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For Asthma, COPD, Warning, Dosage, Side Effects & Interactions

CLINICAL PHARMACOLOGY

Mechanism Of Action

ADVAIR DISKUS

ADVAIR DISKUS contains both fluticasone propionate and
salmeterol. The mechanisms of action described below for the individual
components apply to ADVAIR DISKUS. These drugs represent 2 different classes of
medications (a synthetic corticosteroid and a LABA) that have different effects
on clinical, physiologic, and inflammatory indices.

Fluticasone Propionate

Fluticasone propionate is a synthetic trifluorinated
corticosteroid with anti-inflammatory activity. Fluticasone propionate has been
shown in vitro to exhibit a binding affinity for the human glucocorticoid
receptor that is 18 times that of dexamethasone, almost twice that of
beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone
dipropionate, and over 3 times that of budesonide. Data from the McKenzie
vasoconstrictor assay in man are consistent with these results. The clinical
significance of these findings is unknown.

Inflammation is an important component in the
pathogenesis of asthma. Corticosteroids have been shown to have a wide range of
actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils,
macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes,
cytokines) involved in inflammation. These anti-inflammatory actions of
corticosteroids contribute to their efficacy in asthma.

Inflammation is also a component in the pathogenesis of
COPD. In contrast to asthma, however, the predominant inflammatory cells in
COPD include neutrophils, CD8+ T-lymphocytes, and macrophages. The effects of
corticosteroids in the treatment of COPD are not well defined and inhaled
corticosteroids and fluticasone propionate when used apart from ADVAIR DISKUS
are not indicated for the treatment of COPD.

Salmeterol Xinafoate

Salmeterol is a selective LABA. In vitro studies show
salmeterol to be at least 50 times more selective for beta2-adrenoceptors than
albuterol. Although beta2-adrenoceptors are the predominant adrenergic
receptors in bronchial smooth muscle and beta1-adrenoceptors are the
predominant receptors in the heart, there are also beta2-adrenoceptors in the
human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise
function of these receptors has not been established, but their presence raises
the possibility that even selective beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-adrenoceptor agonist
drugs, including salmeterol, are at least in part attributable to stimulation
of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of
adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine
monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of
bronchial smooth muscle and inhibition of release of mediators of immediate
hypersensitivity from cells, especially from mast cells.

In vitro tests show that salmeterol is a potent and
long-lasting inhibitor of the release of mast cell mediators, such as
histamine, leukotrienes, and prostaglandin D2, from human lung. Salmeterol
inhibits histamine-induced plasma protein extravasation and inhibits
platelet-activating factor– induced eosinophil accumulation in the lungs of
guinea pigs when administered by the inhaled route. In humans, single doses of
salmeterol administered via inhalation aerosol attenuate allergen-induced
bronchial hyper-responsiveness.

Pharmacodynamics

ADVAIR DISKUS

Healthy Subjects: Cardiovascular Effects: Since systemic pharmacodynamic effects of salmeterol are
not normally seen at the therapeutic dose, higher doses were used to produce
measurable effects. Four (4) trials were conducted with healthy adult subjects:
(1) a single-dose crossover trial using 2 inhalations of ADVAIR DISKUS 500/50,
fluticasone propionate powder 500 mcg and salmeterol powder 50 mcg given
concurrently, or fluticasone propionate powder 500 mcg given alone, (2) a
cumulative dose trial using 50 to 400 mcg of salmeterol powder given alone or
as ADVAIR DISKUS 500/50, (3) a repeat-dose trial for 11 days using 2
inhalations twice daily of ADVAIR DISKUS 250/50, fluticasone propionate powder
250 mcg, or salmeterol powder 50 mcg, and (4) a single-dose trial using 5
inhalations of ADVAIR DISKUS 100/50, fluticasone propionate powder 100 mcg
alone, or placebo. In these trials no significant differences were observed in
the pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc
interval, potassium, and glucose) whether the salmeterol was given as ADVAIR
DISKUS, concurrently with fluticasone propionate from separate inhalers, or as
salmeterol alone. The systemic pharmacodynamic effects of salmeterol were not
altered by the presence of fluticasone propionate in ADVAIR DISKUS. The
potential effect of salmeterol on the effects of fluticasone propionate on the
HPA axis was also evaluated in these trials.

Hypothalamic-Pituitary-Adrenal Axis Effects: No significant differences across treatments were
observed in 24-hour urinary cortisol excretion and, where measured, 24-hour
plasma cortisol AUC. The systemic pharmacodynamic effects of fluticasone
propionate were not altered by the presence of salmeterol in ADVAIR DISKUS in
healthy subjects.

Subjects with Asthma: Adult and Adolescent Subjects: Cardiovascular Effects: In clinical trials with ADVAIR
DISKUS in adult and adolescent subjects aged 12 years and older with asthma, no
significant differences were observed in the systemic pharmacodynamic effects
of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and
glucose) whether the salmeterol was given alone or as ADVAIR DISKUS. In 72
adult and adolescent subjects with asthma given either ADVAIR DISKUS 100/50 or
ADVAIR DISKUS 250/50, continuous 24-hour electrocardiographic monitoring was
performed after the first dose and after 12 weeks of therapy, and no clinically
significant dysrhythmias were noted.

Hypothalamic-Pituitary-Adrenal Axis Effects: In a 28-week trial in adult and adolescent subjects with
asthma, ADVAIR DISKUS 500/50 twice daily was compared with the concurrent use
of salmeterol powder 50 mcg plus fluticasone propionate powder 500 mcg from
separate inhalers or fluticasone propionate powder 500 mcg alone. No
significant differences across treatments were observed in serum cortisol AUC
after 12 weeks of dosing or in 24-hour urinary cortisol excretion after 12 and
28 weeks.

In a 12-week trial in adult and adolescent subjects with
asthma, ADVAIR DISKUS 250/50 twice daily was compared with fluticasone
propionate powder 250 mcg alone, salmeterol powder 50 mcg alone, and placebo.
For most subjects, the ability to increase cortisol production in response to
stress, as assessed by 30-minute cosyntropin stimulation, remained intact with
ADVAIR DISKUS. One subject (3%) who received ADVAIR DISKUS 250/50 had an
abnormal response (peak serum cortisol less than 18 mcg/dL) after dosing,
compared with 2 subjects (6%) who received placebo, 2 subjects (6%) who
received fluticasone propionate 250 mcg, and no subjects who received
salmeterol.

