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Fluticasone Propionate;
Salmeterol Xinafoate
CATEGORIES:
DRUG CLASS: Adrenergic agonists;
Bronchodilators; Corticosteroids, inhalation
BRAND NAMES: Advair Diskus (US);
Seretide (Korea, Philippines, Thailand, South-Africa);
Seretide Accuhaler (Australia, Mexico);
(International brand names outside U.S. in italics)
COST OF THERAPY: $ 111.53 (Asthma; Advair
Diskus; 100 μg; 50 μg; 2 inhalations/day; 30 days)
DESCRIPTION:
Advair Diskus 100/50, Advair Diskus 250/50, and Advair
Diskus 500/50 are combinations of fluticasone propionate and salmeterol
xinafoate.
One active component of Advair Diskus is fluticasone propionate, a
corticosteroid having the chemical name S(fluoromethyl)
6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate,
17-propionate.
Fluticasone propionate is a white to off-white powder with a molecular weight
of 500.6, and the empirical formula is C25H31F3O5S.
It is practically insoluble in water, freely soluble in dimethyl sulfoxide and
dimethylformamide, and slightly soluble in methanol and 95% ethanol.
The other active component of Advair Diskus is salmeterol xinafoate, a
highly selective beta2-adrenergic bronchodilator. Salmeterol
xinafoate is the racemic form of the 1-hydroxy-2-naphthoic acid salt of
salmeterol. The chemical name of salmeterol xinafoate is 4-hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol,
1-hydroxy-2-naphthalenecarboxylate.
Salmeterol xinafoate is a white to off-white powder with a molecular weight
of 603.8, and the empirical formula is C25H37NO4·C11H8O3.
It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and
isopropanol; and sparingly soluble in water.
Advair Diskus 100/50, Advair Diskus 250/50, and Advair
Diskus 500/50 are specially designed plastic devices containing a double-foil
blister strip of a powder formulation of fluticasone propionate and salmeterol
xinafoate intended for oral inhalation only. Each blister on the double-foil
strip within the device contains 100, 250, or 500 μg of microfine fluticasone
propionate and 72.5 μg of microfine salmeterol xinafoate salt, equivalent to 50
μg of salmeterol base, in 12.5 mg of formulation containing lactose. Each
blister contains 1 complete dose of both medications. After a blister containing
medication is opened by activating the device, the medication is dispersed into
the airstream created by the patient inhaling through the mouthpiece.
Under standardized in vitro test conditions, Advair Diskus
delivers 93, 233, and 465 μg of fluticasone propionate and 45 μg of salmeterol
base per blister from Advair Diskus 100/50, 250/50, and 500/50,
respectively, when tested at a flow rate of 60 L/min for 2 seconds. In adult
patients (n=9) with obstructive lung disease and severely compromised lung
function (mean forced expiratory volume in 1 second [FEV1] 20-30% of
predicted), mean peak inspiratory flow (PIF) through a DISKUS device was 80.0
L/min (range, 46.1-115.3 L/min).
Inhalation profiles for adolescent (n=13, aged 12-17years) and adult (n=17,
aged 18-50 years) patients with asthma inhaling maximally through the DISKUS
device show mean PIF of 122.2 L/min (range, 81.6-152.1 L/min).
The actual amount of drug delivered to the lung will depend on patient
factors, such as inspiratory flow profile.
CLINICAL PHARMACOLOGY:
Mechanism of Action
Fluticasone Propionate; Salmeterol Xinafoate
Fluticasone propionate; salmeterol xinafoate is designed to produce a greater
improvement in pulmonary function and symptom control than either fluticasone
propionate or salmeterol used alone at their recommended dosages. These drugs
represent 2 classes of medications (a synthetic corticosteroid and a long-acting
beta-adrenergic receptor agonist) that have different effects on clinical,
physiological, and inflammatory indices of asthma.
Fluticasone Propionate
Fluticasone propionate is a synthetic, trifluorinated corticosteroid with
potent anti-inflammatory activity. In vitro assays using human lung
cytosol preparations have established fluticasone propionate as a human
glucocorticoid receptor agonist with an affinity 18 times greater than
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 precise mechanisms of fluticasone propionate action in asthma are
unknown. Inflammation is recognized as an important component in the
pathogenesis of asthma. Corticosteroids have been shown to inhibit multiple cell
types (e.g., mast cells, eosinophils, basophils, lymphocytes,
macrophages, and neutrophils) and mediator production or secretion (e.g.,
histamine, eicosanoids, leukotrienes, and cytokines) involved in the asthmatic
response. These anti-inflammatory actions of corticosteroids contribute to their
efficacy in asthma.
Salmeterol Xinafoate
Salmeterol is a long-acting beta-adrenergic agonist. In vitro studies
and in vivo pharmacologic studies demonstrate that salmeterol is
selective for beta2-adrenoceptors compared with isoproterenol, which
has approximately equal agonist activity on beta1- and beta2-adrenoceptors.
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 10-50% of the total beta-adrenoceptors. The
precise function of these receptors has not been established, but they raise the
possibility that even highly 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.
Pharmacokinetics
Fluticasone Propionate; Salmeterol Xinafoate
Following administration of fluticasone propionate; salmeterol xinafoate to
healthy subjects, peak plasma concentrations of fluticasone propionate were
achieved in 1-2 hours and those of salmeterol were achieved in about 5 minutes.
In a single-dose crossover study, a higher than recommended dose of
fluticasone propionate; salmeterol xinafoate was administered to 14 healthy
subjects. Two inhalations of the following treatments were administered:
fluticasone propionate; salmeterol xinafoate 500/50, fluticasone propionate
powder 500 μg and salmeterol powder 50 μg given concurrently, and fluticasone
propionate powder 500 μg alone. Mean peak plasma concentrations of fluticasone
propionate averaged 107, 94, and 120 pg/ml, respectively, and of salmeterol
averaged 200 and 150 pg/ml, respectively, indicating no significant changes in
systemic exposures of fluticasone propionate and salmeterol.
In a repeat-dose study, the highest recommended dose of Advair Diskus
was administered to 45 asthmatic patients. One inhalation twice daily of the
following treatments was administered: Advair Diskus 500/50, fluticasone
propionate powder 500 μg and salmeterol powder 50 μg given concurrently, or
fluticasone propionate powder 500 μg alone. Mean peak steady-state plasma
concentrations of fluticasone propionate averaged 57, 73, and 70 pg/ml,
respectively, indicating no significant changes in systemic exposure of
fluticasone propionate. No plasma concentrations of salmeterol were measured in
this repeat-dose study.
No significant changes in excretion of fluticasone propionate or salmeterol
were observed. The terminal half-life of fluticasone propionate averaged
5.33-7.65 hours when Advair Diskus was administered, which is similar to
that reported when fluticasone propionate was given concurrently with salmeterol
or when fluticasone propionate was given alone (average, 5.30-6.91 hours). No
terminal half-life of salmeterol was reported upon administration of Advair
Diskus or salmeterol given concurrently with fluticasone propionate.
Special Populations
Formal pharmacokinetic studies using fluticasone propionate; salmeterol
xinafoate were not conducted to examine gender differences or in special
populations, such as elderly patients or patients with hepatic or renal
impairment.
Drug-Drug Interactions
In the repeat- and single-dose studies, there was no evidence of significant
drug interaction in systemic exposure between fluticasone propionate and
salmeterol when given as Advair Diskus.
Fluticasone Propionate
Absorption
Fluticasone propionate acts locally in the lung; therefore, plasma levels do
not predict therapeutic effect. Studies using oral dosing of labeled and
unlabeled drug have demonstrated that the oral systemic bioavailability of
fluticasone propionate is negligible (<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. The systemic bioavailability of fluticasone propionate from the DISKUS
device in healthy volunteers averages 18%.
Peak steady-state fluticasone propionate plasma concentrations in adult
patients (n=11) ranged from undetectable to 266 pg/ml after a 500 μg twice-daily
dose of fluticasone propionate inhalation powder using the DISKUS device. The
mean fluticasone propionate plasma concentration was 110 pg/ml.
Distribution
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 91%. Fluticasone propionate is weakly and reversibly bound to
erythrocytes and is not significantly bound to human transcortin.
Metabolism
The total clearance of fluticasone propionate is high (average, 1093 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 cytochrome P450 3A4 pathway.
This metabolite had less affinity (approximately 1/2000) 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.
Elimination
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.
Hepatic Impairment
Since fluticasone propionate is predominantly cleared by hepatic metabolism,
impairment of liver function may lead to accumulation of fluticasone propionate
in plasma. Therefore, patients with hepatic disease should be closely monitored.
Gender
Full pharmacokinetic profiles were obtained from 9 female and 16 male
patients given fluticasone propionate inhalation powder 500 μg twice daily using
the DISKUS. No overall differences in fluticasone propionate pharmacokinetics
were observed.
Special Populations
Formal pharmacokinetic studies using fluticasone propionate were not carried
out in other special populations.
