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Advair Description

Advair HFA 45/21 Inhalation Aerosol, Advair HFA 115/21 Inhalation Aerosol, and Advair HFA 230/21 Inhalation Aerosol are combinations of fluticasone propionate and salmeterol xinafoate.

One active component of Advair HFA is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9 - difluoro - 11β,17 - dihydroxy - 16α - methyl - 3 - oxoandrosta - 1,4 - diene - 17β - carbothioate, 17-propionate and the following chemical structure:

Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

The other active component of Advair HFA is salmeterol xinafoate, a beta2-adrenergic bronchodilator. Salmeterol xinafoate is the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol. The chemical name of salmeterol xinafoate is 4-hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate, and it has the following chemical structure:

Salmeterol xinafoate is a white powder with a molecular weight of 603.8, and the empirical formula is C25H37NO4•C11H8O3. It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water.

Advair HFA 45/21 Inhalation Aerosol, Advair HFA 115/21 Inhalation Aerosol, and Advair HFA 230/21 Inhalation Aerosol are pressurized, metered-dose aerosol units intended for oral inhalation only. Each unit contains a microcrystalline suspension of fluticasone propionate (micronized) and salmeterol xinafoate (micronized) in propellant HFA-134a (1,1,1,2-tetrafluoroethane). It contains no other excipients.

After priming, each actuation of the inhaler delivers 50, 125, or 250 mcg of fluticasone propionate and 25 mcg of salmeterol in 75 mg of suspension from the valve. Each actuation delivers 45, 115, or 230 mcg of fluticasone propionate and 21 mcg of salmeterol from the actuator. Twenty-one micrograms (21 mcg) of salmeterol base is equivalent to 30.45 mcg of salmeterol xinafoate. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the device and inspiration through the delivery system.

Each 12-g canister provides 120 inhalations.

Advair HFA should be primed before using for the first time by releasing 4 test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 4 weeks or when it has been dropped, prime the inhaler again by shaking well before each spray and releasing 2 test sprays into the air away from the face.

This product does not contain any chlorofluorocarbon (CFC) as the propellant.

Advair - Clinical Pharmacology

Mechanism of Action

Since Advair HFA contains both fluticasone propionate and salmeterol, the mechanisms of action described below for the individual components apply to Advair HFA. These drugs represent 2 classes of medications (a synthetic corticosteroid and a selective, long-acting beta2-adrenergic receptor agonist) that have different effects on clinical, physiologic, and inflammatory indices of asthma.

Fluticasone propionate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. In vitro assays using human lung cytosol preparations have established fluticasone propionate as a human glucocorticoid receptor agonist with an affinity 18 times greater than dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results.

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

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

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

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

Preclinical

In animals and humans, propellant HFA-134a was found to be rapidly absorbed and rapidly eliminated, with an elimination half-life of 3 to 27 minutes in animals and 5 to 7 minutes in humans. Time to maximum plasma concentration (Tmax) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation.

Propellant HFA-134a is devoid of pharmacological activity except at very high doses in animals (i.e., 380 to 1,300 times the maximum human exposure based on comparisons of area under the plasma concentration versus time curve [AUC] values), primarily producing ataxia, tremors, dyspnea, or salivation. These events are similar to effects produced by the structurally related CFCs, which have been used extensively in metered-dose inhalers. In drug interaction studies in male and female dogs, there was a slight increase in the salmeterol-related effect on heart rate (a known effect of beta2-agonists) when given in combination with high doses of fluticasone propionate. This effect was not observed in clinical studies.

Pharmacokinetics

Three single-dose, placebo-controlled, crossover studies were conducted in healthy subjects: (1) a study using 4 inhalations of Advair HFA 230/21, salmeterol CFC inhalation aerosol 21 mcg, or fluticasone propionate CFC inhalation aerosol 220 mcg, (2) a study using 8 inhalations of Advair HFA 45/21, Advair HFA 115/21, or Advair HFA 230/21, and (3) a study using 4 inhalations of Advair HFA 230/21; 2 inhalations of Advair DISKUS® 500/50 (fluticasone propionate 500 mcg and salmeterol 50 mcg inhalation powder); 4 inhalations of fluticasone propionate CFC inhalation aerosol 220 mcg; or 1,010 mcg of fluticasone propionate given intravenously. Peak plasma concentrations of fluticasone propionate were achieved in 0.33 to 1.5 hours and those of salmeterol were achieved in 5 to 10 minutes.