In a repeat-dose, 3-way crossover trial, 1 inhalation
twice daily of ADVAIR DISKUS 100/50, FLOVENT® DISKUS® 100 mcg (fluticasone
propionate inhalation powder, 100 mcg), or placebo was administered to 20 adult
and adolescent subjects with asthma. After 28 days of treatment, geometric mean
serum cortisol AUC over 12 hours showed no significant difference between
ADVAIR DISKUS and FLOVENT DISKUS or between either active treatment and
placebo.

Pediatric Subjects: Hypothalamic-Pituitary-Adrenal Axis
Effects
: In a 12-week trial in subjects with asthma aged 4 to 11
years who were receiving inhaled corticosteroids at trial entry, ADVAIR DISKUS
100/50 twice daily was compared with fluticasone propionate inhalation powder
100 mcg administered twice daily via the DISKUS. The values for 24-hour urinary
cortisol excretion at trial entry and after 12 weeks of treatment were similar
within each treatment group. After 12 weeks, 24-hour urinary cortisol excretion
was also similar between the 2 groups.

Subjects with Chronic Obstructive Pulmonary Disease: Cardiovascular
Effects
: In clinical trials with ADVAIR DISKUS in subjects with
COPD, no significant differences were seen in pulse rate, blood pressure,
potassium, and glucose between ADVAIR DISKUS, the individual components of
ADVAIR DISKUS, and placebo. In a trial of ADVAIR DISKUS 250/50, 8 subjects (2
[1.1%] in the group given ADVAIR DISKUS 250/50, 1 [0.5%] in the fluticasone
propionate 250-mcg group, 3 [1.7%] in the salmeterol group, and 2 [1.1%] in the
placebo group) had QTc intervals greater than 470 msec at least 1 time during
the treatment period. Five (5) of these 8 subjects had a prolonged QTc interval
at baseline.

In a 24-week trial, 130 subjects with COPD received
continuous 24-hour electrocardiographic monitoring prior to the first dose and
after 4 weeks of twice-daily treatment with either ADVAIR DISKUS 500/50,
fluticasone propionate powder 500 mcg, salmeterol powder 50 mcg, or placebo. No
significant differences in ventricular or supraventricular arrhythmias and
heart rate were observed among the groups treated with ADVAIR DISKUS 500/50,
the individual components, or placebo. One (1) subject in the fluticasone
propionate group experienced atrial flutter/atrial fibrillation, and 1 subject
in the group given ADVAIR DISKUS 500/50 experienced heart block. There were 3
cases of nonsustained ventricular tachycardia (1 each in the placebo,
salmeterol, and fluticasone propionate 500-mcg treatment groups).

In 24-week clinical trials in subjects with COPD, the
incidence of clinically significant ECG abnormalities (myocardial ischemia,
ventricular hypertrophy, clinically significant conduction abnormalities,
clinically significant arrhythmias) was lower for subjects who received
salmeterol (1%, 9 of 688 subjects who received either salmeterol 50 mcg or
ADVAIR DISKUS) compared with placebo (3%, 10 of 370 subjects).

No significant differences with salmeterol 50 mcg alone
or in combination with fluticasone propionate as ADVAIR DISKUS 500/50 were
observed on pulse rate and systolic and diastolic blood pressure in a subset of
subjects with COPD who underwent 12-hour serial vital sign measurements after
the first dose (n = 183) and after 12 weeks of therapy (n = 149). Median changes
from baseline in pulse rate and systolic and diastolic blood pressure were
similar to those seen with placebo.

Hypothalamic-Pituitary-Adrenal Axis Effects: Short-cosyntropin stimulation testing was performed both
at Day 1 and Endpoint in 101 subjects with COPD receiving twice-daily ADVAIR
DISKUS 250/50, fluticasone propionate powder 250 mcg, salmeterol powder 50 mcg,
or placebo. For most subjects, the ability to increase cortisol production in
response to stress, as assessed by short cosyntropin stimulation, remained
intact with ADVAIR DISKUS 250/50. One (1) subject (3%) who received ADVAIR
DISKUS 250/50 had an abnormal stimulated cortisol response (peak cortisol less
than 14.5 mcg/dL assessed by high-performance liquid chromatography) after
dosing, compared with 2 subjects (9%) who received fluticasone propionate 250
mcg, 2 subjects (7%) who received salmeterol 50 mcg, and 1 subject (4%) who
received placebo following 24 weeks of treatment or early discontinuation from
trial.

After 36 weeks of dosing, serum cortisol concentrations
in a subset of subjects with COPD (n = 83) were 22% lower in subjects receiving
ADVAIR DISKUS 500/50 and 21% lower in subjects receiving fluticasone propionate
500 mcg than in subjects receiving placebo.

Other Fluticasone Propionate Products

Subjects with Asthma: Hypothalamic-Pituitary-Adrenal
Axis Effects
:
In clinical trials with fluticasone propionate inhalation
powder using dosages up to and including 250 mcg twice daily, occasional
abnormal short cosyntropin tests (peak serum cortisol less than 18 mcg/dL
assessed by radioimmunoassay) were noted both in subjects receiving fluticasone
propionate and in subjects receiving placebo. The incidence of abnormal tests
at 500 mcg twice daily was greater than placebo. In a 2-year trial carried out
with the DISKHALER® inhalation device in 64 subjects with mild, persistent
asthma (mean FEV1 91% of predicted) randomized to fluticasone propionate 500
mcg twice daily or placebo, no subject receiving fluticasone propionate had an
abnormal response to 6-hour cosyntropin infusion (peak serum cortisol less than
18 mcg/dL). With a peak cortisol threshold of less than 35 mcg/dL, 1 subject
receiving fluticasone propionate (4%) had an abnormal response at 1 year;
repeat testing at 18 months and 2 years was normal. Another subject receiving
fluticasone propionate (5%) had an abnormal response at 2 years. No subject on
placebo had an abnormal response at 1 or 2 years.

Subjects with Chronic Obstructive Pulmonary Disease:
Hypothalamic-Pituitary-Adrenal Axis Effects
:
After 4 weeks of dosing, the
steady-state fluticasone propionate pharmacokinetics and serum cortisol levels
were described in a subset of subjects with COPD (n = 86) randomized to
twice-daily fluticasone propionate inhalation powder via the DISKUS 500 mcg,
fluticasone propionate inhalation powder 250 mcg, or placebo. Serial serum
cortisol concentrations were measured across a 12-hour dosing interval. Serum
cortisol concentrations following 250-and 500-mcg twice-daily dosing were 10%
and 21% lower than placebo, respectively, indicating a dose-dependent increase
in systemic exposure to fluticasone propionate.

Other Salmeterol Xinafoate Products

Subjects with Asthma: Cardiovascular Effects: Inhaled
salmeterol, like other beta-adrenergic agonist drugs, can produce dose-related
cardiovascular effects and effects on blood glucose and/or serum potassium [see
WARNINGS AND PRECAUTIONS]. The cardiovascular effects (heart rate, blood
pressure) associated with salmeterol inhalation aerosol occur with similar
frequency, and are of similar type and severity, as those noted following
albuterol administration.

