Advair Diskus For Asthma, COPD: Dosage, Uses, Side Effects, Interactions & Warnings

CLINICAL PHARMACOLOGY

Mechanism Of Action

ADVAIR DISKUS

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

Fluticasone Propionate

Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory action. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid sense organ that is 18 times that of dexamethasone, about doubly 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 coherent with these results. The clinical significance of these findings is nameless .
excitement is an crucial component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide roll of actions on multiple cell types ( for example, mast cells, eosinophils, neutrophils, macrophages, lymphocytes ) and mediators ( for example, histamine, eicosanoids, leukotrienes, cytokines ) involved in excitement. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma .
excitement is besides a component in the pathogenesis of COPD. In line to asthma, however, the overriding incendiary cells in COPD include neutrophils, CD8+ T-lymphocytes, and macrophages. The effects of corticosteroids in the treatment of COPD are not well defined and inhale corticosteroids and fluticasone propionate when used apart from ADVAIR DISKUS are not indicated for the discussion 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 overriding adrenergic receptors in bronchial smooth muscleman and beta1-adrenoceptors are the prevailing receptors in the heart, there are besides beta2-adrenoceptors in the human heart comprising 10 % to 50 % of the sum beta-adrenoceptors. The precise routine of these receptors has not been established, but their presence raises the possibility that even selective beta2-agonists may have cardiac effects .
The pharmacological 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 liberalization of bronchial politic muscle and prohibition of release of mediators of immediate hypersensitivity from cells, particularly from mast cells .
In vitro tests show that salmeterol is a potent and durable 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 inhale route. In humans, one doses of salmeterol administered via inhalant 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 remedy venereal disease, 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 microgram and salmeterol powder 50 microgram given concurrently, or fluticasone propionate powder 500 microgram given alone, ( 2 ) a accumulative acid test using 50 to 400 microgram of salmeterol powder given alone or as ADVAIR DISKUS 500/50, ( 3 ) a repeat-dose trial for 11 days using 2 inhalations twice casual of ADVAIR DISKUS 250/50, fluticasone propionate powder 250 microgram, or salmeterol powder 50 microgram, and ( 4 ) a single-dose test using 5 inhalations of ADVAIR DISKUS 100/50, fluticasone propionate gunpowder 100 microgram entirely, or placebo. In these trials no significant differences were observed in the pharmacodynamic effects of salmeterol ( pulsate rate, blood coerce, 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 besides evaluated in these trials .
Hypothalamic-Pituitary-Adrenal Axis Effects : No significant differences across treatments were observed in 24-hour urinary hydrocortisone elimination and, where measured, 24-hour plasma hydrocortisone 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 pornographic 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 time 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 gear venereal disease and after 12 weeks of therapy, and no clinically significant dysrhythmias were noted .
Hypothalamic-Pituitary-Adrenal Axis Effects : In a 28-week test in adult and adolescent subjects with asthma, ADVAIR DISKUS 500/50 doubly day by day was compared with the coincident use of salmeterol powder 50 microgram plus fluticasone propionate gunpowder 500 microgram from classify inhalers or fluticasone propionate gunpowder 500 microgram alone. No significant differences across treatments were observed in serum hydrocortisone AUC after 12 weeks of dosing or in 24-hour urinary hydrocortisone body waste after 12 and 28 weeks .
