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CLINICAL PHARMACOLOGY

Mechanism of Action

ADVAIR DISKUS

Since ADVAIR DISKUS contains both fluticasone propionate and salmeterol, the mechanisms of action described below for the individual components apply to ADVAIR DISKUS (fluticasone propionate) . These drugs represent 2 classes of medications (a synthetic corticosteroid and a selective, long-acting beta-adrenergic receptor agonist) that have different effects on clinical and physiological indices.

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-17­monopropionate (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.

Inflammation is 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, neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

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

Salmeterol Xinafoate

Salmeterol is a selective, long-acting beta2-adrenergic agonist. In vitro studies show salmeterol to be at least 50 times more selective for beta2-adrenoceptors than albuterol. Although beta2-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors.

The precise function of these receptors has not been established, but 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.

Pharmacodynamics

ADVAIR DISKUS (fluticasone propionate)

Healthy Subjects: Cardiovascular Effects: Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four (4) studies were conducted in healthy adult subjects: (1) a single-dose crossover study using 2 inhalations of ADVAIR DISKUS 500/50, fluticasone propionate powder 500 mcg and salmeterol powder 50 mcg given concurrently, or fluticasone propionate powder 500 mcg given alone, (2) a cumulative dose study using 50 to 400 mcg of salmeterol powder given alone or as ADVAIR DISKUS (fluticasone propionate) 500/50, (3) a repeat-dose study for 11 days using 2 inhalations twice daily of ADVAIR DISKUS 250/50, fluticasone propionate powder 250 mcg, or salmeterol powder 50 mcg, and (4) a single-dose study using 5 inhalations of ADVAIR DISKUS 100/50, fluticasone propionate powder 100 mcg 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 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 (fluticasone propionate) . The potential effect of salmeterol on the effects of fluticasone propionate on the HPA axis was also evaluated in these studies.

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

Asthma: Adults and Adolescent Patients: Cardiovascular Effects: In clinical studies with ADVAIR DISKUS (fluticasone propionate) in adult and adolescent patients aged 12 years and older with asthma, no significant differences were observed in the systemic pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given alone or as ADVAIR DISKUS (fluticasone propionate) . In 72 adolescent and adult patients with asthma given either ADVAIR DISKUS 100/50 (fluticasone propionate) or ADVAIR DISKUS (fluticasone propionate) 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.

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

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

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

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

Chronic Obstructive Pulmonary Disease: Cardiovascular Effects: In clinical studies with ADVAIR DISKUS (fluticasone propionate) in patients with COPD, no significant differences were seen in pulse rate, blood pressure, potassium, and glucose between ADVAIR DISKUS (fluticasone propionate) , the individual components of ADVAIR DISKUS (fluticasone propionate) , and placebo. In a study of ADVAIR DISKUS (fluticasone propionate) 250/50, 8 patients (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 > 470 msec at least 1 time during the treatment period. Five (5) of these 8 patients had a prolonged QTc interval at baseline.

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

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

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

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

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

Other Fluticasone Propionate Products

Asthma: HPA Axis Effects: In clinical trials with fluticasone propionate inhalation powder using doses up to and including 250 mcg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol < 18 mcg/dL assessed by radioimmunoassay) were noted both in patients receiving fluticasone propionate and in patients receiving placebo. The incidence of abnormal tests at 500 mcg twice daily was greater than placebo. In a 2-year study carried out with the DISKHALER® inhalation device in 64 patients with mild, persistent asthma (mean FEV1 91% of predicted) randomized to fluticasone propionate 500 mcg twice daily or placebo, no patient receiving fluticasone propionate had an abnormal response to 6-hour cosyntropin infusion (peak serum cortisol < 18 mcg/dL). With a peak cortisol threshold of < 35 mcg/dL, 1 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.

