Title: PharmaNote
Full Citation
Permanent Link: http://ufdc.ufl.edu/UF00087345/00059
 Material Information
Title: PharmaNote
Series Title: PharmaNote
Physical Description: Serial
Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: December 2007
 Record Information
Bibliographic ID: UF00087345
Volume ID: VID00059
Source Institution: University of Florida
Rights Management: All rights reserved by the source institution and holding location.


This item has the following downloads:

December2007 ( PDF )

Full Text


Donna L. Smith, Pharm. D. Candidate

More than 22 million people in the United
States have asthma according to the Centers for Dis-
ease Control and Prevention (CDC).1 Asthma is a
chronic inflammatory disorder of the airways which
can be life threatening if not properly managed.
Without appropriate treatment, asthma can signifi-
cantly limit individuals' activities and result in
asthma exacerbations, resulting in hospitalization
and death. The CDC estimates that 4,000 Americans
die from asthma exacerbations each year.1
The goal of pharmacologic therapy is to pre-
vent and control asthma symptoms, improve quality
of life, reduce frequency and severity of asthma ex-
acerbations and reverse airflow obstruction with the
minimum effective drug dose to reduce risk of ad-
verse effects.2 The evidence in the recently revised
NIH Asthma 2007 guidelines continue to support the
use of low-dose inhaled corticosteroids (ICS) as
standard maintenance therapy with the use of short-
acting beta agonists (SABA) for relief of acute exac-
erbations. For asthma inadequately controlled with
the low-dose ICS, the 2007 guidelines give the op-
tion of increasing the dose of ICS equal weight to
adding a long-acting beta agonist (LABA). This
change acknowledges the potential risks associated
with LABA, and at the same time validating the evi-

dence showing greater improvements in lung func-
tion, symptoms, and less use of short-acting beta
agonists (SABA) with adding LABA compared to
doubling the ICS dose.
Symbicort, AstraZeneca's combination
product of the ICS budesonide and the LABA for-
moterol in a pressurized meter dose inhaler (pMDI)
was released to US markets in June 2007. It was
approved for long-term maintenance for asthma in
adults, including elderly, adolescents and children >
12 years old. Though not recommended or approved
for acute exacerbations, the quick onset of action of
formoterol is similar to albuterol.3 This has gener-
ated interest in the potential of the combination prod-
uct of budesonide/formoterol to be used as both
maintenance and rescue treatment for asthma. This
article will review budesonide/formoterol's safety
and efficacy in asthma maintenance therapy and the
potential use in treatment of acute exacerbations.

Pharmacology and Pharmacokinetics

Budesonide is an inhaled corticosteroid with





Volume 23, Issue 3 December 2007


mainly glucocorticoid activity. Corticosteroids are
the most potent and effective anti-inflammatory
medication available.2 Glucocorticoids have a direct
inhibitory effect on many cells involved in airway
inflammation in asthma, including macrophages, T-
lymphocytes, eosinophils and airway epithelial cells.
After inhalation, the lipophilic property of budeson-
ide allows for rapid absorption into the cell cyto-
plasm where it binds to glucocorticoid receptors re-
sulting in changes in gene transcription within the
nucleus. The result can include inhibition of leuko-
cyte infiltration at the site of inflammation, interfer-
ence in the function of mediators of inflammatory
response, and suppression of humoral immune re-
Budesonide is rapidly absorbed from the
lungs after oral inhalation with peak plasma concen-
trations within 20 minutes. Most of the dose deliv-
ered to lungs is systemically absorbed. Budesonide
is metabolized in the liver into weakly active me-
tabolites via the CYP 3A4 enzyme and excreted in
urine and feces. The mean terminal half life is 4.7

Formoterol is a highly selective beta-2 adren-
ergic agonist with duration of action over 12 hours
compared to three hours for the short acting beta-2
agonist albuterol. The lipophilic side chain of for-
moterol enters the cell membrane and forms a depot
that is gradually released into the aqueous phase to
stimulate the beta-2 receptor. The length of the side
chain prolongs the duration of action, but maintains a
quick onset of action after inhalation that is similar to
albuterol.3 5 Once the airway receptors are stimu-
lated, the mechanism of action is similar to other
beta-2 agonists resulting in relaxation of bronchial
smooth muscle.
Formoterol is rapidly absorbed in the lungs
after inhalation, with peak plasma levels occurring in
5-10 minutes. Most of the drug systemically ab-
sorbed is due to swallowing and absorbed through GI
tract. Formoterol is metabolized CYP 2D6, 2C19,
2C9 and 2A6, then excreted in urine and feces over
104 hours. The mean terminal half-life is around 8

