Advair

Indications : Asthma

Pregnancy Category C

FDA Approved 2000 Aug

DRUG CLASS : : Adrenergic agonists; Bronchodilators; Corticosteroids, inhalation

BRAND NAMES : Advair Diskus (US); Seretide (Korea, Philippines, Thailand, South-Africa); Seretide Accuhaler (Australia, Mexico);
(International brand names outside U.S. in italics)

COST OF THERAPY : $ 111.53 (Asthma; Advair Diskus; 100 µg; 50 µg; 2 inhalations/day; 30 days)

DESCRIPTION :

Advair Diskus 100/50, Advair Diskus 250/50, and Advair Diskus 500/50 are combinations of fluticasone propionate and salmeterol xinafoate.

One active component of Advair Diskus is fluticasone propionate, a corticosteroid having the chemical name S­(fluoromethyl) 6a,9-difluoro-11ß,17-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17ß-carbothioate, 17-propionate.

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

The other active component of Advair Diskus is salmeterol xinafoate, a highly selective beta₂-adrenergic bronchodilator. Salmeterol xinafoate is the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol. The chemical name of salmeterol xinafoate is 4-hydroxy-a¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate.

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

Advair Diskus 100/50, Advair Diskus 250/50, and Advair Diskus 500/50 are specially designed plastic devices containing a double-foil blister strip of a powder formulation of fluticasone propionate and salmeterol xinafoate intended for oral inhalation only. Each blister on the double-foil strip within the device contains 100, 250, or 500 µg of microfine fluticasone propionate and 72.5 µg of microfine salmeterol xinafoate salt, equivalent to 50 µg of salmeterol base, in 12.5 mg of formulation containing lactose. Each blister contains 1 complete dose of both medications. After a blister containing medication is opened by activating the device, the medication is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, Advair Diskus delivers 93, 233, and 465 µg of fluticasone propionate and 45 µg of salmeterol base per blister from Advair Diskus 100/50, 250/50, and 500/50, respectively, when tested at a flow rate of 60 L/min for 2 seconds. In adult patients (n=9) with obstructive lung disease and severely compromised lung function (mean forced expiratory volume in 1 second [FEV₁] 20-30% of predicted), mean peak inspiratory flow (PIF) through a DISKUS device was 80.0 L/min (range, 46.1-115.3 L/min).

Inhalation profiles for adolescent (n=13, aged 12-17years) and adult (n=17, aged 18-50 years) patients with asthma inhaling maximally through the DISKUS device show mean PIF of 122.2 L/min (range, 81.6-152.1 L/min).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

CLINICAL PHARMACOLOGY :

Mechanism of Action
Fluticasone Propionate; Salmeterol Xinafoate

Fluticasone propionate; salmeterol xinafoate is designed to produce a greater improvement in pulmonary function and symptom control than either fluticasone propionate or salmeterol used alone at their recommended dosages. These drugs represent 2 classes of medications (a synthetic corticosteroid and a long-acting beta-adrenergic receptor agonist) that have different effects on clinical, physiological, and inflammatory indices of asthma.

Fluticasone Propionate

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

The precise mechanisms of fluticasone propionate action in asthma are unknown. Inflammation is recognized as an important component in the pathogenesis of asthma. Corticosteroids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Salmeterol Xinafoate

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

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

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

Pharmacokinetics
Fluticasone Propionate; Salmeterol Xinafoate

Following administration of fluticasone propionate; salmeterol xinafoate to healthy subjects, peak plasma concentrations of fluticasone propionate were achieved in 1-2 hours and those of salmeterol were achieved in about 5 minutes.

In a single-dose crossover study, a higher than recommended dose of fluticasone propionate; salmeterol xinafoate was administered to 14 healthy subjects. Two inhalations of the following treatments were administered: fluticasone propionate; salmeterol xinafoate 500/50, fluticasone propionate powder 500 µg and salmeterol powder 50 µg given concurrently, and fluticasone propionate powder 500 µg alone. Mean peak plasma concentrations of fluticasone propionate averaged 107, 94, and 120 pg/ml, respectively, and of salmeterol averaged 200 and 150 pg/ml, respectively, indicating no significant changes in systemic exposures of fluticasone propionate and salmeterol.