In a 12-week trial in adult and adolescent subjects with asthma, ADVAIR DISKUS 250/50 twice day by day was compared with fluticasone propionate powder 250 microgram alone, salmeterol powder 50 microgram alone, and placebo. For most subjects, the ability to increase hydrocortisone production in reaction to stress, as assessed by 30-minute cosyntropin foreplay, remained entire with ADVAIR DISKUS. One subject ( 3 % ) who received ADVAIR DISKUS 250/50 had an abnormal reception ( bill serum hydrocortisone less than 18 mcg/dL ) after dosing, compared with 2 subjects ( 6 % ) who received placebo, 2 subjects ( 6 % ) who received fluticasone propionate 250 microgram, and no subjects who received salmeterol .
In a repeat-dose, 3-way crossover voter trial, 1 inhalant doubly casual of ADVAIR DISKUS 100/50, FLOVENT® DISKUS® 100 microgram ( fluticasone propionate inhalation powder, 100 microgram ), or placebo was administered to 20 adult and adolescent subjects with asthma. After 28 days of treatment, geometric beggarly serum hydrocortisone AUC over 12 hours showed no significant deviation between ADVAIR DISKUS and FLOVENT DISKUS or between either active treatment and placebo .
Pediatric Subjects: Hypothalamic-Pituitary-Adrenal Axis
Effects
: In a 12-week test in subjects with asthma aged 4 to 11 years who were receiving inhale corticosteroids at trial entrance, ADVAIR DISKUS 100/50 doubly casual was compared with fluticasone propionate inhalation powder 100 microgram administered twice daily via the DISKUS. The values for 24-hour urinary hydrocortisone elimination at trial introduction and after 12 weeks of discussion were like within each discussion group. After 12 weeks, 24-hour urinary hydrocortisone body waste was besides 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 pulsation 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 drawn-out QTc time interval at baseline .
In a 24-week trial, 130 subjects with COPD received continuous 24-hour electrocardiographic monitoring anterior to the first acid and after 4 weeks of twice-daily discussion with either ADVAIR DISKUS 500/50, fluticasone propionate powder 500 microgram, salmeterol powder 50 microgram, or placebo. No significant differences in ventricular or supraventricular cardiac arrhythmia and heart pace were observed among the groups treated with ADVAIR DISKUS 500/50, the individual components, or placebo. One ( 1 ) topic in the fluticasone propionate group experienced atrial palpitate / atrial fibrillation, and 1 subject in the group given ADVAIR DISKUS 500/50 experienced heart blocking. 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 cardiac arrhythmia ) was lower for subjects who received salmeterol ( 1 %, 9 of 688 subjects who received either salmeterol 50 microgram or ADVAIR DISKUS ) compared with placebo ( 3 %, 10 of 370 subjects ) .
No significant differences with salmeterol 50 microgram alone or in combination with fluticasone propionate as ADVAIR DISKUS 500/50 were observed on pulsation rate and systolic and diastolic blood pressure in a subset of subjects with COPD who underwent 12-hour consecutive full of life sign measurements after the foremost venereal disease ( newton = 183 ) and after 12 weeks of therapy ( nitrogen = 149 ). median changes from baseline in pulse rate and systolic and diastolic blood pressure were alike to those seen with placebo .
Hypothalamic-Pituitary-Adrenal Axis Effects : Short-cosyntropin foreplay test was performed both at Day 1 and Endpoint in 101 subjects with COPD receiving twice-daily ADVAIR DISKUS 250/50, fluticasone propionate powder 250 microgram, salmeterol powder 50 microgram, or placebo. For most subjects, the ability to increase hydrocortisone production in answer to stress, as assessed by abruptly cosyntropin foreplay, remained entire with ADVAIR DISKUS 250/50. One ( 1 ) submit ( 3 % ) who received ADVAIR DISKUS 250/50 had an abnormal stimulated hydrocortisone reply ( extremum hydrocortisone less than 14.5 mcg/dL assessed by high-performance liquid chromatography ) after dosing, compared with 2 subjects ( 9 % ) who received fluticasone propionate 250 microgram, 2 subjects ( 7 % ) who received salmeterol 50 microgram, and 1 national ( 4 % ) who received placebo following 24 weeks of treatment or early discontinuance from trial .
After 36 weeks of dose, serum hydrocortisone concentrations in a subset of subjects with COPD ( newton = 83 ) were 22 % lower in subjects receiving ADVAIR DISKUS 500/50 and 21 % lower in subjects receiving fluticasone propionate 500 microgram than in subjects receiving placebo .