Peak plasma concentrations of fluticasone propionate (N = 20 subjects) following 8 inhalations of Advair HFA 45/21, Advair HFA 115/21, and Advair HFA 230/21 averaged 41, 108, and 173 pg/mL, respectively. Peak plasma salmeterol concentrations ranged from 220 to 470 pg/mL.

Systemic exposure (N = 20 subjects) from 4 inhalations of Advair HFA 230/21 was 53% of the value from the individual inhaler for fluticasone propionate CFC inhalation aerosol and 42% of the value from the individual inhaler for salmeterol CFC inhalation aerosol. Peak plasma concentrations from Advair HFA for fluticasone propionate (86 vs. 120 pg/mL) and salmeterol (170 vs. 510 pg/mL) were significantly lower compared to individual inhalers.

In 15 healthy subjects, systemic exposure to fluticasone propionate from 4 inhalations of Advair HFA 230/21 (920/84 mcg) and 2 inhalations of Advair DISKUS 500/50 (1,000/100 mcg) were similar between the 2 inhalers (i.e., 799 vs. 832 pg•h/mL) but approximately half the systemic exposure from 4 inhalations of fluticasone propionate CFC inhalation aerosol 220 mcg (1,543 pg•h/mL). Similar results were observed for peak fluticasone propionate plasma concentrations (186 and 182 pg/mL from Advair HFA and Advair DISKUS, respectively, and 307 pg/mL from the fluticasone propionate CFC inhalation aerosol). Systemic exposure to salmeterol was higher (317 vs. 169 pg•h/mL) and peak salmeterol concentrations were lower (196 vs. 223 pg/mL) following Advair HFA compared to Advair DISKUS, although pharmacodynamic results were comparable.

Absolute bioavailability of fluticasone propionate from Advair HFA in 15 healthy subjects was 5.3%. Terminal half-life estimates of fluticasone propionate for Advair HFA, Advair DISKUS, and fluticasone propionate CFC inhalation aerosol were similar and averaged 5.9 hours. No terminal half-life estimates were calculated for salmeterol.

A double-blind crossover study was conducted in 13 adult patients with asthma to evaluate the steady-state pharmacokinetics of fluticasone propionate and salmeterol following administration of 2 inhalations of Advair HFA 115/21 twice daily or 1 inhalation of Advair DISKUS 250/50 twice daily for 4 weeks. Systemic exposure (AUC) to fluticasone propionate was similar for Advair HFA (274 pg•h/mL [95% CI 150, 502]) and Advair DISKUS (338 pg•h/mL [95% CI 197, 581]). Systemic exposure to salmeterol was also similar for Advair HFA (53 pg•h/mL [95% CI 17, 164]) and Advair DISKUS (70 pg•h/mL [95% CI 19, 254]).

Special Populations

Hepatic and Renal Impairment

Formal pharmacokinetic studies using Advair HFA have not been conducted to examine gender differences or in special populations, such as elderly patients or 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 repeat- and single-dose studies, there was no evidence of significant drug interaction on systemic exposure to fluticasone propionate and salmeterol when given alone or in combination via the DISKUS. Similar definitive studies have not been performed with Advair HFA.

Absorption

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

Distribution

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

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

Metabolism

The total clearance of fluticasone propionate is high (average, 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 cytochrome P450 3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

Elimination

Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.

Special Populations

Gender

In 19 male and 33 female patients with asthma, systemic exposure was similar from 2 inhalations of fluticasone propionate CFC inhalation aerosol 44, 110, and 220 mcg twice daily.

Drug Interactions

Fluticasone propionate is a substrate of cytochrome P450 3A4. Coadministration of fluticasone propionate and the highly potent cytochrome P450 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 18.8 pg•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 systemic fluticasone propionate exposure resulted in a significant decrease (86%) in serum cortisol AUC.

Caution should be exercised when other potent cytochrome P450 3A4 inhibitors are coadministered with fluticasone propionate. In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased systemic fluticasone propionate exposure and reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol.

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

Absorption

Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of recommended doses (42 mcg of salmeterol inhalation aerosol twice daily). Following chronic administration of an inhaled dose of 42 mcg twice daily, salmeterol was detected in plasma within 5 to 10 minutes in 6 patients with asthma; plasma concentrations were very low, with mean peak concentrations of 150 pg/mL and no accumulation with repeated doses.

Distribution

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

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

Elimination

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.