Clinical Trials

Maintenance Therapy

Two recent US multi-center randomized, pla-
cebo-controlled trials compared the use of budeson-
ide/formoterol combination in one pMDI to the indi-
vidual components and placebo for safety and effi-
cacy in asthma patients >12 years old. The designs
of the studies are similar with the major difference
being one targeted mild-to-moderate asthma and the
second targeted moderate-to-severe.

Clinical Trial Targeting Mild-to-Moderate Asthma

A total of 480 mild to moderate asthma pa-
tients were randomized to compare safety and effi-
cacy of twice daily budesonide/formoterol pMDI
80/4.5 mcg (Symbicort pMDI) x 2 inhalations,
budesonide pMDI 80 mcg (Pulmicort DPI) x 2 in-
halations, formoterol DPI 4.5 mcg (Oxis Turbu-
haler') x 2 inhalations or placebo for 12 weeks.
Study participants included patients with a docu-
mented diagnosis of asthma for at least 6 months
treated with ICS consistently 4 weeks prior to
screening and with a FEV1 of > 60% to 90% of pre-
dicted normal on ICS treatment. Excluded were pa-
tients that were hospitalized once or > 1 emergency
department (ED) visit in the previous 6 months, re-
quiring systemic corticosteroids in the 4 weeks prior
to the study, and >10 pack-per-year smokers. After
a two week run-in in which patients were given a
singe-blinded placebo pMDI and rescue albuterol,
patients who demonstrating reversibility in FEV1
from a baseline of> 12% and > 0.20 L within 15-30
minutes after a standard dose of albuterol were ran-
The primary end points of the study were pre-
dose FEVi and 12-hour mean FEV1. The end points
were selected to measure the contributions of the in-
dividual components with pre-dose FEV1, to assess
the efficacy of budesonide with regards to pulmonary
function and the 12 hour mean FEV1, and to assess
the bronchodilator effect of formoterol. Modified
intention-to-treat approach was used to calculate pri-
mary end points, including data for all subjects who
received at least one dose of study drug and recorded
sufficient data points for the calculation of at least
one primary end point7
Secondary end points included morning and
evening peak expiratory flow (PEF), daytime and
nighttime symptom scores, nighttime awakenings
due to asthma, and daily rescue medication use.
Safety was assessed based on adverse events, routine

PharmaNote Volume 23, Issue 3 December 2007

Volume 23, Issue 3 December 2007


Table 1. Primary endpoints for patients with mild-to-moderate asthma7

BUD/FM minus BUD BUD/FM minus FM BUD/FM minus placebo
(95% CI) (95% CI) (95% CI)

Pre-dose FEV1 (L) 0.15 (0.05 to 0.26)* 0.20 (0.09 to 0.31)* 0.34 (0.23 to 0.45)*

12-hour mean FEV1 (L)