Other Fluticasone Propionate Products

Subjects with Asthma: Hypothalamic-Pituitary-Adrenal
Axis Effects
:
In clinical trials with fluticasone propionate inhalant gunpowder using dosages up to and including 250 microgram doubly daily, episodic abnormal short cosyntropin tests ( top out serum hydrocortisone 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 microgram doubly daily was greater than placebo. In a 2-year test carried out with the DISKHALER® inhalant device in 64 subjects with meek, persistent asthma ( mean FEV1 91 % of predicted ) randomized to fluticasone propionate 500 microgram doubly daily or placebo, no topic receiving fluticasone propionate had an abnormal response to 6-hour cosyntropin infusion ( top out serum hydrocortisone less than 18 mcg/dL ). With a bill hydrocortisone doorsill of less than 35 mcg/dL, 1 capable receiving fluticasone propionate ( 4 % ) had an abnormal response at 1 year ; repeat testing at 18 months and 2 years was normal. Another subjugate receiving fluticasone propionate ( 5 % ) had an abnormal reply at 2 years. No capable 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 drug, the steady-state fluticasone propionate pharmacokinetics and serum hydrocortisone levels were described in a subset of subjects with COPD ( north = 86 ) randomized to twice-daily fluticasone propionate inhalant powder via the DISKUS 500 microgram, fluticasone propionate inhalation gunpowder 250 microgram, or placebo. serial serum hydrocortisone concentrations were measured across a 12-hour dose interval. Serum hydrocortisone concentrations following 250-and 500-mcg twice-daily dose 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 early beta-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on lineage glucose and/or serum potassium [ see WARNINGS AND PRECAUTIONS ]. The cardiovascular effects ( heart rate, blood coerce ) associated with salmeterol inhalant aerosol occur with exchangeable frequency, and are of similar type and asperity, as those note following albuterol administration .
The effects of rising inhale doses of salmeterol and standard inhale doses of albuterol were studied in volunteers and in subjects with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in center rate increases of 3 to 16 beats/min, about the like as albuterol dosed at 180 microgram by inhalation aerosol ( 4 to 10 beats/min ). Adult and adolescent subjects receiving 50-mcg doses of salmeterol inhalant gunpowder ( N = 60 ) undergo continuous electrocardiographic monitor during two 12-hour periods after the first dose and after 1 calendar 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 necessitate for albuterol by 166 pornographic 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 percentage ( 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 test in subjects with COPD, the bastardly casual necessitate for albuterol for subjects using ADVAIR DISKUS 250/50 was 4.1 inhalations/day. twenty-six percentage ( 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 coincident use of intravenously or orally administered methylxanthines ( for example, 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 merchandise had adverse consequence rates similar to those in 304 subjects receiving ADVAIR DISKUS without theophylline. alike results were observed in subjects receiving salmeterol 50 microgram plus fluticasone propionate 500 microgram twice daily concurrently with a theophylline merchandise ( normality = 39 ) or without theophylline ( n = 132 ) .
In a clinical test in subjects with COPD, 17 subjects receiving ADVAIR DISKUS 250/50 doubly casual 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 attendant administration of methylxanthines with ADVAIR DISKUS did not alter the respect adverse consequence 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 microgram concurrently ( nitrogen = 46 ) and those who were not ( normality = 130 ) .