Drug-Drug Interactions
In a multiple-dose drug interaction study, coadministration of fluticasone
propionate (500 μg twice daily) and erythromycin (333 mg 3 times daily) did not
affect fluticasone propionate pharmacokinetics. In another drug interaction
study, coadministration of fluticasone propionate (1000 μg) and ketoconazole
(200 mg once daily) resulted in increased fluticasone propionate concentrations
and reduced plasma cortisol area under the plasma concentration versus time
curve (AUC), but had no effect on urinary excretion of cortisol. Since
fluticasone propionate is a substrate of cytochrome P450 3A4, caution should be
exercised when cytochrome P450 3A4 inhibitors (e.g., ritonavir,
ketoconazole) are coadministered with fluticasone propionate as this could
result in increased plasma concentrations of fluticasone propionate.
Salmeterol Xinafoate
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.
Absorption
Because of the small therapeutic dose, systemic levels of salmeterol are low
or undetectable after inhalation of recommended doses (50 μg of salmeterol
inhalation powder twice daily). Following chronic administration of an inhaled
dose of 50 μg of salmeterol inhalation powder twice daily, salmeterol was
detected in plasma within 5-45 minutes in 7 asthmatic patients; plasma
concentrations were very low, with mean peak concentrations of 167 pg/ml at 20
minutes and no accumulation with repeated doses.
Distribution
Binding of salmeterol to human plasma proteins averages 96% in vitro
over the concentration range of 8-7722 ng of salmeterol base per milliliter,
much higher concentrations than those achieved following therapeutic doses of
salmeterol.
Metabolism
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.
Elimination
In 2 healthy 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 (>99%) and has a long elimination half-life of 11
days.
Special Populations
Formal pharmacokinetic studies of salmeterol base have not been conducted in
special populations. Since salmeterol is predominantly cleared by hepatic
metabolism, impairment of liver function may lead to accumulation of salmeterol
in plasma. Therefore, patients with hepatic disease should be closely monitored.
Pharmacodynamics
Fluticasone Propionate; Salmeterol Xinafoate
Since systemic pharmacodynamic effects of salmeterol are not normally seen at
the therapeutic dose, higher doses were used to produce measurable effects. Four
studies were conducted in healthy subjects:
A single-dose crossover study using 2 inhalations of fluticasone propionate;
salmeterol xinafoate 500/50, fluticasone propionate powder 500 μg and salmeterol
powder 50 μg given concurrently, or fluticasone propionate powder 500 μg given
alone,
A cumulative dose study using 50-400 μg of salmeterol powder given alone or as
fluticasone propionate; salmeterol xinafoate 500/50.
A repeat-dose study for 11 days using 2 inhalations twice daily of fluticasone
propionate; salmeterol xinafoate 250/50, fluticasone propionate powder 250 μg,
or salmeterol powder 50 μg.
a single-dose study using 5 inhalations of fluticasone propionate; salmeterol
xinafoate 100/50, fluticasone propionate powder 100 μg alone, or placebo.
In these studies 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 fluticasone
propionate; salmeterol xinafoate, 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
fluticasone propionate; salmeterol xinafoate. The potential effect of salmeterol
on the effects of fluticasone propionate on the hypothalamic-pituitary-adrenal (HPA)
axis was also evaluated in these studies. 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
fluticasone propionate; salmeterol xinafoate in healthy subjects.
In clinical studies with fluticasone propionate; salmeterol xinafoate in
patients 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 fluticasone
propionate; salmeterol xinafoate. In 72 adolescent and adult patients with
asthma given either fluticasone propionate; salmeterol xinafoate 100/50 or
fluticasone propionate; salmeterol xinafoate 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.
In a 28 week study in patients with asthma, fluticasone propionate;
salmeterol xinafoate 500/50 twice daily was compared with the concurrent use of
salmeterol powder 50 μg plus fluticasone propionate powder 500 μg from separate
inhalers or fluticasone propionate powder 500 μg alone. No significant
differences across treatments were observed in plasma cortisol AUC after 12
weeks of dosing or in 24 hour urinary cortisol excretion after 12 and 28 weeks.
In a 12 week study in patients with asthma, fluticasone propionate;
salmeterol xinafoate 250/50 twice daily was compared with fluticasone propionate
powder 250 μg alone, salmeterol powder 50 μg alone, and placebo. For most
patients, the ability to increase cortisol production in response to stress, as
assessed by 30-minute cosyntropin stimulation, remained intact with fluticasone
propionate; salmeterol xinafoate. One patient (3%) who received fluticasone
propionate; salmeterol xinafoate 250/50 had an abnormal response (peak serum
cortisol <18 μg/dl) after dosing, compared with 2 patients (6%) who received
placebo, 2 patients (6%) who received fluticasone propionate 250 μg, and no
patients who received salmeterol.
Fluticasone Propionate
In clinical trials with fluticasone propionate inhalation powder using doses
up to and including 250 μg twice daily, occasional abnormal short cosyntropin
tests (peak serum cortisol <18 μg/dl) were noted both in patients receiving
fluticasone propionate and in patients receiving placebo. The incidence of
abnormal tests at 500 μg twice daily was greater than placebo. In a 2 year study
carried out in 64 patients with mild, persistent asthma (mean FEV1
91% of predicted) randomized to fluticasone propionate 500 μg twice daily or
placebo, no patient receiving fluticasone propionate had an abnormal response to
6 hour cosyntropin infusion (peak serum cortisol <18 μg/dl). With a peak
cortisol threshold of <35 μg/dl, one patient receiving fluticasone propionate
(4%) had an abnormal response at 1 year; repeat testing at 18 months and 2 years
was normal. Another patient receiving fluticasone propionate (5%) had an
abnormal response at 2 years. No patient on placebo had an abnormal response at
1 or 2 years.
Salmeterol Xinafoate
Inhaled salmeterol, like other beta-adrenergic agonist drugs, can in some
patients produce dose-related cardiovascular effects and effects on blood
glucose and/or serum potassium (see PRECAUTIONS). The
cardiovascular effects (heart rate, blood pressure) associated with salmeterol
occur with similar frequency, and are of similar type and severity, as those
noted following albuterol administration.
The effects of rising doses of salmeterol and standard inhaled doses of
albuterol were studied in volunteers and in patients with asthma. Salmeterol
doses up to 84 μg administered as inhalation aerosol resulted in heart rate
increases of 3-16 beats/min, about the same as albuterol dosed at 180 μg by
inhalation aerosol (4-10 beats/min). Adolescent and adult patients receiving 50
μg 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.
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 significance of these findings is unknown.
CLINICAL STUDIES:
In clinical trials comparing Advair Diskus (fluticasone propionate;
salmeterol xinafoate) with the 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.
Studies Comparing Advair Diskus to Fluticasone Propionate Alone or Salmeterol
Alone
Three double-blind, parallel-group clinical trials were conducted with
Advair Diskus in 1208 adolescent and adult patients (≥12 years, baseline FEV1
63-72% 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 device twice daily, and other maintenance therapies
were discontinued.
Study 1, Clinical Trial with Advair Diskus 100/50
This placebo-controlled, 12 week, US study compared Advair Diskus
100/50 with its individual components, fluticasone propionate 100 μg and
salmeterol 50 μg. The study was stratified according to baseline asthma
maintenance therapy; patients were using either inhaled corticosteroids (n=250)
(daily doses of beclomethasone dipropionate 252-420 μg, flunisolide 1000 μg,
fluticasone propionate inhalation aerosol 176 μg, or triamcinolone acetonide
600-1000 μg) or salmeterol (n=106). Baseline FEV1 measurements were
similar across treatments: Advair Diskus 100/50, 2.17 L; fluticasone
propionate 100 μg, 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 study. Worsening
asthma was defined as a clinically important decrease in FEV1 or peak
expiratory flow (PEF), increase in use of albuterol 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 1, statistically significantly fewer
patients receiving Advair Diskus 100/50 were withdrawn due to worsening
asthma compared with fluticasone propionate, salmeterol, and placebo.
TABLE 1 Percent of Patients Withdrawn due to Worsening
Asthma in Patients Previously Treated With Either Inhaled Corticosteroids or
Salmeterol (Study 1)
| Advair Diskus |
Fluticasone Propionate |
Salmeterol |
Placebo |
| 100/50 |
100 μg |
50 μg |
|
| (n=87) |
(n=85) |
(n=86) |
(n=77) |
| 3% |
11% |
35% |
49% |
Patients receiving Advair Diskus 100/50 had significantly greater
improvements in FEV1 (0.51 L, 25%) compared with fluticasone
propionate 100 μg (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).
The effect of Advair Diskus 100/50 on morning and evening peak
expiratory flow (PEF) endpoints is shown in TABLE 2.
