Advair hfa (Fluticasone propionate; salmeterol xinafoate) 45/21 Inhalation Aerosol, Advair hfa (Fluticasone propionate; salmeterol xinafoate) 115/21 Inhalation Aerosol, and Advair hfa (Fluticasone propionate; salmeterol xinafoate) 230/21 Inhalation Aerosol are combinations of fluticasone propionate and salmeterol xinafoate.

One active component of Advair hfa (Fluticasone propionate; salmeterol xinafoate) is fluticasone propionate, a corticosteroid having the chemical name -(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 CHFOS. 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 beta-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-α-[[[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 CHNO•CHO. It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water.

Advair hfa (Fluticasone propionate; salmeterol xinafoate) 45/21 Inhalation Aerosol, Advair hfa (Fluticasone propionate; salmeterol xinafoate) 115/21 Inhalation Aerosol, and Advair hfa (Fluticasone propionate; salmeterol xinafoate) 230/21 Inhalation Aerosol are pressurized metered-dose aerosol units fitted with a counter. Advair hfa (Fluticasone propionate; salmeterol xinafoate) is 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 8-g canister contains 60 inhalations. Each 12-g canister provides 120 inhalations.

Advair hfa (Fluticasone propionate; salmeterol xinafoate) 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 releasing 2 test sprays into the air away from the face, shaking well for 5 seconds before each spray.

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

2
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.

The pharmacologic effects of beta-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 D, 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.

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 (T) 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 beta-agonists) when given in combination with high doses of fluticasone propionate. This effect was not observed in clinical studies.

®
Peak plasma concentrations of fluticasone propionate (N = 20 subjects) following 8 inhalations of Advair hfa (Fluticasone propionate; salmeterol xinafoate) 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 (Fluticasone propionate; salmeterol xinafoate) 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 (Fluticasone propionate; salmeterol xinafoate) for fluticasone propionate (86 versus 120 pg/mL) and salmeterol (170 versus 510 pg/mL) were significantly lower compared with 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 versus 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 (Fluticasone propionate; salmeterol xinafoate) and ADVAIR DISKUS, respectively, and 307 pg/mL from the fluticasone propionate CFC inhalation aerosol). Systemic exposure to salmeterol was higher (317 versus 169 pg•hr/mL) and peak salmeterol concentrations were lower (196 versus 223 pg/mL) following ADVAIR HFA compared with 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 (Fluticasone propionate; salmeterol xinafoate) , ADVAIR DISKUS, and fluticasone propionate CFC inhalation aerosol were similar and averaged 5.6 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•hr/mL [95% CI: 150, 502]) and ADVAIR DISKUS (338 pg•hr/mL [95% CI: 197, 581]). Systemic exposure to salmeterol was also similar for ADVAIR HFA (53 pg•hr/mL [95% CI: 17, 164]) and ADVAIR DISKUS (70 pg•hr/mL [95% CI: 19, 254]).

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.

Caution should be exercised when other strong CYP3A4 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.

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

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.

max
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 (Fluticasone propionate; salmeterol xinafoate) 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 (Fluticasone propionate; salmeterol xinafoate) With Fluticasone Propionate Alone or Salmeterol Alone: ) in patients with asthma, Advair hfa (Fluticasone propionate; salmeterol xinafoate) 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 (Fluticasone propionate; salmeterol xinafoate) 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 (Fluticasone propionate; salmeterol xinafoate) 115/21 had an abnormal response (peak serum cortisol
In another 12-week study (see CLINICAL TRIALS: Studies Comparing Advair hfa (Fluticasone propionate; salmeterol xinafoate) With Fluticasone Propionate Alone or Salmeterol Alone: ) 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.

1
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.

ADVAIR HFA has been studied in patients with asthma aged 12 years and older. ADVAIR HFA has not been studied in patients less than 12 years of age or in patients with chronic obstructive pulmonary disease (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 (Fluticasone propionate; salmeterol xinafoate) and ADVAIR DISKUS.

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 [FEV] 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.

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 FEV 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 (Fluticasone propionate; salmeterol xinafoate) 45/21 were withdrawn due to worsening asthma compared with salmeterol and placebo. Fewer patients receiving Advair hfa (Fluticasone propionate; salmeterol xinafoate) 45/21 were withdrawn due to worsening asthma compared with fluticasone propionate 44 mcg; however, the difference was not statistically significant.