Pharmacokinetics

Absorption

Fluticasone Propionate: Healthy Subjects: Fluticasone propionate acts locally in the lung ; therefore, plasma levels do not predict remedy impression. Trials using oral drug of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible ( less than 1 % ), primarily due to incomplete assimilation and presystemic metamorphosis 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 pornographic subjects, bill plasma concentrations of fluticasone propionate were achieved in 1 to 2 hours. In a single-dose crossing over trial, a higher-than-recommended dose of ADVAIR DISKUS was administered to 14 healthy adult subjects. Two ( 2 ) inhalations of the follow treatments were administered : ADVAIR DISKUS 500/50, fluticasone propionate powder 500 microgram and salmeterol powder 50 microgram given concurrently, and fluticasone propionate powder 500 microgram alone. entail vertex 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 photograph to fluticasone propionate from 4 inhalations of ADVAIR® HFA 230/21 ( fluticasone propionate 230 microgram and salmeterol 21 microgram ) Inhalation Aerosol ( 920/84 microgram ) and 2 inhalations of ADVAIR DISKUS 500/50 ( 1,000/100 microgram ) were similar between the 2 inhalers ( i, 799 versus 832 pg•h/mL, respectively ), but approximately half the systemic vulnerability from 4 inhalations of fluticasone propionate CFC inhalant aerosol 220 microgram ( 880 microgram, AUC = 1,543 pg•h/mL ). similar results were observed for top out 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 inhalant 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 powderize using the DISKUS inhaler. The bastardly 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 inhalant powder 500 microgram doubly daily using the DISKUS inhaler and from 14 female and 43 male subjects with COPD given 250 or 500 microgram doubly day by day. 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 discussion with 250 mcg doubly daily ( nitrogen = 30 ) and 84 pg/mL ( image : 24.3 to 197.1 pg/mL ) after treatment with 500 mcg twice daily ( north = 27 ) via the fluticasone propionate DISKUS inhaler. In another trial in subjects with COPD, point steady-state fluticasone propionate plasma concentrations averaged 115 pg/mL ( stove : 52.6 to 366.0 pg/mL ) after treatment with 500 mcg twice daily via the fluticasone propionate DISKUS inhaler ( newton = 15 ) and 105 pg/mL ( range : 22.5 to 299.0 pg/mL ) via ADVAIR DISKUS ( newton = 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 curative consequence .
Following administration of ADVAIR DISKUS to healthy adult subjects, top out plasma concentrations of salmeterol were achieved in about 5 minutes .
In 15 healthy subjects receiving ADVAIR HFA 230/21 Inhalation Aerosol ( 920/84 microgram ) and ADVAIR DISKUS 500/50 ( 1,000/100 microgram ), 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 little remedy dose, systemic levels of salmeterol are low or undetectable after inhalant of recommend doses ( 50 microgram of salmeterol inhalation powder twice day by day ). Following chronic administration of an inhale dose of 50 microgram of salmeterol inhalant gunpowder doubly daily, salmeterol was detected in plasma within 5 to 45 minutes in 7 subjects with asthma ; plasma concentrations were very low, with entail peak concentrations of 167 pg/mL at 20 minutes and no accumulation with repeat doses .

Distribution

Fluticasone Propionate: Following intravenous administration, the initial inclination phase for fluticasone propionate was rapid and coherent with its high lipid solvability and tissue bind. The volume of distribution averaged 4.2 L/kg .
The share of fluticasone propionate jump to human plasma proteins averages 99 %. Fluticasone propionate is weakly and reversibly tie to erythrocytes and is not importantly bound to human transcortin .
Salmeterol: The percentage of salmeterol adhere to homo plasma proteins averages 96 % in vitro over the assiduity 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 nephritic clearance account for less than 0.02 % of the total. The lone circulate 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 rear drug for the glucocorticoid receptor of homo lung cytosol in vitro and negligible pharmacological activity in animal studies. other metabolites detected in vitro using civilized human hepatoma cells have not been detected in serviceman .
Salmeterol: Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant sum of unaltered salmeterol al-qaeda was detected in either urine or feces .
An in vitro study using homo liver microsomes showed that salmeterol is extensively metabolized to α-hydroxysalmeterol ( aliphatic oxidation ) by CYP3A4. Ketoconazole, a impregnable inhibitor of CYP3A4, basically wholly 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 end excreted in the feces as rear 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 goodly adult subjects who received 1 magnesium 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 tennessean alone ) .
The xinafoate moiety has no apparent pharmacological activity. The xinafoate moiety is highly protein bind ( 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 control 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 inhalant aerosol ( FLOVENT® HFA ), or CFC-propelled fluticasone propionate inhalant 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 percentage of predict FEV1 on apparent clearance and apparent volume of distribution.