TABLE 2 Peak Expiratory Flow Results for Patients
Previously Treated With Either Inhaled Corticosteroids or Salmeterol (Study 1)
|
|
Advair Diskus |
Fluticasone Propionate |
Salmeterol |
|
|
|
100/50 |
100 μg |
50 μg |
Placebo |
| Efficacy Variable* |
(n=87) |
(n=85) |
(n=86) |
(n=77) |
| AM PEF (L/min) |
|
Baseline |
393 |
374 |
369 |
382 |
|
Change from baseline |
53 |
17 |
-2 |
-24 |
| AM PEF (L/min) |
|
Baseline |
418 |
390 |
396 |
398 |
|
Change from baseline |
35 |
18 |
-7 |
-13 |
| * Change from
baseline=change from baseline at Endpoint (last available data). |
The subjective impact of asthma on patients' 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). Patients 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 to placebo).
Study 2, Clinical Trial with Advair Diskus 250/50
This placebo-controlled, 12 week, US study compared Advair Diskus
250/50 with its individual components, fluticasone propionate 250 μg and
salmeterol 50 μg in 349 patients using inhaled corticosteroids (daily doses of
beclomethasone dipropionate 462-672 μg, flunisolide 1250-2000 μg, fluticasone
propionate inhalation aerosol 440 μg, or triamcinolone acetonide 1100-1600 μg).
Baseline FEV1 measurements were similar across treatments: Advair
Diskus 250/50, 2.23 L; fluticasone propionate 250 μg, 2.12 L; salmeterol, 2.20
L; and placebo, 2.19 L.
Efficacy results in this study were similar to those observed in Study 1.
Patients receiving Advair Diskus 250/50 had significantly greater
improvements in FEV1 (0.48 L, 23%) compared with fluticasone
propionate 250 μg (0.25 L, 13%), salmeterol (0.05 L, 4%), and placebo (decrease
of 0.11 L, decrease of 5%). Statistically significantly fewer patients receiving
Advair Diskus 250/50 were withdrawn from this study 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.
Patients receiving Advair Diskus 250/50 also had clinically meaningful
improvements in overall asthma-specific quality of life as described in Study 1
(difference in AQLQ score of 1.29 compared to placebo).
Study 3, Clinical Trial with Advair Diskus 500/50
This 28 week, non-US study compared Advair Diskus 500/50 with
fluticasone propionate 500 μg alone and concurrent therapy (salmeterol 50 μg
plus fluticasone propionate 500 μg administered from separate inhalers) twice
daily in 503 patients using inhaled corticosteroids [daily doses of
beclomethasone dipropionate 1260-1680 μg, budesonide 1500-2000 μg, flunisolide
1500-2000 μg, or fluticasone propionate inhalation aerosol 660-880 μg (750-1000
μg inhalation powder)]. The primary efficacy parameter, morning PEF, was
collected daily for the first 12 weeks of the study. The primary purpose of
weeks 13-28 was to collect safety data.
Baseline PEF Measurements were Similar Across Treatments
Advair Diskus 500/50, 359 L/min; fluticasone propionate 500 μg, 351
L/min; and concurrent therapy, 345 L/min. Morning PEF improved significantly
with Advair Diskus 500/50 compared with fluticasone propionate 500 μg
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 US trials. Following the first dose, the
median time to onset of clinically significant bronchodilatation (≥15%
improvement in FEV1) in most patients was seen within 30-60 minutes.
Maximum improvement in FEV1 generally occurred within 3 hours, and
clinically significant improvement was maintained for 12 hours.
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 studies.
No diminution in the 12 hour bronchodilator effect was observed with either
Advair Diskus 100/50 or Advair Diskus 250/50 as assessed by FEV1
following 12 weeks of therapy.
Reduction in asthma symptoms, use of rescue albuterol 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 studies.
INDICATIONS AND USAGE:
Fluticasone propionate; salmeterol xinafoate is indicated for the long-term,
twice-daily, maintenance treatment of asthma in patients 12 years of age and
older.
Fluticasone propionate; salmeterol xinafoate is NOT indicated for the relief
of acute bronchospasm.
CONTRAINDICATIONS:
Fluticasone propionate; salmeterol xinafoate is contraindicated in the
primary treatment of status asthmaticus or other acute episodes of asthma where
intensive measures are required.
Hypersensitivity to any of the ingredients of these preparations
contraindicates their use.
WARNINGS:
Fluticasone propionate; salmeterol xinafoate should not be used for
transferring patients from systemic corticosteroid therapy.
| Particular care is needed for patients who have been transferred from
systemically active corticosteroids to inhaled corticosteroids because
deaths due to adrenal insufficiency have occurred in patients with asthma
during and after transfer from systemic corticosteroids to less systemically
available inhaled corticosteroids. After withdrawal from systemic
corticosteroids, a number of months are required for recovery of HPA
function. Patients who have been previously maintained on 20 mg or more
per day of prednisone (or its equivalent) may be most susceptible,
particularly when their systemic corticosteroids have been almost completely
withdrawn. During this period of HPA suppression, patients may exhibit signs
and symptoms of adrenal insufficiency when exposed to trauma, surgery, or
infection (particularly gastroenteritis) or other conditions associated with
severe electrolyte loss. Although inhaled corticosteroids may provide
control of asthma symptoms during these episodes, in recommended doses they
supply less than normal physiological amounts of glucocorticoid systemically
and do NOT provide the mineralocorticoid activity that is necessary for
coping with these emergencies.
During periods of stress or a severe asthma attack, patients who have
been withdrawn from systemic corticosteroids should be instructed to resume
oral corticosteroids (in large doses) immediately and to contact their
physicians for further instruction. These patients should also be instructed
to carry a warning card indicating that they may need supplementary systemic
corticosteroids during periods of stress or a severe asthma attack. |
1. FLUTICASONE PROPIONATE; SALMETEROL XINAFOATE SHOULD NOT BE
INITIATED IN PATIENTS DURING RAPIDLY DETERIORATING OR POTENTIALLY
LIFE-THREATENING EPISODES OF ASTHMA. Serious acute respiratory events,
including fatalities, have been reported both in the United States and
worldwide when salmeterol, a component of Advair Diskus, has been initiated in
patients with significantly worsening or acutely deteriorating asthma. In
most cases, these have occurred in patients with severe asthma (e.g.,
patients with a history of corticosteroid dependence, low pulmonary function,
intubation, mechanical ventilation, frequent hospitalizations, or previous
life-threatening acute asthma exacerbations) and/or in some patients in whom
asthma has been acutely deteriorating (e.g., unresponsive to usual
medications; increasing need for inhaled, short-acting beta2-agonists;
increasing need for systemic corticosteroids; significant increase in
symptoms; recent emergency room visits; sudden or progressive deterioration in
pulmonary function). However, they have occurred in a few patients with less
severe asthma as well. It was not possible from these reports to determine
whether salmeterol contributed to these events or simply failed to relieve the
deteriorating asthma.
2. Do not use fluticasone propionate; salmeterol xinafoate to treat
acute symptoms: An inhaled, short-acting beta2-agonist, not
fluticasone propionate; salmeterol xinafoate, should be used to relieve acute
asthma symptoms. When prescribing fluticasone propionate; salmeterol xinafoate,
the physician must also provide the patient with an inhaled, short-acting beta2-agonist
(e.g., albuterol) for treatment of symptoms that occur acutely, despite
regular twice daily (morning and evening) use of fluticasone propionate;
salmeterol xinafoate.
When beginning treatment with fluticasone propionate; salmeterol xinafoate,
patients who have been taking oral or inhaled, short-acting beta2-agonists
on a regular basis (e.g., 4 times a day) should be instructed to
discontinue the regular use of these drugs. For patients on fluticasone
propionate; salmeterol xinafoate, short-acting, inhaled beta2-agonists
should only be used for symptomatic relief of acute asthma symptoms (see
PRECAUTIONS, Information for the Patient).
3. Watch for increasing use of inhaled, short-acting beta2-agonists,
which is a marker of deteriorating asthma: Asthma may deteriorate acutely
over a period of hours or chronically over several days or longer. If the
patient's inhaled, short-acting beta2-agonist becomes less
effective, the patient needs more inhalations than usual, or the patient
develops a significant decrease in PEF, these may be a marker of
destabilization of asthma. In this setting, the patient requires immediate
reevaluation with reassessment of the treatment regimen, giving special
consideration to the possible need for replacing the current strength of
fluticasone propionate; salmeterol xinafoate with a higher strength, adding
additional inhaled corticosteroid, or initiating systemic corticosteroids.
Patients should not use more than one inhalation twice daily (morning and
evening) of fluticasone propionate; salmeterol xinafoate.
4. Do not use an inhaled, long-acting beta2-agonist in
conjunction with fluticasone propionate; salmeterol xinafoate: Patients
who are receiving fluticasone propionate; salmeterol xinafoate twice daily
should not use salmeterol or other long-acting inhaled beta2-agonists
for prevention of exercise-induced bronchospasm or the maintenance treatment
of asthma. Additional benefit would not be gained from using supplemental
salmeterol for prevention of exercise-induced bronchospasm since fluticasone
propionate; salmeterol xinafoate already contains salmeterol.
5. Do not exceed recommended dosage: Fluticasone propionate;
salmeterol xinafoate should not be used more often or at higher doses than
recommended. Fatalities have been reported in association with excessive use
of inhaled sympathomimetic drugs. Large doses of inhaled or oral salmeterol
(12-20 times the recommended dose) have been associated with clinically
significant prolongation of the QTc interval, which has the
potential for producing ventricular arrhythmias.