Day 1 0.24 (0.17 to9 0.31)* -0.04 (-0.11 to 0.02) 0.25 (0.19 to 0.32)*

Week 2 0.18 (0.09 to 0.27)* 0.07 (-0.02 to 0.16) 0.35 (0.26 to 0.44)*

End of trial 0.20 (0.11 to 0.29)* 0.09 (0.00 to 0.19)* 0.39 (0.30 to 0.47)*

BUD= budesonide; FM =formoterol; FEVy

Forced expiratory volume in 1 sec; CI confidence interval

laboratory analysis, ECG, 24-hour Holter monitor
assessment, and physical exam including vital signs.7
The mean change from baseline in pre-dose
FEV1 at end of study was significantly greater in the
budesonide/formoterol pMDI group compared to the
formoterol, budesonide, and placebo group (0.37 vs.
0.23, 0.17, and 0.3 L, respectively; all, p < 0.05). At
the end of the 12 week study, the mean change from
baseline in 12 hour FEV1 was significantly greater
with budesonide/formoterol pMDI (0.50 L) com-
pared with budesonide pMDI (0.32 L) or placebo
(0.12 L) (all, p > 0.001). The bronchodilatory effect
of budesonide/formoterol pMDI remained relatively
constant between week 2 and week 12.7 (Table 1)
Mean increases from baseline in morning and
evening PEF were significantly greater with
budesonide/formoterol pMDI compared with
budesonide pMDI and formoterol DPI (all, p <
0.001). Changes in baseline daytime and nighttime
symptom scores and increases in symptom free days
were similar between the budesonide/formoterol
pMDI and the budesonide pMDI. No severe adverse
events considered study drug related were recorded
for patients receiving treatment with budesonide/
formoterol. Overall incidence of asthma related ad-
verse events in the study for all groups was 2.5% but
none occurred in the budesonide/formoterol groups.
No changes in baseline heart rate, mean post-dose
serum glucose, potassium or physical examination
were identified between treatment groups.'

Clinical Trial Targeting Moderate-to-Severe Asthma

A total of 596 patients with moderate-to-
severe asthma were randomized in this 12-week
study evaluating the efficacy and safety of the 160
mcg/4.5 mcg budesonide and formoterol pressurized
metered dose inhaler with 160 mcg budesonide
pMDI, 4.5 mcg formoterol DPI, 160 mcg budeson-
ide and 4.5 mcg formoterol in separate inhalers and
placebo.8 Each treatment group received 2 inhala-
tions twice daily. Inclusion criteria were a diagnosis
of asthma for > 6 months with a FEVI> 45% to <
85% of predicted normal and treated with a moder-
ate-to-high dose of ICS for at least 4 weeks prior to
the study. Excluded were patients hospitalized once
or > 1 ED visit in the previous 6 months, patients
who required systemic corticosteroids in the 4 weeks
prior to study, and > 10 pack-per-year smokers.8
During a 2-week run-in period, patients dis-
continued use of their current therapy and received
two inhalations of 80 mcg budesonide pMDI twice
daily and rescue SABA as needed. Patients with
documented daytime and night-time symptoms of >
3 of 7 days during the run-in period were random-
ized. Randomization was stratified into 2 groups
according to patient's current ICS dosage (high,
moderate) allowing investigators to analyze the re-
sponse to treatment based on severity of asthma.8
The primary efficacy measure was the change
from baseline in morning pre-dose FEV1 and the 12-

PharmaNote Volume 23, Issue 3 December 2007

Volume 23, Issue 3 December 2007


Table 2. Primary efficacy variables for patients with moderate-to-severe asthma8

BUD/FM minus- BUD/FM minus pla-
Parameter BUD+FM cebo
(95% CI) (95% CI)

Pre-dose FEV1 (L) 0.10 (0.0 to 0.21)* 0.31 (0.20 to 0.41)* 0.05 (-0.05 to 0.15) 0.37 (0.27 to 0.47)*

12-h mean FEV1 (L)

Day 1 0.26 (0.20 to 0.33)* 0.02 (-0.04 to 0.08) -0.01 (-0.07 to 0.06) 0.29 (0.22 to 0.35)*

Week 2 0.20 (0.11 to 0.28)* 0.15 (0.07 to 0.23)* 0.01 (-0.07 to 0.09) 0.37 (0.29 to 0.45)*

End of Trial 0.23 (0.14 to 0.31)* 0.19 (0.11 to 0.28)* 0.01 (-0.08 to 0.09) 0.40 (0.32 to 0.48)*

BUD = budesonide; FM = formoterol; FEV1 = forced expiratory volume in 1 sec; CI

hour mean change in FEVi over a 12-hour period.
Secondary efficacy measures included morning PEF,
daytime and night-time symptom scores, night-time
awakenings due to asthma and daily rescue medica-
tions required. The primary treatment comparison
was budesonide/formoterol pMDI verses formoterol
DPI for pre-dose FEV1 and budesonide/formoterol
pMDI verses budesonide pMDI for 12-hour mean
FEV1. Safety was evaluated based on adverse
events, laboratory evaluations, vital signs, ECGs, 24-
hour Holter monitoring and physical examination.8
Patient treated with budesonide/formoterol
pMDI achieved a significant improvement (p<0.001)
in pre-dose FEVi from baseline compared with for-
moterol DPI throughout the study. Mean changes
from baseline in 12-hour FEVi were significantly
(p<0.001) greater for patients treated with budeson-
ide/formoterol pMDI compared with budesonide
pMDI. The difference in formulation and device did
not alter the efficacy or safety.8 (Table 2)
The safety profile of budesonide/formoterol
combination was similar to placebo, with no clini-
cally relevant differences in mean post-serum glu-
cose, potassium levels, vital signs or physical exami-