In a repeat-dose study, the highest recommended dose of Advair Diskus was administered to 45 asthmatic patients. One inhalation twice daily of the following treatments was administered: Advair Diskus 500/50, fluticasone propionate powder 500 µg and salmeterol powder 50 µg given concurrently, or fluticasone propionate powder 500 µg alone. Mean peak steady-state plasma concentrations of fluticasone propionate averaged 57, 73, and 70 pg/ml, respectively, indicating no significant changes in systemic exposure of fluticasone propionate. No plasma concentrations of salmeterol were measured in this repeat-dose study.

No significant changes in excretion of fluticasone propionate or salmeterol were observed. The terminal half-life of fluticasone propionate averaged 5.33-7.65 hours when Advair Diskus was administered, which is similar to that reported when fluticasone propionate was given concurrently with salmeterol or when fluticasone propionate was given alone (average, 5.30-6.91 hours). No terminal half-life of salmeterol was reported upon administration of Advair Diskus or salmeterol given concurrently with fluticasone propionate.

Special Populations

Formal pharmacokinetic studies using fluticasone propionate; salmeterol xinafoate were not conducted to examine gender differences or in special populations, such as elderly patients or patients with hepatic or renal impairment.

Drug-Drug Interactions

In the repeat- and single-dose studies, there was no evidence of significant drug interaction in systemic exposure between fluticasone propionate and salmeterol when given as Advair Diskus.

Fluticasone Propionate
Absorption

Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Studies using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed. The systemic bioavailability of fluticasone propionate from the DISKUS device in healthy volunteers averages 18%.

Peak steady-state fluticasone propionate plasma concentrations in adult patients (n=11) ranged from undetectable to 266 pg/ml after a 500 µg twice-daily dose of fluticasone propionate inhalation powder using the DISKUS device. The mean fluticasone propionate plasma concentration was 110 pg/ml.

Distribution

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

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

Metabolism

The total clearance of fluticasone propionate is high (average, 1093 ml/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17ß-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This metabolite had less affinity (approximately 1/2000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

Elimination

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

Hepatic Impairment

Since fluticasone propionate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be closely monitored.

Gender

Full pharmacokinetic profiles were obtained from 9 female and 16 male patients given fluticasone propionate inhalation powder 500 µg twice daily using the DISKUS. No overall differences in fluticasone propionate pharmacokinetics were observed.

Special Populations

Formal pharmacokinetic studies using fluticasone propionate were not carried out in other special populations.

Drug-Drug Interactions

In a multiple-dose drug interaction study, coadministration of fluticasone propionate (500 µg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics. In another drug interaction study, coadministration of fluticasone propionate (1000 µg) and ketoconazole (200 mg once daily) resulted in increased fluticasone propionate concentrations and reduced plasma cortisol area under the plasma concentration versus time curve (AUC), but had no effect on urinary excretion of cortisol. Since fluticasone propionate is a substrate of cytochrome P450 3A4, caution should be exercised when cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole) are coadministered with fluticasone propionate as this could result in increased plasma concentrations of fluticasone propionate.

Salmeterol Xinafoate

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

Absorption

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

Distribution

Binding of salmeterol to human plasma proteins averages 96% in vitro over the concentration range of 8-7722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol.

Metabolism

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

Elimination

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

The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (>99%) and has a long elimination half-life of 11 days.

Special Populations

Formal pharmacokinetic studies of salmeterol base have not been conducted in special populations. Since salmeterol is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.

Pharmacodynamics
Fluticasone Propionate; Salmeterol Xinafoate

Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four studies were conducted in healthy subjects:

A single-dose crossover study using 2 inhalations of fluticasone propionate; salmeterol xinafoate 500/50, fluticasone propionate powder 500 µg and salmeterol powder 50 µg given concurrently, or fluticasone propionate powder 500 µg given alone,
A cumulative dose study using 50-400 µg of salmeterol powder given alone or as fluticasone propionate; salmeterol xinafoate 500/50.
A repeat-dose study for 11 days using 2 inhalations twice daily of fluticasone propionate; salmeterol xinafoate 250/50, fluticasone propionate powder 250 µg, or salmeterol powder 50 µg.
a single-dose study using 5 inhalations of fluticasone propionate; salmeterol xinafoate 100/50, fluticasone propionate powder 100 µg alone, or placebo.