Age: When the population pharmacokinetic psychoanalysis for fluticasone propionate was divided into subgroups based on fluticasone propionate military capability, 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 microgram 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 microgram in adolescents and adults, no differences in systemic effects of corticosteroid treatment ( for example, HPA axis effects ) were observed. alike fluticasone propionate exposure was observed from ADVAIR DISKUS 500/50 and FLOVENT DISKUS 500 microgram ( ratio 0.83 [ 90 % CI : 0.65, 1.07 ] ) in adolescents and adults .
Steady-state systemic vulnerability to salmeterol when delivered as ADVAIR DISKUS 100/50, ADVAIR DISKUS 250/50, or ADVAIR HFA 115/21 ( fluticasone propionate 115 microgram and salmeterol 21 microgram ) Inhalation Aerosol was evaluated in 127 subjects aged 4 to 57 years. The geometric intend 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 microgram. Higher fluticasone propionate photograph ( AUC ) was observed in children from ADVAIR DISKUS 100/50 compared with FLOVENT DISKUS 100 microgram ( proportion 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 microgram in both adolescents and adults and in children, no differences in systemic effects of corticosteroid discussion ( for example, 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 ( for example, 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 sex 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 sex differences for salmeterol pharmacokinetics .
Hepatic and Renal Impairment: Formal pharmacokinetic studies using ADVAIR DISKUS have not been conducted in patients with liverwort or nephritic disability. however, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism, damage 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 operate 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 impregnable CYP3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction test in 18 healthy subjects. Fluticasone propionate aqueous adenoidal spray ( 200 microgram once daily ) was coadministered for 7 days with ritonavir ( 100 magnesium doubly daily ). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous adenoidal spray alone were indiscernible ( less than 10 pg/mL ) in most subjects, and when concentrations were detectable point levels ( Cmax ) averaged 11.9 pg/mL ( rate : 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 meaning decrease ( 86 % ) in serum hydrocortisone AUC .
Ketoconazole: Fluticasone Propionate: In a placebo-controlled crossing trial in 8 healthy adult volunteers, coadministration of a single drug of orally inhaled fluticasone propionate ( 1,000 microgram ) with multiple doses of ketoconazole ( 200 milligram ) to steady state resulted in increase plasma fluticasone propionate exposure, a reduction in plasma hydrocortisone AUC, and no effect on urinary elimination of hydrocortisone .
Salmeterol: In a placebo-controlled, crossing drug interaction trial in 20 healthy male and female subjects, coadministration of salmeterol ( 50 microgram doubly daily ) and the strong CYP3A4 inhibitor ketoconazole ( 400 milligram once daily ) for 7 days resulted in a meaning increase in plasma salmeterol exposure as determined by a 16-fold increase in AUC ( proportion with and without ketoconazole 15.76 [ 90 % CI : 10.66, 23.31 ] ) chiefly due to increased bioavailability of the swallow share 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 entail kernel rate, mean blood potassium, or mean rake 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 microgram twice day by day ) and erythromycin ( 333 magnesium 3 times daily ) did not affect fluticasone propionate pharmacokinetics .
Salmeterol: In a repeat-dose trial in 13 healthy subjects, attendant presidency of erythromycin ( a tone down CYP3A4 inhibitor ) and salmeterol inhalation aerosol resulted in a 40 % addition 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 time interval ( [ 95 % CI : -6.14, 17.77 ], P = 0.34 ), and no change in plasma potassium .

Animal Toxicology And/Or Pharmacology

Preclinical

Studies in testing ground animals ( minipigs, rodents, and dogs ) have demonstrated the occurrence of cardiac cardiac arrhythmia and sudden death ( with histological tell 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 consumption of either fluticasone propionate or salmeterol entirely. In addition, clinical trials showed exchangeable results between ADVAIR DISKUS and the coincident habit 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, service line FEV1 63 % to 72 % of predicted normal ) with asthma that was not optimally controlled on their current therapy. All treatments were inhalant powders given as 1 inhalant from the DISKUS inhaler doubly casual, and other care therapies were discontinued .
Trial 1: Clinical Trial with ADVAIR DISKUS 100/50: This placebo-controlled, 12-week, U.S. test compared ADVAIR DISKUS 100/50 with its individual components, fluticasone propionate 100 microgram and salmeterol 50 microgram. The trial was stratified according to baseline asthma sustenance therapy ; subjects were using either inhale corticosteroids ( north = 250 ) ( daily doses of beclomethasone dipropionate 252 to 420 microgram ; flunisolide 1,000 microgram ; fluticasone propionate inhalant aerosol 176 microgram ; or triamcinolone acetonide 600 to 1,000 microgram ) or salmeterol ( newton = 106 ). Baseline FEV1 measurements were exchangeable across treatments : ADVAIR DISKUS 100/50, 2.17 L ; fluticasone propionate 100 microgram, 2.11 L ; salmeterol, 2.13 L ; and placebo, 2.15 L .
Predefined secession criteria for miss 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, addition in nox awakenings due to asthma, emergency intervention or hospitalization due to asthma, or requirement for asthma medication not allowed by the protocol. As shown in board 4, statistically importantly 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 leave ) are besides provided. Subjects receiving ADVAIR DISKUS 100/50 had importantly greater improvements in FEV1 ( 0.51 L, 25 % ) compared with fluticasone propionate 100 microgram ( 0.28 L, 15 % ), salmeterol ( 0.11 L, 5 % ), and placebo ( 0.01 L, 1 % ). These improvements in FEV1 with ADVAIR DISKUS were achieved careless of baseline asthma maintenance therapy ( inhale 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)