The FEV 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, FEV results at Endpoint (last available FEV result) are also provided. Patients receiving Advair hfa (Fluticasone propionate; salmeterol xinafoate) 45/21 had significantly greater improvements in FEV (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 FEV with Advair hfa (Fluticasone propionate; salmeterol xinafoate) 45/21 were achieved regardless of baseline asthma therapy (albuterol alone, salmeterol, or inhaled corticosteroids).

The effect of Advair hfa (Fluticasone propionate; salmeterol xinafoate) 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.

a
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 (Fluticasone propionate; salmeterol xinafoate) 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 with placebo).

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

Efficacy results in this study were similar to those observed in Studies 1 and 2. Patients receiving Advair hfa (Fluticasone propionate; salmeterol xinafoate) 115/21 had significantly greater improvements in FEV (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 (Fluticasone propionate; salmeterol xinafoate) 115/21 were withdrawn from this study for worsening asthma (7%) compared with salmeterol (24%) and placebo (54%). Fewer patients receiving Advair hfa (Fluticasone propionate; salmeterol xinafoate) 115/21 were withdrawn due to worsening asthma (7%) compared with fluticasone propionate 110 mcg (11%); however, the difference was not statistically significant.

Baseline morning PEF measurements were similar across treatments: Advair hfa (Fluticasone propionate; salmeterol xinafoate) 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 (Fluticasone propionate; salmeterol xinafoate) 230/21 compared with fluticasone propionate 220 mcg over the 12-week treatment period. Improvements in morning PEF observed with Advair hfa (Fluticasone propionate; salmeterol xinafoate) 230/21 were similar to improvements observed with ADVAIR DISKUS 500/50.

Improvements in FEV (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.

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 FEV) in most patients was seen within 30 to 60 minutes. Maximum improvement in FEV occurred within 4 hours, and clinically significant improvement was maintained for 12 hours (see Figure 3).

Following the initial dose, predose FEV 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 (Fluticasone propionate; salmeterol xinafoate) 45/21 (Figures 3 and 4) or Advair hfa (Fluticasone propionate; salmeterol xinafoate) 230/21 as assessed by FEV following 12 weeks of therapy.

First Treatment Day
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 (Fluticasone propionate; salmeterol xinafoate) , and continued to improve over the 12 weeks of therapy in all 3 studies.

Advair hfa (Fluticasone propionate; salmeterol xinafoate) is indicated for the treatment of asthma in patients aged 12 years and older.

LABAs, such as salmeterol, one of the active ingredients in Advair hfa (Fluticasone propionate; salmeterol xinafoate) , increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and adolescent patients (see WARNINGS). Therefore, when treating patients with asthma, physicians should only prescribe Advair hfa (Fluticasone propionate; salmeterol xinafoate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Advair hfa (Fluticasone propionate; salmeterol xinafoate) ) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Advair hfa (Fluticasone propionate; salmeterol xinafoate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Advair hfa (Fluticasone propionate; salmeterol xinafoate) is NOT indicated for the relief of acute bronchospasm.

Advair hfa (Fluticasone propionate; salmeterol xinafoate) is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.

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

LABAs, such as salmeterol, one of the active ingredients in Advair hfa (Fluticasone propionate; salmeterol xinafoate) , increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABAs. Available data from controlled clinical trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe Advair hfa (Fluticasone propionate; salmeterol xinafoate) for patients not adequately controlled on a long-term asthma control medication such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Advair hfa (Fluticasone propionate; salmeterol xinafoate) ) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Advair hfa (Fluticasone propionate; salmeterol xinafoate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
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 LABA-naive patients with asthma to assess the safety of salmeterol (SEREVENT Inhalation Aerosol) 42 mcg twice daily over 28 weeks compared with 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% versus 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% versus 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% versus 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 beta-agonists, the findings seen in the SMART study are considered a class effect.

Post-hoc analyses in pediatric patients aged 12 to 18 years were also performed. Pediatric patients accounted for approximately 12% of patients in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]). All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (
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 (Fluticasone propionate; salmeterol xinafoate) , or other long-term asthma-control therapy mitigates the risk of asthma-related death.

a
b
c
d
A 16-week clinical study performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) study, showed results similar to the SMART study. In the SNS study, the rate of asthma-related death was numerically, though not statistically significantly, greater in patients with asthma treated with salmeterol (42 mcg twice daily) than those treated with albuterol (180 mcg 4 times daily) added to usual asthma therapy.