Pharmacodynamics

Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four placebo-controlled, crossover studies were conducted in healthy subjects: (1) a cumulative-dose study using 42 to 336 mcg of salmeterol CFC inhalation aerosol given alone or as Advair HFA 115/21, (2) a single-dose study using 4 inhalations of Advair HFA 230/21, salmeterol CFC inhalation aerosol 21 mcg, or fluticasone propionate CFC inhalation aerosol 220 mcg, (3) a single-dose study using 8 inhalations of Advair HFA 45/21, Advair HFA 115/21, or Advair HFA 230/21, and (4) a single-dose study using 4 inhalations of Advair HFA 230/21; 2 inhalations of Advair DISKUS 500/50; 4 inhalations of fluticasone propionate CFC inhalation aerosol 220 mcg; or 1,010 mcg of fluticasone propionate given intravenously. In these studies pulse rate, blood pressure, QTc interval, glucose, and/or potassium were measured. Comparable or lower effects were observed for Advair HFA compared to Advair DISKUS or salmeterol alone. The effect of salmeterol on pulse rate and potassium was not altered by the presence of different amounts of fluticasone propionate in Advair HFA. The potential effect of salmeterol on the effects of fluticasone propionate on the hypothalamic-pituitary-adrenal (HPA) axis was also evaluated in 3 of these studies. Compared with fluticasone propionate CFC inhalation aerosol, Advair HFA had less effect on 24-hour urinary cortisol excretion and less or comparable effect on 24-hour serum cortisol. In these crossover studies in healthy subjects, Advair HFA and Advair DISKUS had similar effects on urinary and serum cortisol.

In clinical studies with Advair HFA in patients with asthma, systemic pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) were similar to or slightly lower in patients treated with Advair HFA compared with patients treated with salmeterol CFC inhalation aerosol 21 mcg. In 61 adolescent and adult patients with asthma given Advair HFA (45/21 or 115/21 mcg), continuous 24-hour electrocardiographic monitoring was performed after the first dose and after 12 weeks of twice-daily therapy, and no clinically significant dysrhythmias were noted.

A 4-way crossover study in 13 patients with asthma compared pharmacodynamics at steady state following 4 weeks of twice-daily treatment with 2 inhalations of Advair HFA 115/21, 1 inhalation of Advair DISKUS 250/50 mcg, 2 inhalations of fluticasone propionate HFA inhalation aerosol 110 mcg, and placebo. No significant differences in serum cortisol AUC were observed between active treatments and placebo. Mean 12-hour serum cortisol AUC ratios comparing active treatment with placebo ranged from 0.9 to 1.2. No statistically or clinically significant increases in heart rate or QTc interval were observed for any active treatment compared with placebo.

In a 12-week study (see CLINICAL TRIALS: Studies Comparing Advair HFA to Fluticasone Propionate Alone or Salmeterol Alone: Study 3) in patients with asthma, Advair HFA 115/21 was compared with the individual components, fluticasone propionate CFC inhalation aerosol 110 mcg and salmeterol CFC inhalation aerosol 21 mcg, and placebo. All treatments were administered as 2 inhalations twice daily. After 12 weeks of treatment with these therapeutic doses, the geometric mean ratio of urinary cortisol excretion compared with baseline was 0.9 for Advair HFA and fluticasone propionate and 1.0 for placebo and salmeterol. In addition, the ability to increase cortisol production in response to stress, as assessed by 30-minute cosyntropin stimulation in 23 to 32 patients per treatment group, remained intact for the majority of patients and was similar across treatments. Three patients who received Advair HFA 115/21 had an abnormal response (peak serum cortisol <18 mcg/dL) after dosing,compared with 1 patient who received placebo, 2 patients who received fluticasone propionate 110 mcg, and 1 patient who received salmeterol.

In another 12-week study (see CLINICAL TRIALS: Studies Comparing Advair HFA to Fluticasone Propionate Alone or Salmeterol Alone: Study 4) in patients with asthma, Advair HFA 230/21 (2 inhalations twice daily) was compared with Advair DISKUS 500/50 (1 inhalation twice daily) and fluticasone propionate CFC inhalation aerosol 220 mcg (2 inhalations twice daily). The geometric mean ratio of 24-hour urinary cortisol excretion at week 12 compared with baseline was 0.9 for all 3 treatment groups.

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) 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 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.

Inhaled salmeterol, like other beta-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium in some patients (see PRECAUTIONS). The cardiovascular effects (heart rate, blood pressure) associated with salmeterol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration.