Confidence interval

Maintenance and Rescue Therapy
The safety and efficacy of budesonide/
formoterol in a single inhaler (DPI) for both mainte-
nance therapy and symptom relief was compared to a
higher dose of budesonide plus as needed SABA ter-
butaline in a double-blind, randomized, parallel
group, active-controlled study.9 This 6-month study
was conducted in 77 centers outside the US and in-
cluded 697 subjects between the ages of 12-80 with
mild-to-moderate asthma symptoms currently on any
brand of ICS (doses 200-500 mcg/day) for at least 3
months. Patients were randomized into one of two
groups; budesonide/formoterol (80 mcg/4.5 mcg) 2
inhalations daily for maintenance plus budesonide/
formoterol as needed for relief or double the dose of
budesonide (160 mcg) two inhalations daily plus ter-
butaline (0.4 mg) as needed for relief.9
After an open run-in period of 14 to 18 days,
patients were randomized only if they required 7 or
more doses of terbutaline on the last 10 days of the
run-in period. At the end of the 6-month study, the
primary outcome variable, morning PEF, showed
greater improvement from baseline for the budeson-
ide/formoterol group vs. the budesonide treatment.
(34.5 L/min vs. 9.5 L/min, p< 0.001) Fewer total
and severe asthma exacerbations were seen in the

PharmaNote Volume 23, Issue 3 December 2007

Volume 23, Issue 3 December 2007


Table 3. Mean efficacy variables for budesonide/formoterol compared to budesonide and terbutaline for both maintenance
and symptom relief

Efficacy variables Adjusted between group difference (BUD/FM minus-
Efficacy variables P value
BUD) (95% CI)

Morning PEF (L/min) 25.0 (19.4 to 30.6) < 0.001

Evening PEF (L/min) 18.8 (13.3 to 24.3) < 0.001

As needed inhalations/day -0.34 (-0.51 to -0.17) < 0.001

As needed medication free days (%) 8.1 (3.5 to 12.7) < 0.001

Total asthma symptoms score (0-6) -0.17 (-0.26 to -0.07) < 0.001

Nighttime awakening (%) -2.2 (-4.5 to 0.1) < 0.065

Symptom free days 6.5 (2.0 to 11.0) < 0.00043

Asthma control days 7.6 (3.0 to 12.3) < 0.0012

BUD = budesonide; FM = formoterol; PEF = peak expiratory flow

budesonide/formoterol group compared to budeson- of budesonide and 18 mcg of formoterol via oral in-
ide treatment (43 total/14 severe and 94 total/57 se- halation.5
vere, respectively).9 (Table 3)
Even though budesonide/formoterol was Toxicity & Safety
used in both treatment and relief, the overall mean The FDA placed a black box warning on all
daily dosage of ICS was 160-320mcg for 85% of pa- LABA containing products, which includes budeson-
tients. This was lower than the fixed dosage of 320 ide/formoterol for the potential increased risk of
mcg of ICS in the budesonide treatment group. The death from asthma. A large clinical trial comparing
frequency of adverse events was similar between daily treatment with salmeterol or placebo added to
treatment groups with no differences in lab values or usual asthma therapy resulted in an increased risk of
ECG.9 asthma-related deaths in patients treated with salmet-
erol.10 In addition, an increased number of severe
Dosing and Administration asthma exacerbations was noted in the formoterol
Budesonide/formoterol is indicated for long- trials submitted to the FDA for formoterol approval,
term maintenance therapy for treatment of mild-to- particularly in the higher dose arms of the trials."
moderate asthma when a low-dose inhaled corticos-
teroid is not adequately controlling asthma.2 The rec- Cost and Availability
ommended dosing is 2 inhalations of budesonide/ Budesonide/formoterol pMDI is available in
formoterol 80 mcg/4.5 mcg twice daily or 2 inhala- the US in two dosages, 80 mcg/4.5 mcg and 160
tions of budesonide/formoterol 160 mcg/4.5 mcg mcg/4.5 mcg of budesonide and formoterol, respec-
twice daily. Maximum dosage in adults is 640 mcg tively. They are dispensed in a 10.2 gram canister