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

Other Salmeterol Xinafoate Products

Asthma: Cardiovascular Effects: Inhaled salmeterol, like other beta-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium [see WARNINGS AND PRECAUTIONS]. The cardiovascular effects (heart rate, blood pressure) associated with salmeterol 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 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). Adolescent and adult patients receiving 50-mcg doses of salmeterol inhalation powder (N = 60) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted.

Concomitant Use of ADVAIR DISKUS (fluticasone propionate) With Other Respiratory Medications

Short-Acting Beta2-Agonists: In clinical trials with patients with asthma, the mean daily need for albuterol by 166 adult and adolescent patients aged 12 years and older using ADVAIR DISKUS (fluticasone propionate) was approximately 1.3 inhalations/day, and ranged from 0 to 9 inhalations/day. Five percent (5%) of patients using ADVAIR DISKUS (fluticasone propionate) 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 reactions was observed among patients who averaged 6 or more inhalations per day.

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

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

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

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

Pharmacokinetics

Absorption

Fluticasone Propionate: Healthy Subjects: Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. 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.

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

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

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

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

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

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

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

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

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

Distribution

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

The percentage of fluticasone propionate bound to human plasma proteins averages 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin.

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

Metabolism

Fluticasone Propionate: The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP 3A4 pathway. This metabolite had less affinity (approximately ½,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

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

An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to α-hydroxysalmeterol (aliphatic oxidation) by CYP 3A4. Ketoconazole, a strong inhibitor of CYP 3A4, essentially completely inhibited the formation of α-hydroxysalmeterol in vitro .

Elimination

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

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

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

Special Populations

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

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

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

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

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

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

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

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

Drug Interactions

In the repeat- and single-dose studies, there was no evidence of significant drug interaction in systemic exposure between fluticasone propionate and salmeterol when given as ADVAIR DISKUS (fluticasone propionate) . The population pharmacokinetic analysis from 9 controlled clinical trials in 350 patients 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 CYP 3A4. Coadministration of fluticasone propionate and the strong CYP 3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable ( < 10 pg/mL) in most subjects, and when concentrations were detectable peak levels (Cmax) averaged 11.9 pg/mL (range, 10.8 to 14.1 pg/mL) and AUC(0-τ ) averaged 8.43 pg•hr/mL (range, 4.2 to 18.8pg•hr/mL). Fluticasone propionate Cmax and AUC(0-τ ) increased to 318 pg/mL (range, 110 to 648 pg/mL) and 3,102.6 pg•hr/mL (range, 1,207.1 to 5,662.0 pg•hr/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in serum cortisol AUC.

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

Salmeterol: In a placebo-controlled, crossover drug interaction study in 20 healthy male and female subjects, coadministration of salmeterol (50 mcg twice daily) and the strong CYP 3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a significant increase in plasma salmeterol exposure as determined by a 16-fold increase in AUC (ratio with and without ketoconazole 15.76 [90% CI: 10.66, 23.31]) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations were increased by 1.4-fold [90% CI: 1.23, 1.68]. Three (3) out of 20 subjects (15%) were withdrawn from salmeterol and ketoconazole coadministration due to beta-agonist–mediated systemic effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, mean blood potassium, or mean blood glucose. Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.

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

Salmeterol: In a repeat-dose study in 13 healthy subjects, concomitant administration of erythromycin (a moderate CYP 3A4 inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase in salmeterol Cmax at steady state (ratio with and without erythromycin 1.4 [90% CI: 0.96, 2.03], p = 0.12), a 3.6-beat/min increase in heart rate ([95% CI: 0.19, 7.03], p < 0.04), a 5.8-msec increase in QTc interval ([95% CI: -6.14, 17.77], p = 0.34), and no change in plasma potassium.