The effects of rising inhaled doses of salmeterol and
standard inhaled doses of albuterol were studied in volunteers and in subjects
with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol
resulted in heart rate increases of 3 to 16 beats/min, about the same as
albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). Adult and
adolescent subjects receiving 50-mcg doses of salmeterol inhalation powder (N =
60) underwent continuous electrocardiographic monitoring during two 12-hour
periods after the first dose and after 1 month of therapy, and no clinically
significant dysrhythmias were noted.

Concomitant Use Of ADVAIR DISKUS With Other Respiratory
Medications

Short-Acting Beta2-Agonists: In clinical trials in
subjects with asthma, the mean daily need for albuterol by 166 adult and
adolescent subjects aged 12 years and older using ADVAIR DISKUS was
approximately 1.3 inhalations/day and ranged from 0 to 9 inhalations/day. Five
percent (5%) of subjects using ADVAIR DISKUS in these trials averaged 6 or more
inhalations per day over the course of the 12-week trials. No increase in
frequency of cardiovascular adverse events was observed among subjects who
averaged 6 or more inhalations per day.

In a clinical trial in subjects with COPD, the mean daily
need for albuterol for subjects using ADVAIR DISKUS 250/50 was 4.1
inhalations/day. Twenty-six percent (26%) of subjects using ADVAIR DISKUS
250/50 averaged 6 or more inhalations of albuterol per day over the course of
the 24-week trial. No increase in frequency of cardiovascular adverse reactions
was observed among subjects who averaged 6 or more inhalations per day.

Methylxanthines: The concurrent use of intravenously or
orally administered methylxanthines (e.g., aminophylline, theophylline) by
adult and adolescent subjects aged 12 years and older receiving ADVAIR DISKUS
has not been completely evaluated. In clinical trials in subjects with asthma,
39 subjects receiving ADVAIR DISKUS 100/50, ADVAIR DISKUS 250/50, or ADVAIR
DISKUS 500/50 twice daily concurrently with a theophylline product had adverse
event rates similar to those in 304 subjects receiving ADVAIR DISKUS without
theophylline. Similar results were observed in subjects receiving salmeterol 50
mcg plus fluticasone propionate 500 mcg twice daily concurrently with a
theophylline product (n = 39) or without theophylline (n = 132).

In a clinical trial in subjects with COPD, 17 subjects
receiving ADVAIR DISKUS 250/50 twice daily concurrently with a theophylline
product had adverse event rates similar to those in 161 subjects receiving
ADVAIR DISKUS without theophylline. Based on the available data, the
concomitant administration of methylxanthines with ADVAIR DISKUS did not alter
the observed adverse event profile.

Fluticasone Propionate Nasal Spray: In adult and
adolescent subjects aged 12 years and older taking ADVAIR DISKUS in clinical
trials, no difference in the profile of adverse events or HPA axis effects was
noted between subjects who were taking FLONASE® (fluticasone propionate) Nasal
Spray, 50 mcg concurrently (n = 46) and those who were not (n = 130).

Pharmacokinetics

Absorption

Fluticasone Propionate: Healthy Subjects: Fluticasone
propionate acts locally in the lung; therefore, plasma levels do not predict
therapeutic effect. Trials using oral dosing of labeled and unlabeled drug have
demonstrated that the oral systemic bioavailability of fluticasone propionate
is negligible (less than 1%), primarily due to incomplete absorption and
presystemic metabolism in the gut and liver. In contrast, the majority of the
fluticasone propionate delivered to the lung is systemically absorbed.

Following administration of ADVAIR DISKUS to healthy
adult subjects, peak plasma concentrations of fluticasone propionate were
achieved in 1 to 2 hours. In a single-dose crossover trial, a
higher-than-recommended dose of ADVAIR DISKUS was administered to 14 healthy
adult subjects. Two (2) inhalations of the following treatments were
administered: ADVAIR DISKUS 500/50, fluticasone propionate powder 500 mcg and
salmeterol powder 50 mcg given concurrently, and fluticasone propionate powder
500 mcg alone. Mean peak plasma concentrations of fluticasone propionate
averaged 107, 94, and 120 pg/mL, respectively, indicating no significant
changes in systemic exposures of fluticasone propionate.

In 15 healthy subjects, systemic exposure to fluticasone
propionate from 4 inhalations of ADVAIR® HFA 230/21 (fluticasone propionate 230
mcg and salmeterol 21 mcg) Inhalation Aerosol (920/84 mcg) and 2 inhalations of
ADVAIR DISKUS 500/50 (1,000/100 mcg) were similar between the 2 inhalers (i.e.,
799 versus 832 pg•h/mL, respectively), but approximately half the systemic
exposure from 4 inhalations of fluticasone propionate CFC inhalation aerosol
220 mcg (880 mcg, AUC = 1,543 pg•h/mL). Similar results were observed for peak
fluticasone propionate plasma concentrations (186 and 182 pg/mL from ADVAIR HFA
and ADVAIR DISKUS, respectively, and 307 pg/mL from the fluticasone propionate
CFC inhalation aerosol). Absolute bioavailability of fluticasone propionate was
5.3% and 5.5% following administration of ADVAIR HFA and ADVAIR DISKUS,
respectively.

Subjects with Asthma and COPD: Peak steady-state
fluticasone propionate plasma concentrations in adult subjects with asthma (N =
11) ranged from undetectable to 266 pg/mL after a 500-mcg twice-daily dose of
fluticasone propionate inhalation powder using the DISKUS inhaler. The mean
fluticasone propionate plasma concentration was 110 pg/mL.

Full pharmacokinetic profiles were obtained from 9 female
and 16 male subjects with asthma given fluticasone propionate inhalation powder
500 mcg twice daily using the DISKUS inhaler and from 14 female and 43 male
subjects with COPD given 250 or 500 mcg twice daily. No overall differences in
fluticasone propionate pharmacokinetics were observed.

Peak steady-state fluticasone propionate plasma
concentrations in subjects with COPD averaged 53 pg/mL (range: 19.3 to 159.3
pg/mL) after treatment with 250 mcg twice daily (n = 30) and 84 pg/mL (range:
24.3 to 197.1 pg/mL) after treatment with 500 mcg twice daily (n = 27) via the
fluticasone propionate DISKUS inhaler. In another trial in subjects with COPD,
peak steady-state fluticasone propionate plasma concentrations averaged 115
pg/mL (range: 52.6 to 366.0 pg/mL) after treatment with 500 mcg twice daily via
the fluticasone propionate DISKUS inhaler (n = 15) and 105 pg/mL (range: 22.5
to 299.0 pg/mL) via ADVAIR DISKUS (n = 24).