In these studies no significant differences were observed in the pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given as fluticasone propionate; salmeterol xinafoate, concurrently with fluticasone propionate from separate inhalers, or as salmeterol alone. The systemic pharmacodynamic effects of salmeterol were not altered by the presence of fluticasone propionate in fluticasone propionate; salmeterol xinafoate. The potential effect of salmeterol on the effects of fluticasone propionate on the hypothalamic-pituitary-adrenal (HPA) axis was also evaluated in these studies. No significant differences across treatments were observed in 24 hour urinary cortisol excretion and, where measured, 24 hour plasma cortisol AUC. The systemic pharmacodynamic effects of fluticasone propionate were not altered by the presence of salmeterol in fluticasone propionate; salmeterol xinafoate in healthy subjects.

In clinical studies with fluticasone propionate; salmeterol xinafoate in patients with asthma, no significant differences were observed in the systemic pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given alone or as fluticasone propionate; salmeterol xinafoate. In 72 adolescent and adult patients with asthma given either fluticasone propionate; salmeterol xinafoate 100/50 or fluticasone propionate; salmeterol xinafoate 250/50, continuous 24 hour electrocardiographic monitoring was performed after the first dose and after 12 weeks of therapy, and no clinically significant dysrhythmias were noted.

In a 28 week study in patients with asthma, fluticasone propionate; salmeterol xinafoate 500/50 twice daily was compared with the concurrent use of salmeterol powder 50 µg plus fluticasone propionate powder 500 µg from separate inhalers or fluticasone propionate powder 500 µg alone. No significant differences across treatments were observed in plasma cortisol AUC after 12 weeks of dosing or in 24 hour urinary cortisol excretion after 12 and 28 weeks.

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

Fluticasone Propionate

In clinical trials with fluticasone propionate inhalation powder using doses up to and including 250 µg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol <18 µg/dl) were noted both in patients receiving fluticasone propionate and in patients receiving placebo. The incidence of abnormal tests at 500 µg twice daily was greater than placebo. In a 2 year study carried out in 64 patients with mild, persistent asthma (mean FEV₁ 91% of predicted) randomized to fluticasone propionate 500 µg twice daily or placebo, no patient receiving fluticasone propionate had an abnormal response to 6 hour cosyntropin infusion (peak serum cortisol <18 µg/dl). With a peak cortisol threshold of <35 µg/dl, one patient receiving fluticasone propionate (4%) had an abnormal response at 1 year; repeat testing at 18 months and 2 years was normal. Another patient receiving fluticasone propionate (5%) had an abnormal response at 2 years. No patient on placebo had an abnormal response at 1 or 2 years.

Salmeterol Xinafoate

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

The effects of rising doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in patients with asthma. Salmeterol doses up to 84 µg administered as inhalation aerosol resulted in heart rate increases of 3-16 beats/min, about the same as albuterol dosed at 180 µg by inhalation aerosol (4-10 beats/min). Adolescent and adult patients receiving 50 µg doses of salmeterol inhalation powder (n=60) underwent continuous electrocardiographic monitoring during two 12 hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted.

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

CLINICAL STUDIES :

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

Studies Comparing Advair Diskus to Fluticasone Propionate Alone or Salmeterol Alone

Three double-blind, parallel-group clinical trials were conducted with Advair Diskus in 1208 adolescent and adult patients (=12 years, baseline FEV₁ 63-72% of predicted normal) with asthma that was not optimally controlled on their current therapy. All treatments were inhalation powders, given as 1 inhalation from the Diskus device twice daily, and other maintenance therapies were discontinued.

Study 1, Clinical Trial with Advair Diskus 100/50

This placebo-controlled, 12 week, US study compared Advair Diskus 100/50 with its individual components, fluticasone propionate 100 µg and salmeterol 50 µg. The study was stratified according to baseline asthma maintenance therapy; patients were using either inhaled corticosteroids (n=250) (daily doses of beclomethasone dipropionate 252-420 µg, flunisolide 1000 µg, fluticasone propionate inhalation aerosol 176 µg, or triamcinolone acetonide 600-1000 µg) or salmeterol (n=106). Baseline FEV₁ measurements were similar across treatments: Advair Diskus 100/50, 2.17 L; fluticasone propionate 100 µg, 2.11 L; salmeterol, 2.13 L; and placebo, 2.15 L.