The following additional WARNINGS about Advair hfa (Fluticasone propionate; salmeterol xinafoate) should be noted.
1. Serious acute respiratory events, including fatalities, have been reported both in the United States and worldwide when salmeterol, a component of Advair hfa (Fluticasone propionate; salmeterol xinafoate) , has been initiated in patients with significantly worsening or acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life-threatening acute asthma exacerbations) and/or in some patients in whom asthma has been acutely deteriorating (e.g., unresponsive to usual medications; increasing need for inhaled, short-acting beta-agonists; increasing need for systemic corticosteroids; significant increase in symptoms; recent emergency room visits; sudden or progressive deterioration in pulmonary function). However, they have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events.

2. An inhaled, short-acting beta-agonist, not Advair hfa (Fluticasone propionate; salmeterol xinafoate) , should be used to relieve acute symptoms of shortness of breath. When prescribing Advair hfa (Fluticasone propionate; salmeterol xinafoate) , the physician must also provide the patient with an inhaled, short-acting beta-agonist (e.g., albuterol) for treatment of shortness of breath that occurs acutely, despite regular twice-daily (morning and evening) use of Advair hfa (Fluticasone propionate; salmeterol xinafoate) .

When beginning treatment with Advair hfa (Fluticasone propionate; salmeterol xinafoate) , patients who have been taking oral or inhaled, short-acting beta-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs. For patients taking Advair hfa (Fluticasone propionate; salmeterol xinafoate) , inhaled, short-acting beta-agonists should only be used for symptomatic relief of acute symptoms of shortness of breath (see PRECAUTIONS: Information for Patients).

3. The physician and patient should be alert to such changes. The patient’s condition may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient’s inhaled, short-acting beta-agonist becomes less effective, the patient needs more inhalations than usual, or the patient develops a significant decrease in lung function, this may be a marker of destabilization of the disease. In this setting, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of Advair hfa (Fluticasone propionate; salmeterol xinafoate) with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 2 inhalations twice daily (morning and evening) of Advair hfa (Fluticasone propionate; salmeterol xinafoate) .

4. Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of HPA function.

Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although inhaled corticosteroids may provide control of asthma symptoms during these episodes, in recommended doses they supply less than normal physiologic amounts of glucocorticoid (cortisol) systemically and do NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

5. Patients who are receiving Advair hfa (Fluticasone propionate; salmeterol xinafoate) twice daily should not use additional salmeterol or other LABAs (e.g., formoterol) for prevention of exercise-induced bronchospasm (EIB) or the treatment of asthma. Additional benefit would not be gained from using supplemental salmeterol or formoterol for prevention of EIB since Advair hfa (Fluticasone propionate; salmeterol xinafoate) already contains an inhaled LABA.

6. Advair hfa (Fluticasone propionate; salmeterol xinafoate) should not be used more often or at higher doses than recommended. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias.

7. As with other inhaled asthma medications, Advair hfa (Fluticasone propionate; salmeterol xinafoate) can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Advair hfa (Fluticasone propionate; salmeterol xinafoate) , it should be treated immediately with an inhaled, short-acting bronchodilator; Advair hfa (Fluticasone propionate; salmeterol xinafoate) should be discontinued immediately; and alternative therapy should be instituted.

8. Immediate hypersensitivity reactions may occur after administration of Advair hfa (Fluticasone propionate; salmeterol xinafoate) , as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm.

9. Symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving fluticasone propionate and salmeterol, components of Advair hfa (Fluticasone propionate; salmeterol xinafoate) .

10. Advair hfa (Fluticasone propionate; salmeterol xinafoate) , like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Salmeterol, a component of Advair hfa (Fluticasone propionate; salmeterol xinafoate) , can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of salmeterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown.

11. Transfer of patients from systemic corticosteroid therapy to Advair hfa (Fluticasone propionate; salmeterol xinafoate) may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.

12. Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

13. Lower respiratory tract infections, including pneumonia, have been reported in patients with COPD following the inhaled administration of corticosteroids, including fluticasone propionate and ADVAIR DISKUS. In 2 replicate 12-month studies of 1,579 patients with COPD, there was a higher incidence of pneumonia reported in patients receiving ADVAIR DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in the patients treated with ADVAIR DISKUS was higher in patients over 65 years of age (9%) compared with the incidence in patients less than 65 years of age (4%).