Salmeterol Xinafoate: Healthy Subjects: Salmeterol
xinafoate, an ionic salt, dissociates in solution so that the salmeterol and
1-hydroxy-2-naphthoic acid (xinafoate) moieties are absorbed, distributed,
metabolized, and eliminated independently. Salmeterol acts locally in the lung;
therefore, plasma levels do not predict therapeutic effect.

Following administration of ADVAIR DISKUS to healthy
adult subjects, peak plasma concentrations of salmeterol were achieved in about
5 minutes.

In 15 healthy subjects receiving ADVAIR HFA 230/21
Inhalation Aerosol (920/84 mcg) and ADVAIR DISKUS 500/50 (1,000/100 mcg),
systemic exposure to salmeterol was higher (317 versus 169 pg•h/mL) and peak
salmeterol concentrations were lower (196 versus 223 pg/mL) following ADVAIR
HFA compared with ADVAIR DISKUS, although pharmacodynamic results were
comparable.

Subjects with Asthma: Because of the small
therapeutic dose, systemic levels of salmeterol are low or undetectable after
inhalation of recommended doses (50 mcg of salmeterol inhalation powder twice
daily). Following chronic administration of an inhaled dose of 50 mcg of
salmeterol inhalation powder twice daily, salmeterol was detected in plasma
within 5 to 45 minutes in 7 subjects with asthma; plasma concentrations were
very low, with mean peak concentrations of 167 pg/mL at 20 minutes and no
accumulation with repeated doses.

Distribution

Fluticasone Propionate: Following intravenous
administration, the initial disposition phase for fluticasone propionate was
rapid and consistent with its high lipid solubility and tissue binding. The
volume of distribution averaged 4.2 L/kg.

The percentage of fluticasone propionate bound to human
plasma proteins averages 99%. Fluticasone propionate is weakly and reversibly
bound to erythrocytes and is not significantly bound to human transcortin.

Salmeterol: The percentage of salmeterol bound to
human plasma proteins averages 96% in vitro over the concentration range of 8 to
7,722 ng of salmeterol base per milliliter, much higher concentrations than
those achieved following therapeutic doses of salmeterol.

Metabolism

Fluticasone Propionate: The total clearance of
fluticasone propionate is high (average, 1,093 mL/min), with renal clearance
accounting for less than 0.02% of the total. The only circulating metabolite
detected in man is the 17β-carboxylic acid derivative of fluticasone propionate,
which is formed through the CYP3A4 pathway. This metabolite had less affinity
(approximately 1/2,000) than the parent drug for the glucocorticoid receptor of
human lung cytosol in vitro and negligible pharmacological activity in animal
studies. Other metabolites detected in vitro using cultured human hepatoma
cells have not been detected in man.

Salmeterol: Salmeterol base is extensively
metabolized by hydroxylation, with subsequent elimination predominantly in the
feces. No significant amount of unchanged salmeterol base was detected in
either urine or feces.

An in vitro study using human liver microsomes showed
that salmeterol is extensively metabolized to α-hydroxysalmeterol
(aliphatic oxidation) by CYP3A4. Ketoconazole, a strong inhibitor of CYP3A4, essentially
completely inhibited the formation of α-hydroxysalmeterol in vitro.

Elimination

Fluticasone Propionate: Following intravenous
dosing, fluticasone propionate showed polyexponential kinetics and had a
terminal elimination half-life of approximately 7.8 hours. Less than 5% of a
radiolabeled oral dose was excreted in the urine as metabolites, with the
remainder excreted in the feces as parent drug and metabolites. Terminal
half-life estimates of fluticasone propionate for ADVAIR HFA, ADVAIR DISKUS,
and fluticasone propionate CFC inhalation aerosol were similar and averaged 5.6
hours.

Salmeterol: In 2 healthy adult subjects who
received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally,
approximately 25% and 60% of the radiolabeled salmeterol was eliminated in
urine and feces, respectively, over a period of 7 days. The terminal
elimination half-life was about 5.5 hours (1 volunteer only).

The xinafoate moiety has no apparent pharmacologic
activity. The xinafoate moiety is highly protein bound (greater than 99%) and
has a long elimination half-life of 11 days. No terminal half-life estimates
were calculated for salmeterol following administration of ADVAIR DISKUS.

Special Populations

A population pharmacokinetic analysis was performed for
fluticasone propionate and salmeterol utilizing data from 9 controlled clinical
trials that included 350 subjects with asthma aged 4 to 77 years who received
treatment with ADVAIR DISKUS, the combination of HFA-propelled fluticasone
propionate and salmeterol inhalation aerosol (ADVAIR HFA), fluticasone
propionate inhalation powder (FLOVENT DISKUS), HFA-propelled fluticasone propionate
inhalation aerosol (FLOVENT® HFA), or CFC-propelled fluticasone
propionate inhalation aerosol. The population pharmacokinetic analyses for
fluticasone propionate and salmeterol showed no clinically relevant effects of
age, gender, race, body weight, body mass index, or percent of predicted FEV1 on
apparent clearance and apparent volume of distribution.

Age: When the population pharmacokinetic analysis
for fluticasone propionate was divided into subgroups based on fluticasone
propionate strength, formulation, and age (adolescents/adults and children),
there were some differences in fluticasone propionate exposure. Higher
fluticasone propionate exposure from ADVAIR DISKUS 100/50 compared with FLOVENT
DISKUS 100 mcg was observed in adolescents and adults (ratio 1.52 [90% CI:
1.08, 2.13]). However, in clinical trials of up to 12 weeks’ duration comparing
ADVAIR DISKUS 100/50 and FLOVENT DISKUS 100 mcg in adolescents and adults, no
differences in systemic effects of corticosteroid treatment (e.g., HPA axis
effects) were observed. Similar fluticasone propionate exposure was observed
from ADVAIR DISKUS 500/50 and FLOVENT DISKUS 500 mcg (ratio 0.83 [90% CI: 0.65,
1.07]) in adolescents and adults.

Steady-state systemic exposure to salmeterol when
delivered as ADVAIR DISKUS 100/50, ADVAIR DISKUS 250/50, or ADVAIR HFA 115/21
(fluticasone propionate 115 mcg and salmeterol 21 mcg) Inhalation Aerosol was
evaluated in 127 subjects aged 4 to 57 years. The geometric mean AUC was 325
pg•h/mL (90% CI: 309, 341) in adolescents and adults.