6. Paradoxical bronchospasm: As with other inhaled asthma
medications, fluticasone propionate; salmeterol xinafoate can produce
paradoxical bronchospasm, which may be life threatening. If paradoxical
bronchospasm occurs following dosing with fluticasone propionate; salmeterol
xinafoate, it should be treated immediately with a short-acting, inhaled
bronchodilator, fluticasone propionate; salmeterol xinafoate should be
discontinued immediately, and alternative therapy should be instituted.
7. Immediate hypersensitivity reactions: Immediate
hypersensitivity reactions may occur after administration of fluticasone
propionate; salmeterol xinafoate, as demonstrated by cases of urticaria,
angioedema, rash, and bronchospasm.
8. Upper airway symptoms: Symptoms of laryngeal spasm,
irritation, or swelling, such as stridor and choking, have been reported in
patients receiving fluticasone propionate and salmeterol, components of
fluticasone propionate; salmeterol xinafoate.
9. Cardiovascular disorders: Fluticasone propionate; salmeterol
xinafoate, like all products containing sympathomimetic amines, should be used
with caution in patients with cardiovascular disorders, especially coronary
insufficiency, cardiac arrhythmias, and hypertension. Salmeterol, a component
of fluticasone propionate; salmeterol xinafoate, can produce a clinically
significant cardiovascular effect in some patients as measured by pulse rate,
blood pressure, and/or symptoms. Although such effects are uncommon after
administration of salmeterol at recommended doses, if they occur, the drug may
need to be discontinued. In addition, beta-agonists have been reported to
produce electrocardiogram (ECG) changes, such as flattening of the T wave,
prolongation of the QTc interval, and ST segment depression. The clinical
significance of these findings is unknown.
10. Discontinuation of systemic corticosteroids: Transfer of
patients from systemic corticosteroid therapy to fluticasone propionate;
salmeterol xinafoate may unmask conditions previously suppressed by the
systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis,
eczema, and arthritis.
11. Immunosuppression: Persons who are using drugs that suppress
the immune system are more susceptible to infections than healthy individuals.
Chickenpox and measles, for example, can have a more serious or even fatal
course in susceptible children or adults using corticosteroids. In such
children or adults who have not had these diseases or been properly immunized,
particular care should be taken to avoid exposure. How the dose, route, and
duration of corticosteroid administration affect the risk of developing a
disseminated infection is not known. The contribution of the underlying
disease and/or prior corticosteroid treatment to the risk is also not known.
If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG)
may be indicated. If exposed to measles, prophylaxis with pooled intramuscular
immunoglobulin (IG) may be indicated. (See the respective package inserts for
complete VZIG and IG prescribing information.) If chickenpox develops,
treatment with antiviral agents may be considered.
PRECAUTIONS:
General
Cardiovascular Effects
No effect on the cardiovascular system is usually seen after the
administration of inhaled fluticasone propionate; salmeterol xinafoate at
recommended doses. The cardiovascular and central nervous system effects seen
with all sympathomimetic drugs (e.g., increased blood pressure, heart
rate, excitement) can occur after use of salmeterol, a component of fluticasone
propionate; salmeterol xinafoate, and may require discontinuation of fluticasone
propionate; salmeterol xinafoate. Fluticasone propionate; salmeterol xinafoate,
like all medications containing sympathomimetic amines, should be used with
caution in patients with cardiovascular disorders, especially coronary
insufficiency, cardiac arrhythmias, and hypertension; in patients with
convulsive disorders or thyrotoxicosis; and in patients who are unusually
responsive to sympathomimetic amines.
As has been described with other beta-adrenergic agonist bronchodilators,
clinically significant changes in electrocardiograms have been seen infrequently
in individual patients in controlled clinical studies with fluticasone
propionate; salmeterol xinafoate and salmeterol. Clinically significant changes
in systolic and/or diastolic blood pressure and pulse rate have been seen
infrequently in individual patients in controlled clinical studies with
salmeterol, a component of fluticasone propionate; salmeterol xinafoate.
Metabolic and Other Effects
Doses of the related beta2-adrenoceptor agonist albuterol, when
administered intravenously, have been reported to aggravate preexisting diabetes
mellitus and ketoacidosis. Beta-adrenergic agonist medications may produce
significant hypokalemia in some patients, possibly through intracellular
shunting, which has the potential to produce adverse cardiovascular effects. The
decrease in serum potassium is usually transient, not requiring supplementation.
Clinically significant changes in blood glucose and/or serum potassium were
seen rarely during clinical studies with fluticasone propionate; salmeterol
xinafoate at recommended doses.
During withdrawal from oral corticosteroids, some patients may experience
symptoms of systemically active corticosteroid withdrawal, e.g., joint
and/or muscular pain, lassitude, and depression, despite maintenance or even
improvement of respiratory function.
Fluticasone propionate, a component of fluticasone propionate; salmeterol
xinafoate, will often permit control of asthma symptoms with less suppression of
HPA function than therapeutically equivalent oral doses of prednisone. Since
fluticasone propionate is absorbed into the circulation and can be systemically
active at higher doses, the beneficial effects of fluticasone propionate;
salmeterol xinafoate in minimizing HPA dysfunction may be expected only when
recommended dosages are not exceeded and individual patients are titrated to the
lowest effective dose. A relationship between plasma levels of fluticasone
propionate and inhibitory effects on stimulated cortisol production has been
shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol.
Since individual sensitivity to effects on cortisol production exists,
physicians should consider this information when prescribing fluticasone
propionate; salmeterol xinafoate.
Because of the possibility of systemic absorption of inhaled corticosteroids,
patients treated with these drugs should be observed carefully for any evidence
of systemic corticosteroid effects. Particular care should be taken in observing
patients postoperatively or during periods of stress for evidence of inadequate
adrenal response.
It is possible that systemic corticosteroid effects such as hypercorticism
and adrenal suppression may appear in a small number of patients, particularly
at higher doses. If such changes occur, the dose of fluticasone propionate
should be reduced slowly, consistent with accepted procedures for reducing
systemic corticosteroids and for management of asthma symptoms.
Orally inhaled corticosteroids may cause a reduction in growth velocity when
administered to pediatric patients (see , Pediatric
Use). Patients should be maintained on the lowest strength of fluticasone
propionate; salmeterol xinafoate that effectively controls their asthma.
The long-term effects of fluticasone propionate; salmeterol xinafoate in
human subjects are not fully known. In particular, the effects resulting from
chronic use of fluticasone propionate on developmental or immunologic processes
in the mouth, pharynx, trachea, and lung are unknown. Some patients have
received inhaled fluticasone propionate on a continuous basis for periods of 3
years or longer. In clinical studies with patients treated for 2 years with
inhaled fluticasone propionate, no apparent differences in the type or severity
of adverse reactions were observed after long- versus short-term treatment.
Rare instances of glaucoma, increased intraocular pressure, and cataracts
have been reported following the inhaled administration of corticosteroids,
including fluticasone propionate, a component of fluticasone propionate;
salmeterol xinafoate.
In clinical studies with fluticasone propionate; salmeterol xinafoate, the
development of localized infections of the pharynx with Candida albicans
has occurred. When such an infection develops, it should be treated with
appropriate local or systemic (i.e., oral antifungal) therapy while
remaining on treatment with fluticasone propionate; salmeterol xinafoate, but at
times therapy with fluticasone propionate; salmeterol xinafoate may need to be
interrupted.
Inhaled corticosteroids should be used with caution, if at all, in patients
with active or quiescent tuberculosis infections of the respiratory tract;
untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular
herpes simplex.
Eosinophilic Conditions
In rare cases, patients on inhaled fluticasone propionate, a component of
fluticasone propionate; salmeterol xinafoate, may present with systemic
eosinophilic conditions, with some patients presenting with clinical features of
vasculitis consistent with Churg-Strauss syndrome, a condition that is often
treated with systemic corticosteroid therapy. These events usually, but not
always, have been associated with the reduction and/or withdrawal of oral
corticosteroid therapy following the introduction of fluticasone propionate.
Cases of serious eosinophilic conditions have also been reported with other
inhaled corticosteroids in this clinical setting. Physicians should be alert to
eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac
complications, and/or neuropathy presenting in their patients. A causal
relationship between fluticasone propionate and these underlying conditions has
not been established (see ADVERSE REACTIONS).
Information for the Patient
Patients being treated with fluticasone propionate; salmeterol xinafoate
should receive the following information and instructions. This information is
intended to aid them in the safe and effective use of this medication. It is not
a disclosure of all possible adverse or intended effects.
It is important that patients understand how to use the Diskus inhalation
device appropriately and how it should be used in relation to other asthma
medications they are taking. Patients should be given the following information:
Patients should use fluticasone propionate; salmeterol xinafoate at regular
intervals as directed. Results of clinical trials indicate significant
improvement may occur within the first 30 minutes of taking the first dose;
however, the full benefit may not be achieved until treatment has been
administered for 1 week or longer. The patient should not exceed the prescribed
dosage and should contact the physician if symptoms do not improve or if the
condition worsens.