In a 3-year study of 6,184 patients with COPD, there was a higher incidence of pneumonia reported in patients receiving ADVAIR DISKUS 500/50 compared with placebo (16% with ADVAIR DISKUS 500/50, 14% with fluticasone propionate 500 mcg, 11% with salmeterol 50 mcg, and 9% with placebo). Similar to what was seen in the 1-year studies with ADVAIR DISKUS 250/50, the incidence of pneumonia was higher in patients over 65 years of age (18% with ADVAIR DISKUS 500/50 versus 10% with placebo) compared with patients less than 65 years of age (14% with ADVAIR DISKUS 500/50 versus 8% with placebo.

14. Both fluticasone propionate and salmeterol are substrates of CYP3A4.

As has been described with other beta-adrenergic agonist bronchodilators, clinically significant changes in ECGs have been seen infrequently in individual patients in controlled clinical studies with Advair hfa (Fluticasone propionate; salmeterol xinafoate) and salmeterol. Clinically significant changes in systolic and/or diastolic blood pressure and pulse rate have been seen infrequently in individual patients in controlled clinical studies with salmeterol, a component of Advair hfa (Fluticasone propionate; salmeterol xinafoate) .

Doses of the related beta-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation.

Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with Advair hfa (Fluticasone propionate; salmeterol xinafoate) at recommended doses.

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression), despite maintenance or even improvement of respiratory function.

Fluticasone propionate, a component of Advair hfa (Fluticasone propionate; salmeterol xinafoate) , will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of Advair hfa (Fluticasone propionate; salmeterol xinafoate) in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing Advair hfa (Fluticasone propionate; salmeterol xinafoate) .

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with Advair hfa (Fluticasone propionate; salmeterol xinafoate) should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when fluticasone propionate is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of Advair hfa (Fluticasone propionate; salmeterol xinafoate) should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma.

A reduction of growth velocity in children and adolescents may occur as a result of poorly controlled asthma or from the therapeutic use of corticosteroids, including inhaled corticosteroids (see PRECAUTIONS: Pediatric Use). The effects of long-term treatment of children and adolescents with inhaled corticosteroids, including fluticasone propionate, on final adult height are not known. Patients should be maintained on the lowest strength of Advair hfa (Fluticasone propionate; salmeterol xinafoate) that effectively controls their asthma.

The long-term effects of Advair hfa (Fluticasone propionate; salmeterol xinafoate) in human subjects are not fully known. In particular, the effects resulting from chronic use of fluticasone propionate on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown. Some patients received inhaled fluticasone propionate on a continuous basis in a clinical study for up to 4 years. In clinical studies with patients treated for 2 years with inhaled fluticasone propionate, no apparent differences in the type or severity of adverse reactions were observed after long- versus short-term treatment.

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of inhaled corticosteroids, including fluticasone propionate, a component of Advair hfa (Fluticasone propionate; salmeterol xinafoate) .

Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids, including fluticasone propionate, a component of Advair hfa (Fluticasone propionate; salmeterol xinafoate) .

In clinical studies with Advair hfa (Fluticasone propionate; salmeterol xinafoate) , the development of localized infections of the pharynx with has occurred. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while remaining on treatment with Advair hfa (Fluticasone propionate; salmeterol xinafoate) , but at times therapy with Advair hfa (Fluticasone propionate; salmeterol xinafoate) may need to be interrupted.

Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Information for Patients: Patients should be instructed to read the Medication Guide, which is supplied as a tear-off leaflet from this document, with each new prescription and refill.
Patients being treated with Advair hfa (Fluticasone propionate; salmeterol xinafoate) should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. It is important that patients understand how to use Advair hfa (Fluticasone propionate; salmeterol xinafoate) in relation to other asthma medications they are taking.

Advair hfa (Fluticasone propionate; salmeterol xinafoate) has been used concomitantly with other drugs, including short-acting beta-agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma, without adverse drug reactions. No formal drug interaction studies have been performed with Advair hfa (Fluticasone propionate; salmeterol xinafoate) .

2
®
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 systemic fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol.

Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the mouse micronucleus test.

No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at subcutaneous doses up to 50 mcg/kg (less than the MRHD on an mcg/m basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg.

In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 65 times the MRHD on an mg/m basis). No tumors were seen at 0.21 mg/kg (approximately 20 times the MRHD on an mg/m basis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in male and female rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 190 times the MRHD on an mg/m basis).

