0.202-0.282)
-
Peak FEV1 at Day 168
LSMC from baseline
Difference vs. placebo
UMEC/VI vs. monotherapy
0.096 (0.0168)
-
0.226 (0.0136)
0.130 (0.088-0.172)
0.094 (0.057-0.132)
0.204 (0.0136)
0.108 (0.066-0.151)
0.116 (0.078-0.153)
0.320 (0.0135)
0.224 (0.182-0.267)
-
Trough FVC at Day 169
LSMC from baseline
Difference vs. placebo
UMEC/VI vs. monotherapy
0.014 (0.0258)
-
0.188 (0.0207)
0.175 (0.110-0.239)
0.074 (0.016-0.131)
0.118 (0.0208)
0.105 (0.040-0.170)
0.143 (0.086-0.201)
0.262 (0.0206)
0.248 (0.184-0.313)
-
Red denotes p≤0.001
Blue denotes p≤0.01
Green denotes p≤0.05
60%
50%
UMEC 62.5 mcg
30%
Vilanterol 25 mcg
10%
0%
On treatment
AEs
Findings support development of a
combination product with a long-acting
bronchodilator and a medication with a
complementary mechanism of action for oncedaily dosing as maintenance therapy in COPD
Donohue JF et al., Respiratory Medicine. 2013.
Kempsford R, Norris V, Siederer S. Vilatnerol trifenatate, a novel
inhaled long-acting beta2 adrenoceptor agonist, is well tolerated in
healthy subjects and demonstrates prolonged bronchodilation in
subjects with asthma and COPD. Pulmonary Pharmacology &
Therapeutics. 2013; 26(2):256-264.
Kerwin EM, Scott-Wilson C, Sanford L, Rennard S, Agusti A, Barnes
N, et al. A randomised trial of fluticasone furoate/vilanterol (50/25 ug;
100/25 ug) on lung function in COPD. Respiratory Medicine. 2013;
107:560-569.
McKeage K. Fluticasone furoate/vilanterol: A review of its use in
chronic obstructive pulmonary disease. Drugs. 2014; 74:1509-1522.
Jane Vipond, PharmD
On treatment
SAEs
AEs leading
to withdrawal/
discontinuation
Fatal SAEs
Donohue JF et al., Respiratory Medicine. 2013.
Bollmeier SG, Prosser TR. Combination of fluticasone furoate and
vilanterol for the treatment of chronic obstructive pulmonary disease.
Annals of Pharmacotherapy. 2014; 48(2):250-257.
Decramer M, Anzueto A, Kerwin E, Kaelin T, Richard N, Crater G, et al.
Efficacy and safety of umeclidinium 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 Resp Med. 2014; 2:472-486.
Hanania NA, Feldman G, Zachgo W, Shim JJ, Crim C, Sanford L, et al.
The efficacy and safety of the novel long-acting B2 agonist vilanterol in
patients with COPD: A randomized placebo-controlled trial. CHEST.
2012;142(1):119-127.
Kelleher DL, Mehta RS, Jean-Francois BM, Preece AF, Blowers J, Crater
GD, et al. Safety, tolerability, pharmacodynamics and pharmacokinetics of
umeclidinium and vilanterol alone and in combination: A randomized
crossover trial. PLOS ONE. 2012; 7(12):1-9.
Similar safety and tolerability profile
UMEC/Vilanterol
62.5/25 mcg
20%
Donohue JF et al., Respiratory Medicine. 2013.
The combination of umeclidinium/vilanterol
62.5/25 mcg is more effective than treatment
with either component alone over 24 weeks in
patients with COPD
Placebo
40%
5
COPD Drug Update
11/15/2014
Dry powder inhaler (DPI)
Open only when
ready to use a dose
Open the inhaler by
sliding the cover
down fully until you
hear a “click”
Breathe out slowly
and completely, but
not forcefully
Similar to DISKUS® inhaler
Comes in foil tray with desiccant to
decrease moisture
Contains 30 doses
Discard 6 weeks after opening the tray
Sample pack only contains 14 doses
"©2014, WebMD, LLC. All rights reserved"
RxList, Inc., WebMD, LLC. 2014.
Tilt head back slightly and
close lips tightly around
mouthpiece
Ensure fingers are not
blocking the air vents
Inhale quickly and deeply
May not taste or sense
RxList, Inc., WebMD, LLC. 2014.
Remove inhaler from mouth
Hold breath for 3-4 seconds
or as long as comfortable
Slowly and gently exhale
through pursed lips – do
NOT exhale into the inhaler
Close inhaler cover
If fluticasone/vilanterol, rinse
mouth after use to prevent
thrush
"©2014, WebMD, LLC. All rights reserved"
medication going into lungs
"©2014, WebMD, LLC. All rights reserved"
RxList, Inc., WebMD, LLC. 2014.
RxList, Inc., WebMD, LLC. 2014.