The bronchodilation from a single dose of fluticasone propionate; salmeterol
xinafoate may last up to 12 hours or longer. The recommended dosage (1
inhalation twice daily, morning and evening) should not be exceeded. Patients
who are receiving fluticasone propionate; salmeterol xinafoate twice daily
should not use salmeterol or other long-acting inhaled beta2-agonists
for prevention of exercise-induced bronchospasm or maintenance treatment of
asthma.
Fluticasone propionate; salmeterol xinafoate is not meant to relieve acute
asthma symptoms and extra doses should not be used for that purpose. Acute
symptoms should be treated with an inhaled, short-acting beta2-agonist
such as albuterol (the physician should provide the patient with such medication
and instruct the patient in how it should be used).
The physician should be notified immediately if any of the following
situations occur, which may be a sign of seriously worsening asthma:
 | Decreasing effectiveness of inhaled, short-acting beta2-agonists.
|
| Need for more inhalations than usual of inhaled, short-acting beta2-agonists.
|
| Significant decrease in peak flow as outlined by the physician.
|
Patients should be cautioned regarding common adverse cardiovascular
effects, such as palpitations, chest pain, rapid heart rate, tremor, or
nervousness.
When patients are prescribed fluticasone propionate; salmeterol xinafoate,
other inhaled drugs and asthma medications should be used only as directed by
the physician.
Fluticasone propionate; salmeterol xinafoate should not be used with a
spacer device.
If you are pregnant or nursing, contact your physician about the use of
fluticasone propionate; salmeterol xinafoate.
Effective and safe use of fluticasone propionate; salmeterol xinafoate
includes an understanding of the way that it should be used:
| Never exhale into the Diskus.
|
| Never attempt to take the Diskus apart.
|
| Always activate and use the Diskus in a level, horizontal position.
|
| Never wash the mouthpiece or any part of the Diskus. KEEP IT DRY.
|
| Always keep the Diskus in a dry place.
|
| Discard 1 month after removal from the moisture-protective foil
overwrap pouch or after every blister has been used (when the dose indicator
reads "0"), whichever comes first.
|
Patients should be warned to avoid exposure to chickenpox or measles and, if
they are exposed, to consult their physicians without delay.
For the proper use of fluticasone propionate; salmeterol xinafoate and to
attain maximum improvement, the patient should read and follow carefully the
accompanying Patient's Instructions for Use.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Fluticasone Propionate
Fluticasone propionate demonstrated no tumorigenic potential in mice at oral
doses up to 1000 μg/kg (approximately 4 times the maximum recommended daily
inhalation dose in adults on a μg/m2 basis) for 78 weeks or in rats
at inhalation doses up to 57 μg/kg (less than the maximum recommended daily
inhalation dose in adults on a μg/m2 basis) for 104 weeks.
Fluticasone propionate did not induce gene mutation in prokaryotic or
eukaryotic cells in vitro. No significant clastogenic effect was seen in
cultured human peripheral lymphocytes in vitro or in the mouse
micronucleus test.
No evidence of impairment of fertility was observed in reproductive studies
conducted in male and female rats at subcutaneous doses up to 50 μg/kg (less
than the maximum recommended daily inhalation dose in adults on a μg/m2
basis). Prostate weight was significantly reduced at a subcutaneous dose of 50
μg/kg.
Salmeterol
In an 18 month carcinogenicity study in CD-mice, salmeterol at oral doses of
1.4 mg/kg and above (approximately 20 times the maximum recommended daily
inhalation dose in adults based on comparison of the plasma area under the
curves ([AUCs]) caused a dose-related increase in the incidence of smooth muscle
hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and cysts
in the ovaries. The incidence of leiomyosarcomas was not statistically
significant. No tumors were seen at 0.2 mg/kg (approximately 3 times the maximum
recommended daily inhalation doses in adults based on comparison of the AUCs).
In a 24 month oral and inhalation carcinogenicity study in Sprague Dawley
rats, salmeterol caused a dose-related increase in the incidence of mesovarian
leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 60
times the maximum recommended daily inhalation dose in adults on a mg/m2
basis). No tumors were seen at 0.21 mg/kg (approximately 20 times the maximum
recommended daily inhalation dose in adults on a mg/m2 basis). These
findings in rodents are similar to those reported previously for other
beta-adrenergic agonist drugs. The relevance of these findings to human use is
unknown.
Salmeterol produced no detectable or reproducible increases in microbial and
mammalian gene mutation in vitro. No clastogenic activity occurred in
vitro in human lymphocytes or in vivo in a rat micronucleus test. No
effects on fertility were identified in male and female rats treated with
salmeterol at oral doses up to 2 mg/kg (approximately 180 times the maximum
recommended daily inhalation dose in adults on a mg/m2 basis).
Pregnancy Category C
Fluticasone Propionate; Salmeterol Xinafoate
Teratogenic Effects
From the reproduction toxicity studies in mice and rats, no evidence of
enhanced toxicity was seen using combinations of fluticasone propionate and
salmeterol compared to toxicity data from the components administered
separately. In mice combining 150 μg/kg subcutaneously of fluticasone propionate
(less than the maximum recommended daily inhalation dose in adults on a μg/m2
basis) with 10 mg/kg orally of salmeterol (approximately 450 times the maximum
recommended daily inhalation dose in adults on a mg/m2 basis) were
teratogenic. Cleft palate, fetal death, increased implantation loss and delayed
ossification was seen. These observations are characteristic of glucocorticoids.
No developmental toxicity was observed at combination doses up to 40 μg/kg
subcutaneously of fluticasone propionate (less than the maximum recommended
daily inhalation dose in adults on a μg/m2 basis) and up to 1.4 mg/kg
orally of salmeterol (approximately 65 times the maximum recommended daily
inhalation dose in adults on a mg/m2 basis). In rats, no
teratogenicity was observed at combination doses up to 30 μg/kg subcutaneously
of fluticasone propionate (less than the maximum recommended daily inhalation
dose in adults on a μg/m2 basis) and up to 1 mg/kg of salmeterol
(approximately 90 times the maximum recommended daily inhalation dose in adults
on a mg/m2 basis). Combining 100 μg/kg subcutaneously of fluticasone
propionate (less than the maximum recommended daily inhalation dose in adults on
a μg/m2 basis) with 10 mg/kg orally of salmeterol (approximately 900
times the maximum recommended daily inhalation dose in adults on a mg/m2
basis) produced maternal toxicity, decreased placental weight, decreased fetal
weight, umbilical hernia, delayed ossification, and changes in the occipital
bone. There are no adequate and well-controlled studies with fluticasone
propionate; salmeterol xinafoate in pregnant women. Fluticasone propionate;
salmeterol xinafoate should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Fluticasone Propionate
Subcutaneous studies in the mouse and rat at 45 and 100 μg/kg (less than or
equivalent to the maximum recommended daily inhalation dose in adults on a μg/m2
basis), respectively, revealed fetal toxicity characteristic of potent
corticosteroid compounds, including embryonic growth retardation, omphalocele,
cleft palate, and retarded cranial ossification.
In the rabbit, fetal weight reduction and cleft palate were observed at a
subcutaneous dose of 4 μg/kg (less than the maximum recommended daily inhalation
dose in adults on a μg/m2 basis). However, no teratogenic effects
were reported at oral doses up to 300 μg/kg (approximately 5 times the maximum
recommended daily inhalation dose in adults on a μg/m2 basis) of
fluticasone propionate. No fluticasone propionate was detected in the plasma in
this study, consistent with the established low bioavailability following oral
administration (see CLINICAL PHARMACOLOGY).
Fluticasone propionate crossed the placenta following administration of a
subcutaneous dose of 100 μg/kg to mice (less than the maximum recommended daily
inhalation dose in adults on a μg/m2 basis) administration of a
subcutaneous or an oral dose of 100 μg/kg to rats (approximately equivalent to
the maximum recommended daily inhalation dose in adults on a μg/m2
basis) and an oral dose of 300 μg/kg administered to rabbits (approximately 5
times the maximum recommended daily inhalation dose in adults on a μg/m2
basis).
There are no adequate and well-controlled studies in pregnant women.
Fluticasone propionate should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Experience with oral corticosteroids since their introduction in
pharmacologic, as opposed to physiologic, doses suggests that rodents are more
prone to teratogenic effects from corticosteroids than humans. In addition,
because there is a natural increase in corticosteroid production during
pregnancy, most women will require a lower exogenous corticosteroid dose and
many will not need corticosteroid treatment during pregnancy.
Salmeterol
No teratogenic effects occurred in rats at oral doses up to 2 mg/kg
(approximately 180 times the maximum recommended daily inhalation dose in adults
on a mg/m2 basis). In pregnant Dutch rabbits administered oral doses
of 1 mg/kg and above (approximately 50 times the maximum recommended daily
inhalation dose in adults based on comparison of the AUCs), salmeterol exhibited
fetal toxic effects characteristically resulting from beta-adrenoceptor
stimulation. These included precocious eyelid openings, cleft palate, sternebral
fusion, limb and paw flexures, and delayed ossification of the frontal cranial
bones. No significant effects occurred at an oral dose of 0.6 mg/kg
(approximately 20 times the maximum recommended daily inhalation dose in adults
based on comparison of the AUCs).