There are no adequate and well-controlled studies with Advair hfa (Fluticasone propionate; salmeterol xinafoate) in pregnant women. Advair hfa (Fluticasone propionate; salmeterol xinafoate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mcg/kg (less than the MRHD on an mcg/m basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 5 times the MRHD on an mcg/m basis) of fluticasone propionate. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration (see CLINICAL PHARMACOLOGY: Pharmacokinetics: ).

Fluticasone propionate crossed the placenta following administration of a subcutaneous dose of 100 mcg/kg to mice (less than the MRHD on an mcg/m basis), a subcutaneous or an oral dose of 100 mcg/kg to rats (equivalent to the MRHD on an mcg/m basis), and an oral dose of 300 mcg/kg to rabbits (approximately 5 times the MRHD on an mcg/m basis).

There are no adequate and well-controlled studies in pregnant women. Advair hfa (Fluticasone propionate; salmeterol xinafoate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.

2
New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at an oral dose of 10 mg/kg (approximately 1,900 times the MRHD on an mg/m basis). Extensive use of other beta-agonists has provided no evidence that these class effects in animals are relevant to their use in humans.

Salmeterol xinafoate crossed the placenta following oral administration of 10 mg/kg to mice and rats (approximately 480 and 970 times, respectively, the MRHD on an mg/m basis).

There are no adequate and well-controlled studies with salmeterol in pregnant women. Salmeterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Plasma levels of salmeterol, a component of Advair hfa (Fluticasone propionate; salmeterol xinafoate) , after inhaled therapeutic doses are very low. In rats, salmeterol xinafoate is excreted in the milk. There are no data from controlled trials on the use of salmeterol by nursing mothers. It is not known whether fluticasone propionate, a component of Advair hfa (Fluticasone propionate; salmeterol xinafoate) , is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of 10 mcg/kg tritiated fluticasone propionate (less than the MRHD on an mcg/m basis) resulted in measurable radioactivity in milk.

Since there are no data from controlled trials on the use of Advair hfa (Fluticasone propionate; salmeterol xinafoate) by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue Advair hfa (Fluticasone propionate; salmeterol xinafoate) , taking into account the importance of Advair hfa (Fluticasone propionate; salmeterol xinafoate) to the mother.

Caution should be exercised when Advair hfa (Fluticasone propionate; salmeterol xinafoate) is administered to a nursing woman.

Thirty-eight (38) patients aged 12 to 17 years were treated with Advair hfa (Fluticasone propionate; salmeterol xinafoate) in US pivotal clinical trials. Patients in this age-group demonstrated efficacy results similar to those observed in patients aged 18 years and older. There were no obvious differences in the type or frequency of adverse events reported in this age-group compared with patients aged 18 years and older.

The safety and effectiveness of Advair hfa (Fluticasone propionate; salmeterol xinafoate) in children less than 12 years have not been established.

Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appears to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown. The growth of children and adolescents receiving orally inhaled corticosteroids, including Advair hfa (Fluticasone propionate; salmeterol xinafoate) , should be monitored. If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect of corticosteroids should be considered. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including Advair hfa (Fluticasone propionate; salmeterol xinafoate) , each patient should be titrated to the lowest strength that effectively controls his/her asthma (see DOSAGE AND ADMINISTRATION).

The incidence of common adverse events in Table 4 is based upon 2 placebo-controlled, 12-week, US clinical studies (Studies 1 and 3) and 1 active-controlled, 12-week, US clinical study (Study 2). A total of 1,008 adolescent and adult patients with asthma (556 females and 452 males) previously treated with albuterol alone, salmeterol, or inhaled corticosteroids were treated twice daily with 2 inhalations of Advair hfa (Fluticasone propionate; salmeterol xinafoate) 45/21 or Advair hfa (Fluticasone propionate; salmeterol xinafoate) 115/21, fluticasone propionate CFC inhalation aerosol (44- or 110-mcg doses), salmeterol CFC inhalation aerosol 21 mcg, or placebo HFA inhalation aerosol.

Table 4 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in any of the groups receiving Advair hfa (Fluticasone propionate; salmeterol xinafoate) and were more common than in the placebo group. In considering these data, differences in average duration of exposure should be taken into account. These adverse reactions were mostly mild to moderate in severity.

Other adverse events that occurred in the groups receiving Advair hfa (Fluticasone propionate; salmeterol xinafoate) in these studies with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo were:

Rare cases of immediate and delayed hypersensitivity reactions, including rash and other rare events of angioedema and bronchospasm, have been reported.