The population pharmacokinetic analysis included 160
subjects with asthma aged 4 to 11 years who received ADVAIR DISKUS 100/50 or
FLOVENT DISKUS 100 mcg. Higher fluticasone propionate exposure (AUC) was
observed in children from ADVAIR DISKUS 100/50 compared with FLOVENT DISKUS 100
mcg (ratio 1.20 [90% CI: 1.06, 1.37]). Higher fluticasone propionate exposure
(AUC) from ADVAIR DISKUS 100/50 was observed in children compared with
adolescents and adults (ratio 1.63 [90% CI: 1.35, 1.96]). However, in clinical
trials of up to 12 weeks’ duration comparing ADVAIR DISKUS 100/50 and FLOVENT
DISKUS 100 mcg in both adolescents and adults and in children, no differences
in systemic effects of corticosteroid treatment (e.g., HPA axis effects) were
observed.

Exposure to salmeterol was higher in children compared
with adolescents and adults who received ADVAIR DISKUS 100/50 (ratio 1.23 [90%
CI: 1.10, 1.38]). However, in clinical trials of up to 12 weeks’ duration with
ADVAIR DISKUS 100/50 in both adolescents and adults and in children, no
differences in systemic effects of beta2-agonist treatment (e.g.,
cardiovascular effects, tremor) were observed.

Gender: The population pharmacokinetic analysis
involved 202 males and 148 females with asthma who received fluticasone
propionate alone or in combination with salmeterol and showed no gender
differences for fluticasone propionate pharmacokinetics.

The population pharmacokinetic analysis involved 76 males
and 51 females with asthma who received salmeterol in combination with
fluticasone propionate and showed no gender differences for salmeterol
pharmacokinetics.

Hepatic and Renal Impairment: Formal
pharmacokinetic studies using ADVAIR DISKUS have not been conducted in patients
with hepatic or renal impairment. However, since both fluticasone propionate
and salmeterol are predominantly cleared by hepatic metabolism, impairment of
liver function may lead to accumulation of fluticasone propionate and salmeterol
in plasma. Therefore, patients with hepatic disease should be closely
monitored.

Drug Interactions

In the repeat-and single-dose trials, there was no
evidence of significant drug interaction in systemic exposure between
fluticasone propionate and salmeterol when given alone or in combination via
the DISKUS. The population pharmacokinetic analysis from 9 controlled clinical
trials in 350 subjects with asthma showed no significant effects on fluticasone
propionate or salmeterol pharmacokinetics following co-administration with beta2-agonists,
corticosteroids, antihistamines, or theophyllines.

Inhibitors of Cytochrome P450 3A4: Ritonavir:
Fluticasone Propionate: Fluticasone propionate is a substrate of CYP3A4.
Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor
ritonavir is not recommended based upon a multiple-dose, crossover drug
interaction trial in 18 healthy subjects. Fluticasone propionate aqueous nasal
spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg
twice daily). Plasma fluticasone propionate concentrations following
fluticasone propionate aqueous nasal spray alone were undetectable (less than
10 pg/mL) in most subjects, and when concentrations were detectable peak levels
(Cmax) averaged 11.9 pg/mL (range: 10.8 to 14.1 pg/mL) and AUC(0-τ) averaged
8.43 pg•h/mL (range: 4.2 to 18.8 pg•h/mL). Fluticasone propionate Cmax and AUC(0-τ)
increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg•h/mL (range:
1,207.1 to 5,662.0 pg•h/mL), respectively, after coadministration of ritonavir
with fluticasone propionate aqueous nasal spray. This significant increase in
plasma fluticasone propionate exposure resulted in a significant decrease (86%)
in serum cortisol AUC.

Ketoconazole: Fluticasone Propionate: In a
placebo-controlled crossover trial in 8 healthy adult volunteers,
coadministration of a single dose of orally inhaled fluticasone propionate
(1,000 mcg) with multiple doses of ketoconazole (200 mg) to steady state
resulted in increased plasma fluticasone propionate exposure, a reduction in
plasma cortisol AUC, and no effect on urinary excretion of cortisol.

Salmeterol: In a placebo-controlled, crossover
drug interaction trial in 20 healthy male and female subjects, coadministration
of salmeterol (50 mcg twice daily) and the strong CYP3A4 inhibitor ketoconazole
(400 mg once daily) for 7 days resulted in a significant increase in plasma
salmeterol exposure as determined by a 16-fold increase in AUC (ratio with and
without ketoconazole 15.76 [90% CI: 10.66, 23.31]) mainly due to increased
bioavailability of the swallowed portion of the dose. Peak plasma salmeterol
concentrations were increased by 1.4-fold (90% CI: 1.23, 1.68). Three (3) out
of 20 subjects (15%) were withdrawn from salmeterol and ketoconazole
coadministration due to beta-agonist–mediated systemic effects (2 with QTc prolongation
and 1 with palpitations and sinus tachycardia). Coadministration of salmeterol
and ketoconazole did not result in a clinically significant effect on mean
heart rate, mean blood potassium, or mean blood glucose. Although there was no
statistical effect on the mean QTc, coadministration of salmeterol and
ketoconazole was associated with more frequent increases in QTc duration
compared with salmeterol and placebo administration.

Erythromycin: Fluticasone Propionate: In a
multiple-dose drug interaction trial, coadministration of orally inhaled
fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times
daily) did not affect fluticasone propionate pharmacokinetics.

Salmeterol: In a repeat-dose trial in 13 healthy
subjects, concomitant administration of erythromycin (a moderate CYP3A4
inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase in
salmeterol Cmax at steady state (ratio with and without erythromycin 1.4 [90% CI:
0.96, 2.03], P = 0.12), a 3.6-beat/min increase in heart rate ([95% CI: 0.19,
7.03], P < 0.04), a 5.8-msec increase in QTc interval ([95% CI: -6.14, 17.77],
P = 0.34), and no change in plasma potassium.

Animal Toxicology And/Or Pharmacology

Preclinical

Studies in laboratory animals (minipigs, rodents, and
dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death
(with histologic evidence of myocardial necrosis) when beta-agonists and
methylxanthines are administered concurrently. The clinical relevance of these
findings is unknown.

Clinical Studies

Asthma

Adult And Adolescent Subjects Aged 12 Years And Older

In clinical trials comparing ADVAIR DISKUS with its
individual components, improvements in most efficacy endpoints were greater
with ADVAIR DISKUS than with the use of either fluticasone propionate or
salmeterol alone. In addition, clinical trials showed similar results between
ADVAIR DISKUS and the concurrent use of fluticasone propionate plus salmeterol
at corresponding doses from separate inhalers.