Mean Percent Change from Baseline in FEV1 in Subjects with Asthma Previously Treated with Either Inhaled Corticosteroids or Salmeterol - Illustration

The effect of ADVAIR DISKUS 100/50 on good morning and even PEF endpoints is shown in board 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 shock 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 = maximal deterioration and 7 = none ). Subjects receiving ADVAIR DISKUS 100/50 had clinically meaningful improvements in overall asthma-specific quality of life as defined by a remainder between groups of ≥ 0.5 points in change from service line AQLQ scores ( difference in AQLQ sexual conquest 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 microgram and salmeterol 50 microgram, in 349 subjects with asthma using inhale corticosteroids ( casual doses of beclomethasone dipropionate 462 to 672 microgram ; flunisolide 1,250 to 2,000 microgram ; fluticasone propionate inhalation aerosol 440 microgram ; or triamcinolone acetonide 1,100 to 1,600 microgram ). Baseline FEV1 measurements were alike across treatments : ADVAIR DISKUS 250/50, 2.23 L ; fluticasone propionate 250 microgram, 2.12 L ; salmeterol, 2.20 L ; and placebo, 2.19 L .
efficacy results in this trial were exchangeable to those observed in test 1. Subjects receiving ADVAIR DISKUS 250/50 had significantly greater improvements in FEV1 ( 0.48 L, 23 % ) compared with fluticasone propionate 250 microgram ( 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 flush PEF. Subjects receiving ADVAIR DISKUS 250/50 besides 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 microgram alone and coincident therapy ( salmeterol 50 microgram plus fluticasone propionate 500 microgram administered from break inhalers ) doubly day by day in 503 subjects with asthma using inhale corticosteroids ( daily doses of beclomethasone dipropionate 1,260 to 1,680 microgram ; budesonide 1,500 to 2,000 microgram ; flunisolide 1,500 to 2,000 microgram ; or fluticasone propionate inhalant aerosol 660 to 880 mcg [ 750 to 1,000 mcg inhalation powder ] ). The basal efficacy parameter, morning PEF, was collected daily for the first 12 weeks of the test. The basal function of weeks 13 to 28 was to collect safety data .
Baseline PEF measurements were alike across treatments : ADVAIR DISKUS 500/50, 359 L/min ; fluticasone propionate 500 microgram, 351 L/min ; and coincident therapy, 345 L/min. Morning PEF improved significantly with ADVAIR DISKUS 500/50 compared with fluticasone propionate 500 microgram over the 12-week treatment period. Improvements in dawn PEF observed with ADVAIR DISKUS 500/50 were similar to improvements observed with coincident therapy .
Onset of Action and Progression of Improvement in
Asthma Control
:
The onset of natural process and progress of improvement in asthma control were evaluated in the 2 placebo-controlled U.S. trials. Following the first dose, the medial 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 broadly occurred within 3 hours, and clinically significant improvement was maintained for 12 hours ( Figure 3 ). Following the initial drug, predose FEV1 relative to Day 1 baseline improved markedly over the inaugural workweek 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