The incidence of common adverse events reported in Study 4, a 12-week, non-US clinical study of 509 patients previously treated with inhaled corticosteroids who were treated twice daily with 2 inhalations of Advair hfa (Fluticasone propionate; salmeterol xinafoate) 230/21, fluticasone propionate CFC inhalation aerosol 220 mcg, or 1 inhalation of ADVAIR DISKUS 500/50 was similar to the incidences reported in Table 4.

The expected signs and symptoms with overdosage of salmeterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms listed under ADVERSE REACTIONS, e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia. Overdosage with salmeterol may be expected to result in exaggeration of the pharmacologic adverse effects associated with beta-adrenoceptor agonists, including tachycardia and/or arrhythmia, tremor, headache, and muscle cramps. Overdosage with salmeterol can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias. Other signs of overdosage may include hypokalemia and hyperglycemia.

As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of salmeterol.

Treatment consists of discontinuation of salmeterol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of salmeterol. Cardiac monitoring is recommended in cases of overdosage.

No deaths were seen in rats given salmeterol at an inhalation dose of 2.9 mg/kg (approximately 280 times the MRHD on an mg/m basis) and in dogs at an inhalation dose of 0.7 mg/kg (approximately 230 times the MRHD on an mg/m basis). By the oral route, no deaths occurred in mice at 150 mg/kg (approximately 7,200 times the MRHD on an mg/m basis) and in rats at 1,000 mg/kg (approximately 97,000 times the MRHD on an mg/m basis).

Advair hfa (Fluticasone propionate; salmeterol xinafoate) should be administered by the orally inhaled route only in patients aged 12 years and older. Advair hfa (Fluticasone propionate; salmeterol xinafoate) should not be used for transferring patients from systemic corticosteroid therapy. ADVAIR HFA has not been studied in patients less than 12 years of age or in patients with COPD.

LABAs, such as salmeterol, one of the active ingredients in Advair hfa (Fluticasone propionate; salmeterol xinafoate) , increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and adolescent patients (see WARNINGS). Therefore, when treating patients with asthma, physicians should only prescribe Advair hfa (Fluticasone propionate; salmeterol xinafoate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Advair hfa (Fluticasone propionate; salmeterol xinafoate) ) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Advair hfa (Fluticasone propionate; salmeterol xinafoate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Advair hfa (Fluticasone propionate; salmeterol xinafoate) is available in 3 strengths, ADVAIR HFA 45/21 Inhalation Aerosol, Advair hfa (Fluticasone propionate; salmeterol xinafoate) 115/21 Inhalation Aerosol, and Advair hfa (Fluticasone propionate; salmeterol xinafoate) 230/21 Inhalation Aerosol, containing 45, 115, and 230 mcg of fluticasone propionate, respectively, and 21 mcg of salmeterol per inhalation.

Advair hfa (Fluticasone propionate; salmeterol xinafoate) should be administered as 2 inhalations twice daily every day. More frequent administration (more than twice daily) or a higher number of inhalations (more than 2 inhalations twice daily) of the prescribed strength of Advair hfa (Fluticasone propionate; salmeterol xinafoate) is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. The safety and efficacy of Advair hfa (Fluticasone propionate; salmeterol xinafoate) when administered in excess of recommended doses have not been established.

If symptoms arise in the period between doses, an inhaled, short-acting beta-agonist should be taken for immediate relief.

Patients who are receiving Advair hfa (Fluticasone propionate; salmeterol xinafoate) twice daily should not use additional salmeterol or other inhaled LABAs (e.g., formoterol) for prevention of EIB or for any other reason.

For patients aged 12 years and older, the dosage is 2 inhalations twice daily (morning and evening, approximately 12 hours apart).

The recommended starting dosages for Advair hfa (Fluticasone propionate; salmeterol xinafoate) are based upon patients’ current asthma therapy.

The maximum recommended dosage is 2 inhalations of Advair hfa (Fluticasone propionate; salmeterol xinafoate) 230/21 twice daily.

Improvement in asthma control following inhaled administration of Advair hfa (Fluticasone propionate; salmeterol xinafoate) can occur within 30 minutes of beginning treatment, although maximum benefit may not be achieved for 1 week or longer after starting treatment. Individual patients will experience a variable time to onset and degree of symptom relief.

For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, replacing the current strength of Advair hfa (Fluticasone propionate; salmeterol xinafoate) with a higher strength may provide additional improvement in asthma control.