Do not use more than once a day
Oral inhalation route only
Inhale quickly and deeply
Powder on tongue is normal
When <10 doses remain, counter shows
numbers in red as reminder to refill
When counter says “0” the medication is gone
Rinse mouth after use of fluticasone/vilanterol
RxList, Inc., WebMD, LLC. 2014.
Jane Vipond, PharmD
6
COPD Drug Update
11/15/2014
Do not shake
Do not load dose without taking
Do not exhale into the device
Do not get wet or wash – only wipe with dry cloth
Store in a clean, dry environment away from
extremes in temperature
Discard 6 weeks after opening the tray
Mark open and discard dates on inhaler label
RxList, Inc., WebMD, LLC. 2014.
1)
Vilanterol has been
FDA approved for use
in combination with
which other active
ingredient(s)?
A. Fluticasone
Vilanterol is classified
as a:
3)
A. Short acting beta-2
agonist
B. Long acting beta-2
agonist
True or False: Both
FDA approved vilanterol
containing products
have been FDA
approved to reduce
the number of acute
COPD exacerbations.
B. Budesonide
C. Anticholinergic
C. Umeclidinium
D. Inhaled corticosteroid
A. True
D. A and B
E. Phosphodiesterase-4
B. False
E. A and C
5)
2)
The Ellipta™ delivery
device is most similar to
which type of dry
powder inhaler?
A. Diskus
B. Twist & Load
C. Load-a-Capsule
D. Pressair
inhibitor
Patients utilizing a vilanterol containing product should
be counseled to do all of the following except:
A. Do not open the inhaler until ready to use – if you open and
close the device without use you will lose a dose
B. Do not cover the air vents on the inhaler with mouth or
fingers during use
C. Inhale quickly and deeply with use
D. Dispose of this medication 6 weeks after opening or when
the counter reaches “0”, whichever occurs first
E. Rinse the device with warm water and allow to air dry
Jane Vipond, PharmD
4)
1)
Examples of vilanterol
containing products
include which of the
following:
2)
Common adverse
effects of vilanterol
containing products
include:
A. Breo™
A. Nasopharyngitis
B. Anoro™
B. Headache
C. Advair®
C. Cough
D. A and B
D. All of the above
E. All of the above
7
COPD Drug Update
Vilanterol containing
products have undergone
studies for safety and
efficacy in:
11/15/2014
A. Asthma
Vilanterol containing
products are administered
via the Ellipta™ delivery
device which is what type
of inhaler?
B. COPD
A. Metered dose inhaler (MDI)
C. Pain
B. Dry powder inhaler (DPI)
D. All of the above
C. Soft mist inhaler
3)
4)
5)
True or False: Patients utilizing a vilanterol containing
product should receive counseling by a pharmacist
prior to use to ensure appropriate inhaler technique will
be utilized.
A. True
B. False
D. None of the above
PHARMACISTS
1)
2)
3)
4)
5)
E (A and C)
B (long acting beta-2
agonist)
B (false)
A (diskus)
E (rinse the device
with warm water and
allow to air dry)
TECHNICIANS
1)
2)
3)
4)
5)
D (A and B)
D (all of the above)
B (COPD)
B (dry powder
inhaler - DPI)
A (true)
Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C,
Church A. Efficacy and safety of once-daily umeclidinium/vilanterol
62.5/25 mcg in COPD. Respiratory Medicine. 2013; 107:1538-1546.
DrugPoint® Summary Micromedex®: Fluticasone furoate/vilanterol
trifenatate [Internet]. Version 2.0. Greenwood Village (CO): Truven
Health Analytics c1974-2014 [modified 2014 Oct 23; cited 2014 Oct
27]. Available from:
http://www.thomsonhc.com.ezproxy.usd.edu/micromedex2/librarian.
DrugPoint® Summary Micromedex®: Umeclidinium bromide/vilanterol
trifenatate [Internet]. Version 2.0. Greenwood Village (CO): Truven
Health Analytics c1974-2014 [modified 2014 Oct 23; cited 2014 Oct
27]. Available from:
http://www.thomsonhc.com.ezproxy.usd.edu/micromedex2/librarian.
Jane Vipond, PharmD
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global
strategy for the diagnosis, management, and prevention of chronic
obstructive pulmonary disease: Updated 2014 [Internet]. Vancouver
(WA): Global Initiative for Chronic Obstructive Lung Disease (GOLD);
©2014 [updated 2014 Jan; cited 2014 Oct 31]. Available from:
http://www.goldcopd.com/uploads/users/files/GOLD_Report_2014_Oct
30.pdf.
Martinez FJ, Boscia J, Feldman G, Scott-Wilson C, Kilbride S, Fabbri
L, et al. Fluticasone furoate/vilanterol (100/25; 200/25 ug) improves
lung function in COPD: A randomised trial. Respiratory Medicine.
2013; 107:550-559.
RxList, Inc. Breo™ Ellipta™ [Internet]. New York (NY): WebMD, LLC;
©2005-2014 [updated 2013 May 05; cited 2014 Oct 31]. Available
from: http://www.rxlist.com/breo-ellipta-drug/medication-guide.htm.
8