The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in patients with asthma. Salmeterol doses up to 84 mcg 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). In 2 double-blind asthma studies, patients receiving either 42 mcg of salmeterol inhalation aerosol twice daily (n = 81) or 180 mcg of albuterol inhalation aerosol 4 times daily (n = 80) underwent continuous electrocardiographic monitoring during four 24-hour periods; no clinically significant dysrhythmias were noted.

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

Clinical Trials

Advair HFA has been studied in patients with asthma 12 years of age and older. Advair HFA has not been studied in patients under 12 years of age or in patients with COPD. In clinical trials comparing Advair HFA Inhalation Aerosol with the individual components, improvements in most efficacy endpoints were greater with Advair HFA than with the use of either fluticasone propionate or salmeterol alone. In addition, clinical trials showed comparable results between Advair HFA and Advair DISKUS.

Studies Comparing Advair HFA to Fluticasone Propionate Alone or Salmeterol Alone

Four (4) double-blind, parallel-group clinical trials were conducted with Advair HFA in 1,517 adolescent and adult patients (≥12 years, mean baseline forced expiratory volume in 1 second [FEV1] 65% to 75% of predicted normal) with asthma that was not optimally controlled on their current therapy. All metered-dose inhaler treatments were inhalation aerosols given as 2 inhalations twice daily, and other maintenance therapies were discontinued.

This placebo-controlled, 12-week, US study compared Advair HFA 45/21 with fluticasone propionate CFC inhalation aerosol 44 mcg or salmeterol CFC inhalation aerosol 21 mcg, each given as 2 inhalations twice daily. The primary efficacy endpoints were predose FEV1 and withdrawals due to worsening asthma. This study was stratified according to baseline asthma therapy: patients using beta-agonists (albuterol alone [n = 142], salmeterol [n = 84], or inhaled corticosteroids [n = 134] [daily doses of beclomethasone dipropionate 252 to 336 mcg; budesonide 400 to 600 mcg; flunisolide 1,000 mcg; fluticasone propionate inhalation aerosol 176 mcg; fluticasone propionate inhalation powder 200 mcg; or triamcinolone acetonide 600 to 800 mcg]). Baseline FEV1 measurements were similar across treatments: Advair HFA 45/21, 2.29 L; fluticasone propionate 44 mcg, 2.20 L; salmeterol, 2.33 L; and placebo, 2.27 L.

Predefined withdrawal criteria for lack of efficacy, an indicator of worsening asthma, were utilized for this placebo-controlled study. Worsening asthma was defined as a clinically important decrease in FEV1 or peak expiratory flow (PEF), increase in use of 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 1, statistically significantly fewer patients receiving Advair HFA 45/21 were withdrawn due to worsening asthma compared with salmeterol and placebo. Fewer patients receiving Advair HFA 45/21 were withdrawn due to worsening asthma compared to fluticasone propionate 44 mcg; however, the difference was not statistically significant.

The FEV1 results are displayed in Figure 1. 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 HFA 45/21 had significantly greater improvements in FEV1 (0.58 L, 27%) compared with fluticasone propionate 44 mcg (0.36 L, 18%), salmeterol (0.25 L, 12%), and placebo (0.14 L, 5%). These improvements in FEV1 with Advair HFA 45/21 were achieved regardless of baseline asthma therapy (albuterol alone, salmeterol, or inhaled corticosteroids).

Figure 1. Mean Percent Change From Baseline in FEV1 in Patients Previously Treated With Either Beta2-Agonists (Albuterol or Salmeterol) or Inhaled Corticosteroids (Study 1)

The effect of Advair HFA 45/21 on the secondary efficacy parameters, including morning and evening PEF, usage of VENTOLIN Inhalation Aerosol, and asthma symptoms over 24 hours on a scale of 0 to 5 is shown in Table 2.

*Change from baseline = change from baseline at Endpoint (last available data).

The subjective impact of asthma on patients’ perceptions of health was evaluated through use of an instrument called the Asthma Quality of Life Questionnaire (AQLQ) (based on a 7-point scale where 1 = maximum impairment and 7 = none). Patients receiving Advair HFA 45/21 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 1.14 [95% CI 0.85, 1.44] compared to placebo).

This active-controlled, 12-week, US study compared Advair HFA 45/21 with fluticasone propionate CFC inhalation aerosol 44 mcg and salmeterol CFC inhalation aerosol 21 mcg, each given as 2 inhalations twice daily, in 283 patients using as-needed albuterol alone. The primary efficacy endpoint was predose FEV1. Baseline FEV1 measurements were similar across treatments: Advair HFA 45/21, 2.37 L; fluticasone propionate 44 mcg, 2.31 L; and salmeterol, 2.34 L.