Animal Toxicology and/or Pharmacology

Preclinical

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

Reproductive Toxicology Studies

ADVAIR DISKUS (fluticasone propionate) : In mice, combining 150 mcg/kg subcutaneously of fluticasone propionate (less than the MRHD on a mg/m² basis) with 10 mg/kg orally of salmeterol (approximately 410 times the MRHD on a mg/m² basis) produced cleft palate, fetal death, increased implantation loss, and delayed ossification. No such effects were observed at combination subcutaneous doses up to 40 mcg/kg subcutaneously of fluticasone propionate (less than the MRHD on a mg/m² basis) and up to 1.4 mg/kg orally doses of salmeterol (approximately 55 times the MRHD on a mg/m² basis).

In rats, combining 100 mcg/kg subcutaneously of fluticasone propionate (equivalent to the MRHD on a mg/m² basis) and 10 mg/kg orally of salmeterol (approximately 810 times the MRHD on a mg/m² basis) produced decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone. No such effects were observed at combination doses up to 30 mcg/kg subcutaneously of fluticasone propionate (less than the MRHD on a mg/m² basis) and up to 1 mg/kg orally of salmeterol (approximately 80 times the MRHD on a mg/m² basis).

Fluticasone Propionate: Subcutaneous studies in the mouse and rat at 45 and 100 mcg/kg (less than and equivalent to the MRHD on a mg/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 mcg/kg (less than the MRHD on a mg/m² basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 5 times the MRHD on a mg/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.

Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.

Salmeterol: No teratogenic effects occurred in rats at oral doses up to 2 mg/kg (approximately 160 times the MRHD on a mg/m² basis).

In Dutch rabbits administered oral doses of 1 mg/kg and above (approximately 50 times and above the MRHD 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 such effects occurred at an oral dose of 0.6 mg/kg (approximately 20 times the MRHD 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 1,600 times the MRHD on a mg/m² basis).

Salmeterol crossed the placenta following oral administration to mice and rats.

Clinical Studies

Asthma

Adult and Adolescent Patients Aged 12 Years and Older

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

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

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

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

Table 4: Percent of Patients Withdrawn Due to Worsening Asthma in Patients Previously Treated With Either Inhaled Corticosteroids or Salmeterol (Study 1)

ADVAIR DISKUS (fluticasone propionate)
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 patients in the placebo group to be withdrawn, FEV1 results at Endpoint (last available FEV1 result) are also provided. Patients receiving ADVAIR DISKUS (fluticasone propionate) 100/50 had significantly greater improvements in FEV1 (0.51 L, 25%) compared with fluticasone propionate 100 mcg (0.28 L, 15%), salmeterol (0.11 L, 5%), and placebo (0.01 L, 1%). These improvements in FEV1 with ADVAIR DISKUS (fluticasone propionate) were achieved regardless of baseline asthma maintenance therapy (inhaled corticosteroids or salmeterol).

Figure 2. Mean Percent Change From Baseline in FEV1 in Patients With Asthma Previously Treated With Either Inhaled Corticosteroids or Salmeterol (Study 1)

Mean Percent Change From Baseline in FEV1 in Patients With Asthma Previously Treated With Either Inhaled Corticosteroids or Salmeterol (Study 1) - Illustration

N N N N
ADVAIR DISKUS 100/50 87 79 73 86
Fluticasone propionate 100 mcg 85 71 65 85
Salmeterol 50 mcg 86 59 51 86
Placebo 77 34 27 74

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

Table 5. Peak Expiratory Flow Results for Patients With Asthma Previously Treated With Either Inhaled Corticosteroids or Salmeterol (Study 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
aChange 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 7­point scale where 1 = maximum impairment and 7 = none). Patients receiving ADVAIR DISKUS 100/50 (fluticasone propionate) had clinically meaningful improvements in overall asthma-specific quality of life as defined by a difference between groups of ≥ 0.5 points in change from baseline AQLQ scores (difference in AQLQ score of 1.25 compared with placebo).