If a previously effective dosage regimen of Advair hfa (Fluticasone propionate; salmeterol xinafoate) fails to provide adequate improvement in asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options, e.g., replacing the current strength of Advair hfa (Fluticasone propionate; salmeterol xinafoate) with a higher strength, adding additional inhaled corticosteroid, initiating oral corticosteroids, should be considered.

Advair hfa (Fluticasone propionate; salmeterol xinafoate) 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 releasing 2 test sprays into the air away from the face, shaking well for 5 seconds before each spray.

Advair hfa (Fluticasone propionate; salmeterol xinafoate) 45/21 Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered actuations in boxes of 1 (NDC 0173-0715-20) and 8-g pressurized aluminum canisters containing 60 metered actuations in institutional pack boxes of 1 (NDC 0173-0715-22).

Advair hfa (Fluticasone propionate; salmeterol xinafoate) 115/21 Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered actuations in boxes of 1 (NDC 0173-0716-20) and 8-g pressurized aluminum canisters containing 60 metered actuations in institutional pack boxes of 1 (NDC 0173-0716-22).

Advair hfa (Fluticasone propionate; salmeterol xinafoate) 230/21 Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered actuations in boxes of 1 (NDC 0173-0717-20) and 8-g pressurized aluminum canisters containing 60 metered actuations in institutional pack boxes of 1 (NDC 0173-0717-22).

Each canister is fitted with a counter, supplied with a purple actuator with a light purple strapcap, and sealed in a plastic-coated, moisture-protective foil pouch with a desiccant that should be discarded when the pouch is opened. Each canister is packaged with a Medication Guide leaflet.

Advair hfa (Fluticasone propionate; salmeterol xinafoate) Inhalation Aerosol does not contain chlorofluorocarbons (CFCs) as the propellant.

ADVAIR, ADVAIR DISKUS, FLONASE, and VENTOLIN are registered trademarks of GlaxoSmithKline.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2010, GlaxoSmithKline. All rights reserved.

June 2010

ADH:6PI

Read the Medication Guide that comes with Advair hfa (Fluticasone propionate; salmeterol xinafoate) Inhalation Aerosol before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.

Advair hfa (Fluticasone propionate; salmeterol xinafoate) is not for adults and children with asthma who are well controlled with an asthma control medicine, such as a low to medium dose of an inhaled corticosteroid medicine.

Do not use Advair hfa (Fluticasone propionate; salmeterol xinafoate) :

Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Advair hfa (Fluticasone propionate; salmeterol xinafoate) and certain other medicines may interact with each other. This may cause serious side effects. Especially, tell your healthcare provider if you take ritonavir. The anti-HIV medicines NORVIR (ritonavir capsules) Soft Gelatin, NORVIR (ritonavir oral solution), and KALETRA (lopinavir/ritonavir) Tablets contain ritonavir.

Know the medicines you take. Keep a list and show it to your healthcare provider and pharmacist each time you get a new medicine.

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the side effects with Advair hfa (Fluticasone propionate; salmeterol xinafoate) . Ask your healthcare provider or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Medicines are sometimes prescribed for purposes not mentioned in a Medication Guide. Do not use Advair hfa (Fluticasone propionate; salmeterol xinafoate) for a condition for which it was not prescribed. Do not give your Advair hfa (Fluticasone propionate; salmeterol xinafoate) to other people, even if they have the same condition that you have. It may harm them.

This Medication Guide summarizes the most important information about Advair hfa (Fluticasone propionate; salmeterol xinafoate) . If you would like more information, talk with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for information about Advair hfa (Fluticasone propionate; salmeterol xinafoate) that was written for healthcare professionals. You can also contact the company that makes Advair hfa (Fluticasone propionate; salmeterol xinafoate) (toll free) at 1-888-825-5249 or at www.advair.com.

Active ingredients: fluticasone propionate, salmeterol xinafoate

Inactive ingredient: propellant HFA-134a

There are 2 main parts to your Advair hfa (Fluticasone propionate; salmeterol xinafoate) inhaler—the metal canister that holds the medicine and the purple plastic actuator that sprays the medicine from the canister (see Figure 1).

The inhaler also has a cap that covers the mouthpiece of the actuator. The strap on the cap will stay attached to the actuator.

The canister has a counter to show how many sprays of medicine you have left. The number shows through a window in the back of the actuator.