decrease in asthma symptoms and habit of rescue VENTOLIN Inhalation Aerosol and improvement in morning and even PEF besides 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 doubly day by day was compared with fluticasone propionate inhalant powder 100 microgram twice daily in 203 children with asthma aged 4 to 11 years. At trial entrance, the children were diagnostic on depleted doses of inhale 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 inhalant powderize 100 microgram in this age-group ; however, the trial besides included junior-grade efficacy measures of pneumonic function. Morning predose FEV1 was obtained at baseline and Endpoint ( last available FEV1 leave ) in children aged 6 to 11 years. In subjects receiving ADVAIR DISKUS 100/50, FEV1 increased from 1.70 L at service line ( north = 79 ) to 1.88 L at Endpoint ( normality = 69 ) compared with an increase from 1.65 L at service line ( north = 83 ) to 1.77 L at Endpoint ( newton = 75 ) in subjects receiving fluticasone propionate 100 microgram .
The findings of this trial, along with extrapolation of efficacy data from subjects aged 12 years and older, support the overall stopping point 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 randomize, 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 affair 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 phlegm that was not attributable to another disease process on most days for at least 3 months of the class 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 microgram and salmeterol 50 microgram and with placebo, and the other trial evaluated the efficacy of ADVAIR DISKUS 500/50 compared with its components fluticasone propionate 500 microgram and salmeterol 50 microgram 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 officiate ( 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 like 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 submit 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 milliliter, 17 % ) compared with salmeterol 50 microgram ( 91 milliliter, 9 % ) and placebo ( 1 milliliter, 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 milliliter, 27 % ) compared with fluticasone propionate 250 microgram ( 147 milliliter, 14 % ) and placebo ( 58 milliliter, 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 microgram, salmeterol 50 microgram, 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 test entrance, and 8.3 % reversibility. The primary end point 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 milliliter, 10 % ) compared with fluticasone propionate 500 microgram ( 7 milliliter, 2 % ), salmeterol ( 15 milliliter, 2 % ), and placebo ( -60 milliliter, -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 worsen of 2 or more major symptoms ( dyspnea, phlegm book, and phlegm pus ) or worsening of any 1 major symptom together with any 1 of the following minor symptoms : sensitive throat, colds ( nasal consonant discharge and/or adenoidal 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 insurance was required .
Exacerbations were besides evaluated as a secondary result in the 1-and 3-year trials with ADVAIR DISKUS 500/50. There was not a diagnostic definition of exacerbation in these 2 trials. Exacerbations were defined in terms of asperity requiring treatment with antibiotics and/or systemic corticosteroids ( reasonably severe ) or requiring hospitalization ( austere ) .
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 microgram, each given doubly day by day, on exacerbations of COPD over a 12-month menstruation. A full of 1,579 subjects had an established history of COPD ( but no other meaning 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 quarrel menstruation anterior to being assigned trial discussion with twice-daily ADVAIR DISKUS 250/50 or salmeterol 50 microgram. In both trials, treatment with ADVAIR DISKUS 250/50 resulted in a importantly 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 base test and ( 30.4 % reduction [ 95 % CI : 16.9, 41.7 ], P < 0.001 ) in the second trial. Subjects treated with ADVAIR DISKUS 250/50 besides had a significantly lower annual pace of exacerbations requiring treatment with oral corticosteroids compared with subjects treated with salmeterol ( 39.7 % decrease [ 95 % CI : 22.8, 52.9 ], P < 0.001 ) in the first base trial and ( 34.3 % reduction [ 95 % CI : 18.6, 47.0 ], P < 0.001 ) in the second test. secondary endpoints including pneumonic officiate and symptom scores improved more in subjects treated with ADVAIR DISKUS 250/50 than with salmeterol 50 microgram in both trials.

Exacerbations were evaluated in the 1-and the 3-year trials with ADVAIR DISKUS 500/50 as 1 of the junior-grade efficacy endpoints. In the 1-year test, the group receiving ADVAIR DISKUS 500/50 had a significantly lower rate of centrist 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 % decrease 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 mince and dangerous exacerbations compared with each of the other treatment groups ( 25.1 % reduction compared with placebo [ 95 % CI : 18.6, 31.1 ], 9.0 % decrease compared with fluticasone propionate [ 95 % CI : 1.2, 16.2 ], and 12.2 % decrease compared with salmeterol [ 95 % CI : 4.6, 19.2 ] ) .
There were no trials conducted to immediately 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 microgram, salmeterol 50 microgram, and placebo on survival in 6,112 subjects with COPD. During the trial subjects were permitted usual COPD therapy with the exception of other inhale 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 predict reversibility. Each subject who withdrew from double-blind discussion for any reason was followed for the full 3-year trial time period to determine survival condition. The elementary efficacy end point was all-cause deathrate. survival with ADVAIR DISKUS 500/50 was not importantly improved compared with placebo or the individual components ( all-cause deathrate 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 microgram and fluticasone propionate 500 microgram, respectively. secondary outcomes, including pneumonic routine ( post-bronchodilator FEV1 ), improved with ADVAIR DISKUS 500/50, salmeterol 50 microgram, and fluticasone propionate 500 microgram compared with placebo .

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