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

Efficacy results in this study were similar to those observed in Study 1. Patients receiving ADVAIR DISKUS (fluticasone propionate) 250/50 had significantly greater improvements in FEV1 (0.48 L, 23%) compared with fluticasone propionate 250 mcg (0.25 L, 13%), salmeterol (0.05 L, 4%), and placebo (decrease of 0.11 L, decrease of 5%). Statistically significantly fewer patients receiving ADVAIR DISKUS (fluticasone propionate) 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 (fluticasone propionate) 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 with placebo).

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

Baseline PEF measurements were similar across treatments: ADVAIR DISKUS 500/50, 359 L/min; fluticasone propionate 500 mcg, 351 L/min; and concurrent therapy, 345 L/min. Morning PEF improved significantly with ADVAIR DISKUS 500/50 compared with fluticasone propionate 500 mcg over the 12-week treatment period. Improvements in morning PEF observed with ADVAIR DISKUS (fluticasone propionate) 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 to 60 minutes. Maximum improvement in FEV1 generally occurred within 3 hours, and clinically significant improvement was maintained for 12 hours (see Figure 3). Following the initial dose, predose FEV1 relative to Day 1 baseline improved markedly over the first week of treatment and continued to improve over the 12 weeks of treatment in both studies. No diminution in the 12-hour bronchodilator effect was observed with either ADVAIR DISKUS 100/50 (fluticasone propionate) (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 Patients With Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Study 1) First Treatment Day

Percent Change in Serial 12-hour FEV1 in Patients With Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Study 1) - Illustration

Figure 4: Percent Change in Serial 12-hour FEV1 in Patients With Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Study 1) Last Treatment Day (Week 12)

Percent Change in Serial 12-hour FEV<sub>1</sub>
  in Patients With Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol
  (Study 1) - Illustration

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

Pediatric Patients

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

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

Chronic Obstructive Pulmonary Disease

The efficacy of ADVAIR DISKUS (fluticasone propionate) 250/50 and ADVAIR DISKUS (fluticasone propionate) 500/50 in the treatment of patients with COPD was evaluated in 6 randomized, double-blind, parallel-group clinical trials in adult patients aged 40 years and older. These trials were primarily designed to evaluate the efficacy of ADVAIR DISKUS (fluticasone propionate) 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 (fluticasone propionate) on lung function were conducted in 1,414 patients with COPD associated with chronic bronchitis. In these 2 trials, all the patients had a history of cough productive of sputum that was not attributable to another disease process on most days for at least 3 months of the year for at least 2 years. The trials were randomized, double-blind, parallel-group, 24-week treatment duration. One trial evaluated the efficacy of ADVAIR DISKUS 250/50 compared with its components fluticasone propionate 250 mcg and salmeterol 50 mcg and with placebo, and the other trial evaluated the efficacy of ADVAIR DISKUS 500/50 compared with its components fluticasone propionate 500 mcg and salmeterol 50 mcg and with placebo. Study treatments were inhalation powders given as 1 inhalation from the DISKUS device twice daily. Maintenance COPD therapies were discontinued, with the exception of theophylline. The patients had a mean pre-bronchodilator FEV1 of 41% and 20% reversibility at study entry. Percent reversibility was calculated as 100 times (FEV1 post-albuterol minus FEV1 pre-albuterol)/FEV1 pre-albuterol.

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

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

Figure 5: Predose FEV1: Mean Percent Change From Baseline in Patients With Chronic Obstructive Pulmonary Disease

Predose FEV1: Mean Percent Change From Baseline in Patients With Chronic Obstructive Pulmonary Disease - Illustration

Figure 6: Two-Hour Postdose FEV1: Mean Percent Changes From Baseline Over Time in Patients With Chronic Obstructive Pulmonary Disease

Two-Hour Postdose FEV1: Mean Percent Changes From Baseline Over Time in Patients With Chronic Obstructive Pulmonary Disease - Illustration

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

Exacerbations

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

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

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

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

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

Survival

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

Last reviewed on RxList: 1/24/2011
This monograph has been modified to include the generic and brand name in many instances.

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