The counter starts at 124, or at 064 if you have a sample or institutional canister. The number will count down by 1 each time you spray the inhaler. The counter will stop counting at 000.

Take the inhaler out of the foil pouch. Safely throw away the foil pouch and the drying packet that comes inside the pouch. The counter should read 124, or 064 if you have a sample or institutional canister.

The inhaler should be at room temperature before you use it.

Check each time to make sure the canister fits firmly in the plastic actuator. Also look into the mouthpiece to make sure there are no foreign objects there, especially if the strap is no longer attached to the actuator or if the cap is not being used to cover the mouthpiece.

Before you use Advair hfa (Fluticasone propionate; salmeterol xinafoate) for the first time, you must prime the inhaler so that you will get the right amount of medicine when you use it. To prime the inhaler, take the cap off the mouthpiece and shake the inhaler well for 5 seconds. Then spray it 1 time into the air away from your face. Shake and spray the inhaler like this 3 more times to finish priming it. The counter should now read 120, or 060 if you have a sample or institutional canister.

You must prime your inhaler again if you have not used it in more than 4 weeks or if you have dropped it. Take the cap off the mouthpiece, shake the inhaler well for 5 seconds, and spray it into the air away from your face. Shake and spray the inhaler like this 1 more time to finish priming it.

Read through the 7 steps below before using Advair hfa (Fluticasone propionate; salmeterol xinafoate) . If you have any questions, ask your doctor or pharmacist.

1. Take the cap off the mouthpiece of the actuator. for 5 seconds before each spray.

2. Hold the inhaler with the mouthpiece down (see Figure 2). and push as much air from your lungs as you can. Put the mouthpiece in your mouth and close your lips around it.

3. (see Figure 3). Right after the spray comes out, take your finger off the canister. After you have breathed in all the way, take the inhaler out of your mouth and close your mouth.

4. , up to 10 seconds, then breathe normally.

5. Wait about 30 seconds and the inhaler again for 5 seconds. Repeat steps 2 through 4.

6. After you finish taking this medicine, rinse your mouth with water. Spit out the water. Do not swallow it.

7. Put the cap back on the mouthpiece after every time you use the inhaler, and make sure it snaps firmly into place.

Clean the inhaler at least once a week after your evening dose. It is important to keep the canister and plastic actuator clean so the medicine will not build-up and block the spray.

1. Take the cap off the mouthpiece. The strap on the cap will stay attached to the actuator. Do not take the canister out of the plastic actuator.

2. Use a dry cotton swab to clean the small circular opening where the medicine sprays out of the canister. Carefully twist the swab in a circular motion to take off any medicine (see Figure 4).

3. Wipe the inside of the mouthpiece with a clean tissue dampened with water. Let the actuator air-dry overnight.

4. Put the cap back on the mouthpiece after the actuator has dried.

ADVAIR, ADVAIR DISKUS, FLOVENT, and SEREVENT are registered trademarks of GlaxoSmithKline.

The other brands listed are trademarks of their respective owners and are not trademarks of GlaxoSmithKline. The makers of these brands are not affiliated with and do not endorse GlaxoSmithKline or its products.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2011, GlaxoSmithKline. All rights reserved.

January 2011

ADH:7MG

120 Metered Actuations

fluticasone propionate and salmeterol xinafoate in propellant HFA-134a(1,1,1,2,-tetrafluoroethane).

Each actuation delivers 45 mcg of fluticasone propionate and 30.45 mcg of salmeterol xinafoate equivalent to 21 mcg of salmeterol base from the mouthpiece.

Store at 25C (77F); excursions permitted to 15-30C (59-86F).

GlaxoSmithKline, Research Triangle Park, NC 27709

Rev. 1/08 10000000051354

Each actuation delivers 115 mcg of fluticasone propionate and 30.45 mcg of salmeterol xinafoate equivalent to 21 mcg of salmeterol base from the mouthpiece.

Store at 25C (77F); excursions permitted to 15 – 30C (59 – 86F).

GlaxoSmithKline, Research Triangle Park, NC 27709

Rev. 1/08 10000000051450

Each actuation delivers 230 mcg of fluticasone propionate and 30.45 mcg of salmeterol xinafoate equivalent to 21 mcg of salmeterol base from the mouthpiece.

Store at 25C (77F); excursions permitted to 15 – 30C (59 – 86F).

GlaxoSmithKline, Research Triangle Park, NC 27709

Rev. 1/08 10000000051472