Efficacy results in this study were similar to those observed in Study 1. Patients receiving Advair HFA 45/21 had significantly greater improvements in FEV1 (0.69 L, 33%) compared with fluticasone propionate 44 mcg (0.51 L, 25%) and salmeterol (0.47 L, 22%).

This placebo-controlled, 12-week, US study compared Advair HFA 115/21 with fluticasone propionate CFC inhalation aerosol 110 mcg or salmeterol CFC inhalation aerosol 21 mcg, each given as 2 inhalations twice daily, in 365 patients using inhaled corticosteroids (daily doses of beclomethasone dipropionate 378 to 840 mcg; budesonide 800 to 1,200 mcg; flunisolide 1,250 to 2,000 mcg; fluticasone propionate inhalation aerosol 440 to 660 mcg; fluticasone propionate inhalation powder 400 to 600 mcg; or triamcinolone acetonide 900 to 1,600 mcg). The primary efficacy endpoints were predose FEV1 and withdrawals due to worsening asthma. Baseline FEV1 measurements were similar across treatments: Advair HFA 115/21, 2.23 L; fluticasone propionate 110 mcg, 2.18 L; salmeterol, 2.22 L; and placebo, 2.17 L.

Efficacy results in this study were similar to those observed in Studies 1 and 2. Patients receiving Advair HFA 115/21 had significantly greater improvements in FEV1 (0.41 L, 20%) compared with fluticasone propionate 110 mcg (0.19 L, 9%), salmeterol (0.15 L, 8%), and placebo (-0.12 L, -6%). Significantly fewer patients receiving Advair HFA 115/21 were withdrawn from this study for worsening asthma (7%) compared to salmeterol (24%) and placebo (54%). Fewer patients receiving Advair HFA 115/21 were withdrawn due to worsening asthma (7%) compared to fluticasone propionate 110 mcg (11%); however, the difference was not statistically significant.

This active-controlled, 12-week, non-US study compared Advair HFA 230/21 with fluticasone propionate CFC inhalation aerosol 220 mcg, each given as 2 inhalations twice daily, and with Advair DISKUS 500/50 given as 1 inhalation twice daily in 509 patients using inhaled corticosteroids (daily doses of beclomethasone dipropionate CFC inhalation aerosol 1,500 to 2,000 mcg; budesonide 1,500 to 2,000 mcg; flunisolide 1,500 to 2,000 mcg; fluticasone propionate inhalation aerosol 660 to 880 mcg; or fluticasone propionate inhalation powder 750 to 1,000 mcg). The primary efficacy endpoint was morning PEF.

Baseline morning PEF measurements were similar across treatments: Advair HFA 230/21, 327 L/min; Advair DISKUS 500/50, 341 L/min; and fluticasone propionate 220 mcg, 345 L/min. As shown in Figure 2, morning PEF improved significantly with Advair HFA 230/21 compared with fluticasone propionate 220 mcg over the 12-week treatment period. Improvements in morning PEF observed with Advair HFA 230/21 were similar to improvements observed with Advair DISKUS 500/50.

Figure 2. Mean Percent Change From Baseline in Morning Peak Expiratory Flow in Patients Previously Treated With Inhaled Corticosteroids (Study 4)

One-Year Safety Study

This 1-year, open-label, non-US study evaluated the safety of Advair HFA 45/21, 115/21, and 230/21 given as 2 inhalations twice daily in 325 patients. This study was stratified into 3 groups according to baseline asthma therapy: patients using short-acting beta2-agonists alone (n = 42), salmeterol (n = 91), or inhaled corticosteroids (n = 277). Patients treated with short-acting beta2-agonists alone, salmeterol, or low doses of inhaled corticosteroids with or without concurrent salmeterol received Advair HFA 45/21. Patients treated with moderate doses of inhaled corticosteroids with or without concurrent salmeterol received Advair HFA 115/21. Patients treated with high doses of inhaled corticosteroids with or without concurrent salmeterol received Advair HFA 230/21. Baseline FEV1 measurements ranged from 2.3 to 2.6 L.

Improvements in FEV1 (0.17 to 0.35 L at 4 weeks) were seen across all 3 treatments and were sustained throughout the 52-week treatment period. Few patients (3%) were withdrawn due to worsening asthma over 1 year.