New Zealand White rabbits were less sensitive since only delayed ossification
of the frontal bones was seen at an oral dose of 10 mg/kg (approximately 1800
times the maximum recommended daily inhalation dose in adults on a mg/m2
basis). Extensive use of other beta-agonists has provided no evidence that these
class effects in animals are relevant to their use in humans. There are no
adequate and well-controlled studies with salmeterol in pregnant women.
Salmeterol should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Salmeterol xinafoate crossed the placenta following oral administration of 10
mg/kg to mice and rats (approximately 450 and 900 times, respectively, the
maximum recommended daily inhalation dose in adults on a mg/m2
basis).
Labor and Delivery
There are no well-controlled human studies that have investigated effects of
fluticasone propionate; salmeterol xinafoate on preterm labor or labor at term.
Because of the potential for beta-agonist interference with uterine
contractility, use of fluticasone propionate; salmeterol xinafoate for
management of asthma during labor should be restricted to those patients in whom
the benefits clearly outweigh the risks.
Nursing Mothers
Plasma levels of salmeterol, a component of fluticasone propionate;
salmeterol xinafoate, after inhaled therapeutic doses are very low. In rats,
salmeterol xinafoate is excreted in the milk. There are no data from controlled
trials on the use of salmeterol by nursing mothers. It is not known whether
fluticasone propionate, a component of Advair Diskus, is excreted in
human breast milk; however, other corticosteroids have been detected in human
milk. Subcutaneous administration to lactating rats of 10 μg/kg tritiated
fluticasone propionate (less than the maximum recommended daily inhalation dose
in adults on a μg/m2 basis) resulted in measurable radioactivity in
milk.
Since there are no data from controlled trials on the use of fluticasone
propionate; salmeterol xinafoate by nursing mothers, a decision should be made
whether to discontinue nursing or to discontinue fluticasone propionate;
salmeterol xinafoate, taking into account the importance of fluticasone
propionate; salmeterol xinafoate to the mother.
Caution should be exercised when fluticasone propionate; salmeterol xinafoate
is administered to a nursing woman.
Pediatric Use
The safety and effectiveness of fluticasone propionate; salmeterol xinafoate
in children under 12 years of age has not been established. In one 12 week
study, 257 patients 4-11 years inadequately controlled using inhaled
corticosteroids were randomized to fluticasone propionate; salmeterol xinafoate
100/50 or concurrent therapy with fluticasone propionate inhalation powder 100
μg plus salmeterol inhalation powder 50 μg twice daily. The pattern of adverse
events reported in patients 4-11 years of age was similar to that seen in
patients 12 years of age and older treated with fluticasone propionate;
salmeterol xinafoate.
Controlled clinical studies have shown that orally inhaled corticosteroids
may cause a reduction in growth velocity in pediatric patients. This effect has
been observed in the absence of laboratory evidence of HPA axis suppression,
suggesting that growth velocity is a more sensitive indicator of systemic
corticosteroid exposure in pediatric patients than some commonly used tests of
HPA axis function. The long-term effects of this reduction in growth velocity
associated with orally inhaled corticosteroids, including the impact on final
adult height, are unknown. The potential for "catch up" growth following
discontinuation of treatment with orally inhaled corticosteroids has not been
adequately studied.
Inhaled corticosteroids, including fluticasone propionate, a component of
fluticasone propionate; salmeterol xinafoate, may cause a reduction in growth
velocity in children and adolescents (see PRECAUTIONS).
The growth of pediatric patients receiving orally inhaled corticosteroids,
including fluticasone propionate; salmeterol xinafoate, should be monitored. If
a child or adolescent on any corticosteroid appears to have growth suppression,
the possibility that he/she is particularly sensitive to this effect of
corticosteroids should be considered. The potential growth effects of prolonged
treatment should be weighed against the clinical benefits obtained. To minimize
the systemic effects of orally inhaled corticosteroids, including fluticasone
propionate; salmeterol xinafoate, each patient should be titrated to the lowest
strength that effectively controls his/her asthma (see
DOSAGE AND ADMINISTRATION).
Geriatric Use
Of the total number of patients in clinical studies of fluticasone
propionate; salmeterol xinafoate, 44 were 65 years of age or older and 3 were 75
years of age or older. No overall differences in safety were observed between
these patients and younger patients, and other reported clinical experience,
including studies of the individual components, has not identified differences
in responses between the elderly and younger patients, but greater sensitivity
of some older individuals cannot be ruled out. As with other products containing
beta2-agonists, special caution should be observed when using
fluticasone propionate; salmeterol xinafoate in geriatric patients who have
concomitant cardiovascular disease that could be adversely affected by beta2-agonists.
Based on available data for fluticasone propionate; salmeterol xinafoate or its
active components, no adjustment of dosage of fluticasone propionate; salmeterol
xinafoate in geriatric patients is warranted.
DRUG INTERACTIONS:
Fluticasone propionate; salmeterol xinafoate has been used concomitantly with
other drugs, including short-acting beta2-agonists, methylxanthines,
and intranasal corticosteroids, commonly used in patients with asthma, without
adverse drug reactions. No formal drug interaction studies have been performed
with fluticasone propionate; salmeterol xinafoate.
Short-acting beta2-agonists: In clinical trials, the mean
daily need for additional beta2-agonist use in 166 patients using
fluticasone propionate; salmeterol xinafoate was approximately 1.3 inhalations
per day, and ranged from 0-9 inhalations per day. Five percent (5%) of the
fluticasone propionate; salmeterol xinafoate patients in these trials averaged 6
or more inhalations per day over the course of the 12 week trials. No observed
increase in frequency of cardiovascular events was noted among patients who
averaged 6 or more inhalations per day.
Methylxanthines: The concurrent use of intravenously or orally
administered methylxanthines (e.g., aminophylline, theophylline) by
patients receiving fluticasone propionate; salmeterol xinafoate has not been
completely evaluated. In clinical trials, 39 patients receiving fluticasone
propionate; salmeterol xinafoate 100/50, 250/50, or 500/50 twice daily
concurrently with a theophylline product had adverse event rates similar to
those in 304 patients receiving fluticasone propionate; salmeterol xinafoate
without theophylline. Similar results were observed in patients receiving
salmeterol 50 μg plus fluticasone propionate 500 μg twice daily concurrently
with a theophylline product (n=39) or without theophylline (n=132).
Fluticasone propionate nasal spray: In patients taking fluticasone
propionate; salmeterol xinafoate in clinical trials, no difference in the
profile of adverse events or HPA axis effects was noted between patients taking
fluticasone propionate nasal spray, 50 μg concurrently (n=46) and those who were
not (n=130).
Monoamine oxidase inhibitors and tricyclic antidepressants: Fluticasone
propionate; salmeterol xinafoate should be administered with extreme caution to
patients being treated with monoamine oxidase inhibitors or tricyclic
antidepressants, or within 2 weeks of discontinuation of such agents, because
the action of salmeterol, a component of fluticasone propionate; salmeterol
xinafoate, on the vascular system may be potentiated by these agents.
Beta-adrenergic receptor blocking agents: Beta-blockers not only block
the pulmonary effect of beta-agonists, such as salmeterol, a component of
fluticasone propionate; salmeterol xinafoate, but may produce severe
bronchospasm in patients with asthma. Therefore, patients with asthma should not
normally be treated with beta-blockers. However, under certain circumstances,
there may be no acceptable alternatives to the use of beta-adrenergic blocking
agents in patients with asthma. In this setting, cardioselective beta-blockers
could be considered, although they should be administered with caution.
Diuretics: The ECG changes and/or hypokalemia that may result from the
administration of nonpotassium-sparing diuretics (such as loop or thiazide
diuretics) can be acutely worsened by beta-agonists, especially when the
recommended dose of the beta-agonist is exceeded. Although the clinical
significance of these effects is not known, caution is advised in the
coadministration of beta-agonists with nonpotassium-sparing diuretics.
Ketoconazole and other inhibitors of cytochrome P450: In a
placebo-controlled, crossover study in 8 healthy volunteers, coadministration of
a single dose of fluticasone propionate (1000 μg) with multiple doses of
ketoconazole (200 mg) to steady state resulted in increased mean fluticasone
propionate concentrations, a reduction in plasma cortisol AUC, and no effect on
urinary excretion of cortisol. This interaction may be due to an inhibition of
cytochrome P450 3A4 by ketoconazole, which is also the route of metabolism of
fluticasone propionate. Care should be exercised when fluticasone propionate;
salmeterol xinafoate is coadministered with long-term ketoconazole and other
known cytochrome P450 3A4 inhibitors.