Trials Comparing ADVAIR DISKUS with Fluticasone
Propionate Alone or Salmeterol Alone
:
Three (3) double-blind,
parallel-group clinical trials were conducted with ADVAIR DISKUS in 1,208 adult
and adolescent subjects (aged 12 years and older, baseline FEV1 63% to 72% of
predicted normal) with asthma that was not optimally controlled on their
current therapy. All treatments were inhalation powders given as 1 inhalation
from the DISKUS inhaler twice daily, and other maintenance therapies were
discontinued.

Trial 1: Clinical Trial with ADVAIR DISKUS 100/50:
This placebo-controlled, 12-week, U.S. trial compared ADVAIR DISKUS 100/50 with
its individual components, fluticasone propionate 100 mcg and salmeterol 50
mcg. The trial was stratified according to baseline asthma maintenance therapy;
subjects were using either inhaled corticosteroids (n = 250) (daily doses of
beclomethasone dipropionate 252 to 420 mcg; flunisolide 1,000 mcg; fluticasone
propionate inhalation aerosol 176 mcg; or triamcinolone acetonide 600 to 1,000
mcg) or salmeterol  (n = 106). Baseline FEV1 measurements were similar across
treatments: ADVAIR DISKUS 100/50, 2.17 L; fluticasone propionate 100 mcg, 2.11
L; salmeterol, 2.13 L; and placebo, 2.15 L.

Predefined withdrawal criteria for lack of efficacy, an
indicator of worsening asthma, were utilized for this placebo-controlled trial.
Worsening asthma was defined as a clinically important decrease in FEV1 or PEF,
increase in use of VENTOLIN® (albuterol, USP) Inhalation Aerosol, increase in
night awakenings due to asthma, emergency intervention or hospitalization due
to asthma, or requirement for asthma medication not allowed by the protocol. As
shown in Table 4, statistically significantly fewer subjects receiving ADVAIR
DISKUS 100/50 were withdrawn due to worsening asthma compared with fluticasone
propionate, salmeterol, and placebo.

Table 4: Percent of Subjects Withdrawn Due to Worsening
Asthma in Subjects Previously Treated with Either Inhaled Corticosteroids or
Salmeterol (Trial 1)



ADVAIR DISKUS 100/50

(n = 87)
Fluticasone Propionate 100 mcg

(n = 85)
Salmeterol 50 mcg

(n = 86)
Placebo

(n = 77)
3% 11% 35% 49%

The FEV1 results are displayed
in Figure 2. Because this trial used predetermined criteria for worsening
asthma, which caused more subjects in the placebo group to be withdrawn, FEV1 results
at Endpoint (last available FEV1 result) are also provided. Subjects receiving
ADVAIR DISKUS 100/50 had significantly greater improvements in FEV1 (0.51 L,
25%) compared with fluticasone propionate 100 mcg (0.28 L, 15%), salmeterol
(0.11 L, 5%), and placebo (0.01 L, 1%). These improvements in FEV1 with ADVAIR
DISKUS were achieved regardless of baseline asthma maintenance therapy (inhaled
corticosteroids or salmeterol).

Figure 2: Mean Percent Change from Baseline in FEV1 in
Subjects with Asthma Previously Treated with Either Inhaled Corticosteroids or
Salmeterol (Trial 1)


The effect of ADVAIR DISKUS
100/50 on morning and evening PEF endpoints is shown in Table 5.

Table 5: Peak Expiratory
Flow Results for Subjects with Asthma Previously Treated with Either Inhaled
Corticosteroids or Salmeterol (Trial 1)









Efficacy Variablea ADVAIR DISKUS 100/50

(n = 87)
Fluticasone Propionate 100 mcg

(n = 85)
Salmeterol 50 mcg

(n = 86)
Placebo (n = 77)
AM PEF (L/min)
  Baseline 393 374 369 382
  Change from baseline 53 17 -2 -24
PM PEF (L/min)
  Baseline 418 390 396 398
  Change from baseline 35 18 -7 -13
a Change from baseline = change from baseline
at Endpoint (last available data).

The subjective impact of asthma
on subjects’ perception of health was evaluated through use of an instrument
called the Asthma Quality of Life Questionnaire (AQLQ) (based on a 7-point
scale where 1 = maximum impairment and 7 = none). Subjects receiving ADVAIR
DISKUS 100/50 had clinically meaningful improvements in overall asthma-specific
quality of life as defined by a difference between groups of ≥ 0.5 points
in change from baseline AQLQ scores (difference in AQLQ score of 1.25 compared
with placebo).

Trial 2: Clinical Trial with
ADVAIR DISKUS 250/50
:
This placebo-controlled, 12-week, U.S. trial compared
ADVAIR DISKUS 250/50 with its individual components, fluticasone propionate 250
mcg and salmeterol 50 mcg, in 349 subjects with asthma using inhaled
corticosteroids (daily doses of beclomethasone dipropionate 462 to 672 mcg;
flunisolide 1,250 to 2,000 mcg; fluticasone propionate inhalation aerosol 440
mcg; or triamcinolone acetonide 1,100 to 1,600 mcg). Baseline FEV1 measurements
were similar across treatments: ADVAIR DISKUS 250/50, 2.23 L; fluticasone
propionate 250 mcg, 2.12 L; salmeterol, 2.20 L; and placebo, 2.19 L.

Efficacy results in this trial
were similar to those observed in Trial 1. Subjects receiving ADVAIR DISKUS
250/50 had significantly greater improvements in FEV1 (0.48 L, 23%) compared
with fluticasone propionate 250 mcg (0.25 L, 13%), salmeterol (0.05 L, 4%), and
placebo (decrease of 0.11 L, decrease of 5%). Statistically significantly fewer
subjects receiving ADVAIR DISKUS 250/50 were withdrawn from this trial for
worsening asthma (4%) compared with fluticasone propionate (22%), salmeterol
(38%), and placebo (62%). In addition, ADVAIR DISKUS 250/50 was superior to
fluticasone propionate, salmeterol, and placebo for improvements in morning and
evening PEF. Subjects receiving ADVAIR DISKUS 250/50 also had clinically
meaningful improvements in overall asthma-specific quality of life as described
in Trial 1 (difference in AQLQ score of 1.29 compared with placebo).

Trial 3: Clinical Trial with
ADVAIR DISKUS 500/50:
This 28-week, non-U.S. trial compared ADVAIR DISKUS 500/50
with fluticasone propionate 500 mcg alone and concurrent therapy (salmeterol 50
mcg plus fluticasone propionate 500 mcg administered from separate inhalers)
twice daily in 503 subjects with asthma using inhaled corticosteroids (daily
doses of beclomethasone dipropionate 1,260 to 1,680 mcg; budesonide 1,500 to
2,000 mcg; flunisolide 1,500 to 2,000 mcg; or fluticasone propionate inhalation
aerosol 660 to 880 mcg [750 to 1,000 mcg inhalation powder]). The primary
efficacy parameter, morning PEF, was collected daily for the first 12 weeks of
the trial. The primary purpose of weeks 13 to 28 was to collect safety data.