PharmaNote Volume 23, Issue 3 December 2007

that provides 120 actuations. The average retail cost
for one canister of 80 mcg/4.5 mcg is $164.55 and
160 mcg/4.5 mcg is $188.81 as determined by three
community pharmacies in Gainesville, Florida. As
of October 1, 2007, budesonide/formoterol
(Symbicort) is on the preferred Florida Medicaid
drug list.

For asthma patients who are not controlled
on low-dose ICS, the addition of a LABA is one of
the two options currently recommended in recently
updated asthma guidelines.2 The combination prod-
uct of budesonide/formoterol pMDI was associated
with significantly greater efficacy than either compo-
nent alone. Budesonide and formoterol are well tol-
erated at the recommended dosages.
Initial evidence on the use of budesonide/
formoterol pMDI for maintenance and relief are
promising, and could potentially simplify the admini-
stration of asthma medications for patients. How-
ever, the current guidelines and the FDA strongly
warn against the use of LABA for relief until further
studies are done to prove safety and efficacy.2

1. Akinbami L, et al. Asthma Prevalence, Health
care use and Mortality: United States, 2003-05.
National Center for Health Statistics (NCHS),
Centers for Disease Control and Prevention.
Available at http://www.cdc.gov/nchs/products/
05.htm. Accessed on September 28, 2007.
2. National Asthma Education and Prevention Pro-
gram. Expert Panel Report 3: Guidelines for the
diagnosis and Management of Asthma. NIH
Publication 07-4051. Available at http://
asthgdln.pdf Accessed September 28, 2007.
3. Van Noord JA, Smeets JJ, et al. Salmeterol
verses formoterol in patients with moderately
severe asthma: onset and duration of action. Eur
Respir J 1996; 9: 1684-88.
4. Barnes PJ. Inhaled Glucocorticoids for Asthma.
N Eng J Med 1995; 332: 868-75.
5. Clinical Pharmacology [Symbicort]. Gold
Standard Media Inc. Version 2.23. May 2007.
6. Anderson GP, Linden A, Rabe KF. Why are
long acting beta adrenoreceptor agonist long act-
ing? Eur Respir J 1994; 7: 569-78.

7. Corren J, Korenblat PE, Miller CJ, et al. Twelve-
week randomized, placebo-controlled, multicen-
ter study of the efficacy and tolerability of
budesonide and formoterol in one metered-dose
inhaler compared with budesonide alone and for-
moterol alone in adolescents and adults with
asthma. Clinical Therapeutics 2007: 29: 823-43.
8. Noonan M, Rosenwasser LJ, Martin P, et al. Ef-
ficacy and safety of budesonide and formoterol in
one pressurised metered-dosed inhaler in adults
and adolescents with moderate-to-severe asthma.
Drugs 2006; 66: 2235-54.
9. Rabe KF, Pizzichini E, Stallberg B, et al.
Budesonide/Formoterol in a single inhaler for
maintenance and relief in mild-to-moderate
asthma: a randomized double blind trial. Chest
2006; 129: 246-56.
10. 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: 15-26. Erratum in: Chest 2006; 129
11. Mann M, Chowdhury B, Sullivan E, et al. Seri-
ous asthma exacerbations in asthmatics treated
with high-dose formoterol. Chest 2003; 124: 70-

PharmaNote Volume 23, Issue 3 December 2007

The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

Shawn Anderson Assistant Editor


Volume 23, Issue 3 December 2007


University of Florida Home Page
© 2004 - 2010 University of Florida George A. Smathers Libraries.
All rights reserved.

Acceptable Use, Copyright, and Disclaimer Statement
Last updated October 10, 2010 - - mvs