Onset of Action and Progression of Improvement in Asthma Control

The onset of action and progression of improvement in asthma control were evaluated in 2 placebo-controlled US trials and 1 active-controlled US trial. 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 occurred within 4 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 all 3 studies.

No diminution in the 12-hour bronchodilator effect was observed with either Advair HFA 45/21 (Figures 3 and 4) or Advair HFA 230/21 as assessed by FEV1 following 12 weeks of therapy.

Figure 3. Percent Change in Serial 12-Hour FEV1 in Patients Previously Using Either Beta2-Agonists (Albuterol or Salmeterol) or Inhaled Corticosteroids (Study 1)

First Treatment Day

Figure 4. Percent Change in Serial 12-Hour FEV1 in Patients Previously Using Either Beta2-Agonists (Albuterol or Salmeterol) or Inhaled Corticosteroids (Study 1)

Last Treatment Day (Week 12)

Reduction in asthma symptoms and use of rescue VENTOLIN Inhalation Aerosol and improvement in morning and evening PEF also occurred within the first day of treatment with Advair HFA, and continued to improve over the 12 weeks of therapy in all 3 studies.

Indications and Usage for Advair

Advair HFA is indicated for the long-term, twice-daily maintenance treatment of asthma in patients 12 years of age and older.

Long-acting beta2-adrenergic agonists, such as salmeterol, one of the active ingredients in Advair HFA, may increase the risk of asthma-related death (see WARNINGS). Therefore, when treating patients with asthma, physicians shouldonly prescribe Advair HFA for patients not adequately controlled on other asthma-controller medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies. Advair HFA is not indicated in patients whose asthma can be successfully managed by inhaled corticosteroids along with occasional use of inhaled, short-acting beta2-agonists.

Advair HFA is NOT indicated for the relief of acute bronchospasm.

Contraindications

Advair HFA is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.

Hypersensitivity to any of the ingredients of these preparations contraindicates their use.

Warnings

Long-acting beta2-adrenergic agonists, such as salmeterol, one of the active ingredients in Advair HFA, may increase the risk of asthma-related death. Therefore, when treating patients with asthma, physicians should only prescribe Advair HFA for patients not adequately controlled on other asthma-controller medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies.

A large placebo-controlled US study that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol. The Salmeterol Multi-center Asthma Research Trial (SMART) was a randomized, double-blind study that enrolled long-acting beta2-agonist−naive patients with asthma to assess the safety of salmeterol (SEREVENT Inhalation Aerosol) 42 mcg twice daily over 28 weeks compared to placebo when added to usual asthma therapy. A planned interim analysis was conducted when approximately half of the intended number of patients had been enrolled (N = 26,355), which led to premature termination of the study. The results of the interim analysis showed that patients receiving salmeterol were at increased risk for fatal asthma events (see Table 3 and Figure 5). In the total population, a higher rate of asthma-related death occurred in patients treated with salmeterol than those treated with placebo (0.10% vs. 0.02%; relative risk 4.37 [95% CI 1.25, 15.34]).

Post-hoc subpopulation analyses were performed. In Caucasians, asthma-related death occurred at a higher rate in patients treated with salmeterol than in patients treated with placebo (0.07% vs. 0.01%; relative risk 5.82 [95% CI 0.70, 48.37]). In African Americans also, asthma-related death occurred at a higher rate in patients treated with salmeterol than those treated with placebo (0.31% vs. 0.04%; relative risk 7.26 [95% CI 0.89, 58.94]). Although the relative risks of asthma-related death were similar in Caucasians and African Americans, the estimate of excess deaths in patients treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American patients (see Table 3). Given the similar basic mechanisms of action of beta2-agonists, it is possible that the findings seen in the SMART study represent a class effect.

The data from the SMART study are not adequate to determine whether concurrent use of inhaled corticosteroids, such as fluticasone propionate, the other active ingredient in Advair HFA, or other asthma-controller therapy modifies the risk of asthma-related death.

* Life-table 28-week estimate, adjusted according to the patients’ actual lengths of exposure to study treatment to account for early withdrawal of patients from the study.

†Relative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group. The relative risk indicates how many more times likely an asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period.

‡ Estimate of the number of additional asthma-related deaths in patients treated with salmeterol in SMART, assuming 10,000 patients received salmeterol for a 28-week treatment period. Estimate calculated as the difference between the salmeterol and placebo

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