ADVERSE REACTIONS:
The incidence of common adverse experiences in
TABLE 3A and TABLE 3B are based upon 2
placebo-controlled, 12 week, US clinical studies (Studies 1 and 2). A total of
705 adolescent and adult patients (349 females and 356 males) previously treated
with salmeterol or inhaled corticosteroids were treated twice daily with
fluticasone propionate; salmeterol xinafoate (100/50 or 250/50 μg doses),
fluticasone propionate inhalation powder (100 or 250 μg doses), salmeterol
inhalation powder 50 μg, or placebo.
TABLE 3A Overall Adverse Effects With ≥3% Incidence
With Advair Diskus
|
|
Advair Diskus |
|
|
|
100/50 |
250/50 |
Placebo |
| Adverse Event |
(n=92) |
(n=84) |
(n=175) |
| Ear, Nose and Throat |
|
Upper respiratory tract
infection |
27% |
21% |
14% |
|
Pharyngitis |
13% |
10% |
6% |
|
Upper respiratory inflammation |
7% |
6% |
5% |
|
Sinusitis |
4% |
5% |
4% |
|
Hoarseness/dysphonia |
5% |
2% |
<1% |
|
Oral candidiasis |
1% |
4% |
0% |
| Lower Respiratory |
|
Viral respiratory infections |
4% |
4% |
3% |
|
Bronchitis |
2% |
8% |
2% |
|
Cough |
3% |
6% |
2% |
| Neurology |
|
Headaches |
12% |
13% |
7% |
| Gastrointestinal |
|
Nausea and vomiting |
4% |
6% |
1% |
|
Gastrointestinal discomfort and
pain |
4% |
1% |
1% |
|
Diarrhea |
4% |
2% |
1% |
|
Viral gastrointestinal
infections |
3% |
0% |
2% |
| Non-Site Specific |
|
Candidiasis unspecified site |
3% |
0% |
1% |
| Musculoskeletal |
|
Musculoskeletal pain |
4% |
2% |
3% |
| Average duration of exposure
(days) |
77.3 |
78.7 |
42.3 |
TABLE 3B Overall Adverse Effects With ≥3% Incidence
With Advair Diskus
|
|
Fluticasone Propionate |
Salmeterol |
|
|
100 μg |
250 μg |
50 μg |
| Adverse Event |
(n=90) |
(n=84) |
(n=180) |
| Ear, Nose and Throat |
|
Upper respiratory tract
infection |
29% |
25% |
19% |
|
Pharyngitis |
7% |
12% |
8% |
|
Upper respiratory inflammation |
7% |
8% |
8% |
|
Sinusitis |
6% |
1% |
3% |
|
Hoarseness/dysphonia |
2% |
4% |
<1% |
|
Oral candidiasis |
2% |
2% |
0% |
| Lower Respiratory |
|
Viral respiratory infections |
4% |
10% |
6% |
|
Bronchitis |
1% |
2% |
2% |
|
Cough |
0% |
0% |
3% |
| Neurology |
|
Headaches |
14% |
8% |
10% |
| Gastrointestinal |
|
Nausea and vomiting |
3% |
4% |
1% |
|
Gastrointestinal discomfort and
pain |
0% |
2% |
1% |
|
Diarrhea |
2% |
2% |
1% |
|
Viral gastrointestinal
infections |
3% |
1% |
2% |
| Non-Site Specific |
|
Candidiasis unspecified site |
1% |
4% |
0% |
| Musculoskeletal |
|
Musculoskeletal pain |
1% |
5% |
3% |
| Average duration of exposure
(days) |
72.4 |
70.1 |
60.1 |
TABLE 3A and TABLE
3B includes all events (whether considered drug-related or nondrug-related
by the investigator) that occurred at a rate of 3% or greater in either of the
groups receiving fluticasone propionate; salmeterol xinafoate and were more
common than in the placebo group. In considering these data, differences in
average duration of exposure should be taken into account.
These adverse reactions were mostly mild to moderate in severity. Rare cases
of immediate and delayed hypersensitivity reactions, including rash and other
rare events of angioedema and bronchospasm, have been reported.
Other adverse effects that occurred in the groups receiving fluticasone
propionate; salmeterol xinafoate in these studies with an incidence of 1-3% and
that occurred at a greater incidence than with placebo were:
Blood and Lymphatic: Lymphatic signs and symptoms.
Cardiovascular: Palpitations.
Drug Interaction, Overdose, and Trauma: Muscle injuries, fractures,
wounds and lacerations, contusions and hematomas, burns.
Ear, Nose, and Throat: Rhinorrhea/post nasal drip; ear, nose and throat
infections; ear signs and symptoms; nasal signs and symptoms; nasal sinus
disorders; rhinitis; sneezing; nasal irritation; blood in nasal mucosa.
Eye: Keratitis and conjunctivitis, viral eye infections, eye redness.
Gastrointestinal: Dental discomfort and pain, gastrointestinal signs and
symptoms, gastrointestinal infections, gastroenteritis, gastrointestinal
disorders, oral ulcerations, oral erythema and rashes, constipation,
appendicitis, oral discomfort and pain.
Hepatobiliary Tract and Pancreas: Abnormal liver function tests.
Lower Respiratory: Lower respiratory signs and symptoms, pneumonia, lower
respiratory infections.
Musculoskeletal: Arthralgia and articular rheumatism; muscle stiffness,
tightness, and rigidity; bone and cartilage disorders.
Neurology: Sleep disorders, tremors, hypnagogic effects, compressed nerve
syndromes.
Non-Site Specific: Allergies and allergic reactions, congestion, viral
infections, pain, chest symptoms, fluid retention, bacterial infections, wheeze
and hives, unusual taste.
Skin: Viral skin infections, urticaria, skin flakiness and acquired
ichthyosis, disorders of sweat and sebum, sweating.
The incidence of common adverse experiences reported in Study 3, a 28 week,
non-US clinical study of 503 patients previously treated with inhaled
corticosteroids who were treated twice daily with fluticasone propionate;
salmeterol xinafoate 500/50, fluticasone propionate inhalation powder 500 μg and
salmeterol inhalation powder 50 μg used concurrently, or fluticasone propionate
inhalation powder 500 μg was similar to the incidences reported in
TABLE 3A and TABLE 3B.
Observed During Clinical Practice
In addition to adverse events reported from clinical trials, the following
events have been identified during postapproval use of fluticasone propionate;
salmeterol xinafoate, fluticasone propionate, and/or salmeterol. Because they
are reported voluntarily from a population of unknown size, estimates of
frequency cannot be made. These events have been chosen for inclusion due to a
combination of their seriousness, frequency of reporting, or potential causal
connection to fluticasone propionate; salmeterol xinafoate, fluticasone
propionate, and/or salmeterol.
In extensive US and worldwide postmarketing experience with salmeterol, a
component of fluticasone propionate; salmeterol xinafoate, serious exacerbations
of asthma, including some that have been fatal, have been reported. In most
cases, these have occurred in patients with severe asthma and/or in some
patients in whom asthma has been acutely deteriorating (see
WARNINGS), but they have also occurred in a few
patients with less severe asthma. It was not possible from these reports to
determine whether salmeterol contributed to these events or simply failed to
relieve the deteriorating asthma.
Cardiovascular: Arrhythmias (including atrial fibrillation, extrasystoles,
supraventricular tachycardia), ventricular tachycardia.
Ear, Nose, and Throat: Aphonia, earache, paranasal sinus pain, throat
soreness and irritation.
Endocrine and Metabolic: Cushing syndrome, Cushingoid features, growth
velocity reduction in children/adolescents, hypercorticism, hyperglycemia,
weight gain.
Gastrointestinal: Abdominal pain, dyspepsia, xerostomia.
Musculoskeletal: Back pain, cramps, muscle spasm, myositis.
Neurology: Paresthesia, restlessness.
Non-Site Specific: Immediate and delayed hypersensitivity reaction,
pallor.
Psychiatry: Agitation, aggression, depression.
Respiratory: Chest congestion, chest tightness, dyspnea, immediate
bronchospasm, influenza, paradoxical bronchospasm, tracheitis, wheezing, reports
of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such
as stridor or choking.
Skin: Contact dermatitis, contusions, ecchymoses, photodermatitis.
Urogenital: Dysmenorrhea, irregular menstrual cycle, pelvic inflammatory
disease, vaginal candidiasis, vaginitis, vulvovaginitis.
Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone
propionate, a component of Advair Diskus, may present with systemic
eosinophilic conditions, with some patients presenting with clinical features of
vasculitis consistent with Churg-Strauss syndrome, a condition that is often
treated with systemic corticosteroid therapy. These events usually, but not
always, have been associated with the reduction and/or withdrawal of oral
corticosteroid therapy following the introduction of fluticasone propionate.
Cases of serious eosinophilic conditions have also been reported with other
inhaled corticosteroids in this clinical setting. While fluticasone propionate;
salmeterol xinafoate should not be used for transferring patients from systemic
corticosteroid therapy, physicians should be alert to eosinophilia, vasculitic
rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy
presenting in their patients. A causal relationship between fluticasone
propionate and these underlying conditions has not been established (see
PRECAUTIONS, General, Eosinophilic Conditions).