Baseline PEF measurements were
similar across treatments: ADVAIR DISKUS 500/50, 359 L/min; fluticasone
propionate 500 mcg, 351 L/min; and concurrent therapy, 345 L/min. Morning PEF
improved significantly with ADVAIR DISKUS 500/50 compared with fluticasone
propionate 500 mcg over the 12-week treatment period. Improvements in morning
PEF observed with ADVAIR DISKUS 500/50 were similar to improvements observed
with concurrent therapy.

Onset of Action and Progression of Improvement in
Asthma Control
:
The onset of action and progression of improvement in
asthma control were evaluated in the 2 placebo-controlled U.S. trials.
Following the first dose, the median time to onset of clinically significant
bronchodilatation (greater than or equal to 15% improvement in FEV1) in most
subjects was seen within 30 to 60 minutes. Maximum improvement in FEV1 generally
occurred within 3 hours, and clinically significant improvement was maintained
for 12 hours (Figure 3). Following the initial dose, predose FEV1 relative to
Day 1 baseline improved markedly over the first week of treatment and continued
to improve over the 12 weeks of treatment in both trials. No diminution in the
12-hour bronchodilator effect was observed with either ADVAIR DISKUS 100/50
(Figures 3 and 4) or ADVAIR DISKUS 250/50 as assessed by FEV1 following 12
weeks of therapy.

Figure 3: Percent Change in Serial 12-Hour FEV1 in
Subjects with Asthma Previously Using Either Inhaled Corticosteroids or
Salmeterol (Trial 1)


Percent Change in Serial 12-Hour FEV1 in Subjects with Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol - Illustration

Figure 4: Percent Change in
Serial 12-Hour FEV1 in Subjects with Asthma Previously Using Either Inhaled
Corticosteroids or Salmeterol (Trial 1)


Percent Change in Serial 12-Hour FEV1 in Subjects with Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol - Illustration

Reduction in asthma symptoms
and use of rescue VENTOLIN Inhalation Aerosol and improvement in morning and
evening PEF also occurred within the first day of treatment with ADVAIR DISKUS,
and continued to improve over the 12 weeks of therapy in both trials.

Pediatric Subjects

In a 12-week U.S. trial, ADVAIR
DISKUS 100/50 twice daily was compared with fluticasone propionate inhalation
powder 100 mcg twice daily in 203 children with asthma aged 4 to 11 years. At
trial entry, the children were symptomatic on low doses of inhaled
corticosteroids (beclomethasone dipropionate 252 to 336 mcg/day; budesonide 200
to 400 mcg/day; flunisolide 1,000 mcg/day; triamcinolone acetonide 600 to 1,000
mcg/day; or fluticasone propionate 88 to 250 mcg/day). The primary
objective of this trial was to determine the safety of ADVAIR DISKUS 100/50
compared with fluticasone propionate inhalation powder 100 mcg in this
age-group; however, the trial also included secondary efficacy measures of
pulmonary function. Morning predose FEV1 was obtained at baseline and Endpoint
(last available FEV1 result) in children aged 6 to 11 years. In subjects
receiving ADVAIR DISKUS 100/50, FEV1 increased from 1.70 L at baseline (n = 79)
to 1.88 L at Endpoint (n = 69) compared with an increase from 1.65 L at
baseline (n = 83) to 1.77 L at Endpoint (n = 75) in subjects receiving
fluticasone propionate 100 mcg.

The findings of this trial, along with extrapolation of
efficacy data from subjects aged 12 years and older, support the overall
conclusion that ADVAIR DISKUS 100/50 is efficacious in the treatment of asthma
in subjects aged 4 to 11 years.

Chronic Obstructive Pulmonary Disease

The efficacy of ADVAIR DISKUS 250/50 and ADVAIR DISKUS
500/50 in the treatment of subjects with COPD was evaluated in 6 randomized,
double-blind, parallel-group clinical trials in adult subjects aged 40 years
and older. These trials were primarily designed to evaluate the efficacy of
ADVAIR DISKUS on lung function (3 trials), exacerbations (2 trials), and
survival (1 trial).

Lung Function

Two of the 3 clinical trials primarily designed to
evaluate the efficacy of ADVAIR DISKUS on lung function were conducted in 1,414
subjects with COPD associated with chronic bronchitis. In these 2 trials, all
the subjects had a history of cough productive of sputum that was not
attributable to another disease process on most days for at least 3 months of
the year for at least 2 years. The trials were randomized, double-blind,
parallel-group, 24-week treatment duration. One trial evaluated the efficacy of
ADVAIR DISKUS 250/50 compared with its components fluticasone propionate 250
mcg and salmeterol 50 mcg and with placebo, and the other trial evaluated the
efficacy of ADVAIR DISKUS 500/50 compared with its components fluticasone
propionate 500 mcg and salmeterol 50 mcg and with placebo. Trial treatments
were inhalation powders given as 1 inhalation from the DISKUS inhaler twice
daily. Maintenance COPD therapies were discontinued, with the exception of
theophylline. The subjects had a mean pre-bronchodilator FEV1 of 41% and 20%
reversibility at trial entry. Percent reversibility was calculated as 100 times
(FEV1 post-albuterol minus FEV1 pre-albuterol)/FEV1 pre-albuterol.

Improvements in lung function (as defined by predose and
postdose FEV1) were significantly greater with ADVAIR DISKUS than with
fluticasone propionate, salmeterol, or placebo. The improvement in lung
function with ADVAIR DISKUS 500/50 was similar to the improvement seen with
ADVAIR DISKUS 250/50.

Figures 5 and 6 display predose and 2-hour postdose,
respectively, FEV1 results for the trial with ADVAIR DISKUS 250/50. To account
for subject withdrawals during the trial, FEV1 at Endpoint (last evaluable FEV1)
was evaluated. Subjects receiving ADVAIR DISKUS 250/50 had significantly
greater improvements in predose FEV1 at Endpoint (165 mL, 17%) compared with
salmeterol 50 mcg (91 mL, 9%) and placebo (1 mL, 1%), demonstrating the
contribution of fluticasone propionate to the improvement in lung function with
ADVAIR DISKUS (Figure 5). Subjects receiving ADVAIR DISKUS 250/50 had
significantly greater improvements in postdose FEV1 at Endpoint (281 mL, 27%)
compared with fluticasone propionate 250 mcg (147 mL, 14%) and placebo (58 mL,
6%), demonstrating the contribution of salmeterol to the improvement in lung
function with ADVAIR DISKUS (Figure 6).