OVERDOSAGE:
Fluticasone Propionate; Salmeterol Xinafoate
No deaths occurred in rats given combinations of salmeterol and fluticasone
propionate at acute inhalation doses of 3.6 and 1.9 mg/kg, respectively
(approximately 320 and 15 times the maximum recommended daily inhalation dose in
adults on a mg/m2 basis).
Fluticasone Propionate
Chronic overdosage with fluticasone propionate may result in signs/symptoms
of hypercorticism (see PRECAUTIONS). Inhalation by
healthy volunteers of a single dose of 4000 μg of fluticasone propionate
inhalation powder or single doses of 1760 or 3520 μg of fluticasone propionate
inhalation aerosol was well tolerated. Fluticasone propionate given by
inhalation aerosol at doses of 1320 μg twice daily for 7-15 days to healthy
human volunteers was also well tolerated. Repeat oral doses up to 80 mg daily
for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42
days in patients were well tolerated. Adverse reactions were of mild or moderate
severity, and incidences were similar in active and placebo treatment groups.
The oral and subcutaneous median lethal doses in mice and rats were >1000 mg/kg
(>4300 and >8700 times, respectively, the maximum recommended daily inhalation
dose in adults on a mg/m2 basis).
Salmeterol
The expected signs and symptoms with overdosage of salmeterol are those of
excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any
of the signs and symptoms listed under ADVERSE REACTIONS,
e.g., seizures, angina, hypertension or hypotension, tachycardia with
rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle
cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and
insomnia. Overdosage with salmeterol may be expected to result in exaggeration
of the pharmacologic adverse effects associated with beta-adrenoceptor agonists,
including tachycardia and/or arrhythmia, tremor, headache, and muscle cramps.
Overdosage with salmeterol can lead to clinically significant prolongation of
the QTc interval, which can produce ventricular arrhythmias. Other signs of
overdosage may include hypokalemia and hyperglycemia.
As with all sympathomimetic medications, cardiac arrest and even death may be
associated with abuse of salmeterol.
Treatment consists of discontinuation of salmeterol together with appropriate
symptomatic therapy. The judicious use of a cardioselective beta-receptor
blocker may be considered, bearing in mind that such medication can produce
bronchospasm. There is insufficient evidence to determine if dialysis is
beneficial for overdosage of salmeterol. Cardiac monitoring is recommended in
cases of overdosage.
No deaths were seen in rats given salmeterol at an inhalation dose of 2.9
mg/kg (approximately 250 times the maximum recommended daily inhalation dose in
adults on a mg/m2 basis) and in dogs at an inhalation dose of 0.7
mg/kg (approximately 200 times the maximum recommended daily inhalation dose in
adults on a mg/m2 basis). By the oral route, no deaths occurred in
mice at 150 mg/kg (approximately 6500 times the maximum recommended daily
inhalation dose in adults on a mg/m2 basis) and in rats at 1000 mg/kg
(approximately 86,000 times the maximum recommended daily inhalation dose in
adults on a mg/m2 basis).
DOSAGE AND ADMINISTRATION:
Advair Diskus is available in 3 strengths, Advair Diskus
100/50, Advair Diskus 250/50, and Advair Diskus 500/50, containing
100, 250, and 500 μg of fluticasone propionate, respectively, and 50 μg of
salmeterol per inhalation. Advair Diskus should be administered by the
orally inhaled route only (see Patient's Instructions for Use).
For patients 12 years of age and older, the dosage is 1 inhalation twice
daily (morning and evening, approximately 12 hours apart).
The recommended starting doses for fluticasone propionate; salmeterol
xinafoate are based upon patients' current asthma therapy.
| For patients who are not currently on an inhaled corticosteroid, whose
disease severity warrants treatment with 2 maintenance therapies, including
patients on non-corticosteroid maintenance therapy, the recommended starting
dose is fluticasone propionate; salmeterol xinafoate 100/50 twice daily.
|
| For patients on an inhaled corticosteroid,
TABLE 4 provides the recommended starting dose.
|
The maximum recommended dose is fluticasone propionate; salmeterol xinafoate
500/50 twice daily.
For all patients it is desirable to titrate to the lowest effective
strength after adequate asthma stability is achieved.
TABLE 4 Recommended Doses of Advair Diskus for
Patients Taking Inhaled Corticosteroids
| Current Daily Dose of
Inhaled Corticosteroid |
Recommended Strength and
Dosing Schedule of Advair Diskus |
| Beclomethasone Dipropionate |
|
≤420 μg |
100/50 twice daily |
|
462-840 μg |
250/50 twice daily |
| Budenoside |
|
≤400 μg |
100/50 twice daily |
|
800-1200 μg |
250/50 twice daily |
|
1600 μg* |
500/50 twice daily |
| Flunisolide |
|
≤1000 μg |
100/50 twice daily |
|
1250-2000 μg |
250/50 twice daily |
| Fluticasone Propionate
Inhalation Aerosol |
|
≤176 μg |
100/50 twice daily |
|
440 μg |
250/50 twice daily |
|
660-880 μg* |
500/50 twice daily |
| Fluticasone Propionate
Inhalation Powder |
|
≤200 μg |
100/50 twice daily |
|
500 μg |
250/50 twice daily |
|
1000 μg* |
500/50 twice daily |
| Triamcinolone Acetonide |
|
≤1000 μg |
100/50 twice daily |
|
1100-1600 μg |
250/50 twice daily |
| * Advair
Diskus should not be used for transferring patients from systemic
corticosteroid therapy. |
Advair Diskus should be administered twice daily every day. More
frequent administration (more than twice daily) or a higher number of
inhalations (more than 1 inhalation twice daily) of the prescribed strength of
Advair Diskus is not recommended as some patients are more likely to
experience adverse effects with higher doses of salmeterol. The safety and
efficacy of Advair Diskus when administered in excess of recommended
doses have not been established.
If symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist
should be taken for immediate relief.
Patients who are receiving Advair Diskus twice daily should not use
salmeterol for prevention of exercise-induced bronchospasm, or for any other
reason.
Improvement in asthma control following inhaled administration of Advair
Diskus can occur within 30 minutes of beginning treatment, although maximum
benefit may not be achieved for 1 week or longer after starting treatment.
Individual patients will experience a variable time to onset and degree of
symptom relief.
For patients who do not respond adequately to the starting dose after 2 weeks
of therapy, replacing the current strength of Advair Diskus with a higher
strength may provide additional asthma control.
If a previously effective dosage regimen of Advair Diskus fails to
provide adequate control of asthma, the therapeutic regimen should be
reevaluated and additional therapeutic options, e.g., replacing the
current strength of Advair Diskus with a higher strength, adding
additional inhaled corticosteroid, or initiating oral corticosteroids, should be
considered.
Rinsing the mouth after inhalation is advised.
Geriatric Use
In studies where geriatric patients (65 years of age or older, see
PRECAUTIONS, Geriatric Use) have been treated with
Advair Diskus, efficacy and safety did not differ from that in younger
patients. Based on available data for Advair Diskus and its active
components, no dosage adjustment is recommended.
HOW SUPPLIED:
Advair Diskus 100/50 is supplied as a disposable, purple-colored device
containing 60 blisters. The DISKUS inhalation device is packaged within a
purple-colored, plastic-coated, moisture-protective foil pouch.
Advair Diskus 250/50 is supplied as a disposable, purple-colored device
containing 60 blisters. The DISKUS inhalation device is packaged within a
purple-colored, plastic-coated, moisture-protective foil pouch.
Advair Diskus 500/50 is supplied as a disposable, purple-colored device
containing 60 blisters. The DISKUS inhalation device is packaged within a
purple-colored, plastic-coated, moisture-protective foil pouch.
Storage: Store at controlled room temperature, 20-25°C (68-77°F) in a
dry place away from direct heat or sunlight. Keep out of reach of children. The
DISKUS inhalation device is not reusable. The device should be discarded 1 month
after removal from the moisture-protective foil overwrap pouch or after every
blister has been used (when the dose indicator reads "0"), whichever comes
first. Do not attempt to take the device apart.
HOW SUPPLIED - EQUIVALENTS NOT
AVAILABLE:
|
| Powder -- Inhalation -- 100 mcg;50 mcg |
|
|
28's |
$75.27 |
Advair Diskus |
Glaxo Wellcome |
00173-0695-02 |
|
|
60's |
$111.53 |
Advair Diskus |
Glaxo Wellcome |
00173-0695-00 |
| Powder -- Inhalation -- 250 mcg;50 mcg |
|
|
28's |
$92.89 |
Advair Diskus |
Glaxo Wellcome |
00173-0696-02 |
|
|
60's |
$141.16 |
Advair Diskus |
Glaxo Wellcome |
00173-0696-00 |
| Powder -- Inhalation -- 500 mcg;50 mcg |
|
|
28's |
$130.65 |
Advair Diskus |
Glaxo Wellcome |
00173-0697-02 |
|
|
60's |
$194.04 |
Advair Diskus |
Glaxo Wellcome |
00173-0697-00 |
|