Figure 5: Predose FEV1: Mean Percent Change from
Baseline in Subjects with Chronic Obstructive Pulmonary Disease


Predose FEV1: Mean Percent Change from Baseline in Subjects with Chronic Obstructive Pulmonary Disease - Illustration

Figure 6: Two-Hour Postdose
FEV1: Mean Percent Changes from Baseline over Time in Subjects with Chronic
Obstructive Pulmonary Disease


Two-Hour Postdose FEV1: Mean Percent Changes from Baseline over Time in Subjects with Chronic Obstructive Pulmonary Disease - Illustration

The third trial was a 1-year
trial that evaluated ADVAIR DISKUS 500/50, fluticasone propionate 500 mcg,
salmeterol 50 mcg, and placebo in 1,465 subjects. The subjects had an
established history of COPD and exacerbations, a pre-bronchodilator FEV1 less
than 70% of predicted at trial entry, and 8.3% reversibility. The primary
endpoint was the comparison of pre-bronchodilator FEV1 in the groups receiving
ADVAIR DISKUS 500/50 or placebo. Subjects treated with ADVAIR DISKUS 500/50 had
greater improvements in FEV1 (113 mL, 10%) compared with fluticasone propionate
500 mcg (7 mL, 2%), salmeterol (15 mL, 2%), and placebo (-60 mL, -3%).

Exacerbations

Two trials were primarily
designed to evaluate the effect of ADVAIR DISKUS 250/50 on exacerbations. In
these 2 trials, exacerbations were defined as worsening of 2 or more major
symptoms (dyspnea, sputum volume, and sputum purulence) or worsening of any 1 major
symptom together with any 1 of the following minor symptoms: sore throat, colds
(nasal discharge and/or nasal congestion), fever without other cause, and
increased cough or wheeze for at least 2 consecutive days. COPD exacerbations
were considered of moderate severity if treatment with systemic corticosteroids
and/or antibiotics was required and were considered severe if hospitalization
was required.

Exacerbations were also evaluated as a secondary outcome
in the 1-and 3-year trials with ADVAIR DISKUS 500/50. There was not a
symptomatic definition of exacerbation in these 2 trials. Exacerbations were
defined in terms of severity requiring treatment with antibiotics and/or
systemic corticosteroids (moderately severe) or requiring hospitalization
(severe).

The 2 exacerbation trials with ADVAIR DISKUS 250/50 were
identical trials designed to evaluate the effect of ADVAIR DISKUS 250/50 and
salmeterol 50 mcg, each given twice daily, on exacerbations of COPD over a
12-month period. A total of 1,579 subjects had an established history of COPD
(but no other significant respiratory disorders). Subjects had a
pre-bronchodilator FEV1 of 33% of predicted, a mean reversibility of 23% at
baseline, and a history of greater than or equal to 1 COPD exacerbation in the
previous year that was moderate or severe. All subjects were treated with
ADVAIR DISKUS 250/50 twice daily during a 4-week run-in period prior to being
assigned trial treatment with twice-daily ADVAIR DISKUS 250/50 or salmeterol 50
mcg. In both trials, treatment with ADVAIR DISKUS 250/50 resulted in a
significantly lower annual rate of moderate/severe COPD exacerbations compared
with salmeterol (30.5% reduction [95% CI: 17.0, 41.8], P < 0.001) in the first
trial and (30.4% reduction [95% CI: 16.9, 41.7], P < 0.001) in the second
trial. Subjects treated with ADVAIR DISKUS 250/50 also had a significantly
lower annual rate of exacerbations requiring treatment with oral
corticosteroids compared with subjects treated with salmeterol (39.7% reduction
[95% CI: 22.8, 52.9], P < 0.001) in the first trial and (34.3% reduction [95%
CI: 18.6, 47.0], P < 0.001) in the second trial. Secondary endpoints including
pulmonary function and symptom scores improved more in subjects treated with
ADVAIR DISKUS 250/50 than with salmeterol 50 mcg in both trials.

Exacerbations were evaluated in the 1-and the 3-year
trials with ADVAIR DISKUS 500/50 as 1 of the secondary efficacy endpoints. In
the 1-year trial, the group receiving ADVAIR DISKUS 500/50 had a significantly
lower rate of moderate and severe exacerbations compared with placebo (25.4%
reduction compared with placebo [95% CI: 13.5, 35.7]) but not when compared
with its components (7.5% reduction compared with fluticasone propionate [95%
CI: -7.3, 20.3] and 7% reduction compared with salmeterol [95% CI: -8.0,
19.9]). In the 3-year trial, the group receiving ADVAIR DISKUS 500/50 had a
significantly lower rate of moderate and severe exacerbations compared with
each of the other treatment groups (25.1% reduction compared with placebo [95%
CI: 18.6, 31.1], 9.0% reduction compared with fluticasone propionate [95% CI:
1.2, 16.2], and 12.2% reduction compared with salmeterol [95% CI: 4.6, 19.2]).

There were no trials conducted to directly compare the
efficacy of ADVAIR DISKUS 250/50 with ADVAIR DISKUS 500/50 on exacerbations.
Across trials, the reduction in exacerbations seen with ADVAIR DISKUS 500/50
was not greater than the reduction in exacerbations seen with ADVAIR DISKUS
250/50.

Survival

A 3-year multicenter, international trial evaluated the
efficacy of ADVAIR DISKUS 500/50 compared with fluticasone propionate 500 mcg,
salmeterol 50 mcg, and placebo on survival in 6,112 subjects with COPD. During
the trial subjects were permitted usual COPD therapy with the exception of
other inhaled corticosteroids and long-acting bronchodilators. The subjects
were aged 40 to 80 years with an established history of COPD, a
pre-bronchodilator FEV1 less than 60% of predicted at trial entry, and less
than 10% of predicted reversibility. Each subject who withdrew from
double-blind treatment for any reason was followed for the full 3-year trial
period to determine survival status. The primary efficacy endpoint was
all-cause mortality. Survival with ADVAIR DISKUS 500/50 was not significantly
improved compared with placebo or the individual components (all-cause
mortality rate 12.6% ADVAIR DISKUS versus 15.2% placebo). The rates for
all-cause mortality were 13.5% and 16.0% in the groups treated with salmeterol 50
mcg and fluticasone propionate 500 mcg, respectively. Secondary outcomes,
including pulmonary function (post-bronchodilator FEV1), improved with ADVAIR
DISKUS 500/50, salmeterol 50 mcg, and fluticasone propionate 500 mcg compared
with placebo.

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