Predefined withdrawal criteria for lack of efficacy, an indicator of worsening asthma, were utilized for this placebo-controlled study. Worsening asthma was defined as a clinically important decrease in FEV₁ or peak expiratory flow (PEF), increase in use of albuterol inhalation aerosol, increase in night awakenings due to asthma, emergency intervention or hospitalization due to asthma, or requirement for asthma medication not allowed by the protocol. As shown in TABLE 1, statistically significantly fewer patients receiving Advair Diskus 100/50 were withdrawn due to worsening asthma compared with fluticasone propionate, salmeterol, and placebo.

Patients receiving Advair Diskus 100/50 had significantly greater improvements in FEV₁ (0.51 L, 25%) compared with fluticasone propionate 100 µg (0.28 L, 15%), salmeterol (0.11 L, 5%), and placebo (0.01 L, 1%). These improvements in FEV₁ with Advair Diskus were achieved regardless of baseline asthma maintenance therapy (inhaled corticosteroids or salmeterol).

The effect of Advair Diskus 100/50 on morning and evening peak expiratory flow (PEF) endpoints is shown in TABLE 2.

The subjective impact of asthma on patients’ perception of health was evaluated through use of an instrument called the Asthma Quality of Life Questionnaire (AQLQ) (based on a 7 point scale where 1 = maximum impairment and 7 = none). Patients receiving Advair Diskus 100/50 had clinically meaningful improvements in overall asthma-specific quality of life as defined by a difference between groups of =0.5 points in change from baseline AQLQ scores (difference in AQLQ score of 1.25 compared to placebo).

Study 2, Clinical Trial with Advair Diskus 250/50

This placebo-controlled, 12 week, US study compared Advair Diskus 250/50 with its individual components, fluticasone propionate 250 µg and salmeterol 50 µg in 349 patients using inhaled corticosteroids (daily doses of beclomethasone dipropionate 462-672 µg, flunisolide 1250-2000 µg, fluticasone propionate inhalation aerosol 440 µg, or triamcinolone acetonide 1100-1600 µg). Baseline FEV₁ measurements were similar across treatments: Advair Diskus 250/50, 2.23 L; fluticasone propionate 250 µg, 2.12 L; salmeterol, 2.20 L; and placebo, 2.19 L.

Efficacy results in this study were similar to those observed in Study 1. Patients receiving Advair Diskus 250/50 had significantly greater improvements in FEV₁ (0.48 L, 23%) compared with fluticasone propionate 250 µg (0.25 L, 13%), salmeterol (0.05 L, 4%), and placebo (decrease of 0.11 L, decrease of 5%). Statistically significantly fewer patients receiving Advair Diskus 250/50 were withdrawn from this study for worsening asthma (4%) compared with fluticasone propionate (22%), salmeterol (38%), and placebo (62%). In addition, Advair Diskus 250/50 was superior to fluticasone propionate, salmeterol, and placebo for improvements in morning and evening PEF. Patients receiving Advair Diskus 250/50 also had clinically meaningful improvements in overall asthma-specific quality of life as described in Study 1 (difference in AQLQ score of 1.29 compared to placebo).

Study 3, Clinical Trial with Advair Diskus 500/50

This 28 week, non-US study compared Advair Diskus 500/50 with fluticasone propionate 500 µg alone and concurrent therapy (salmeterol 50 µg plus fluticasone propionate 500 µg administered from separate inhalers) twice daily in 503 patients using inhaled corticosteroids [daily doses of beclomethasone dipropionate 1260-1680 µg, budesonide 1500-2000 µg, flunisolide 1500-2000 µg, or fluticasone propionate inhalation aerosol 660-880 µg (750-1000 µg inhalation powder)]. The primary efficacy parameter, morning PEF, was collected daily for the first 12 weeks of the study. The primary purpose of weeks 13-28 was to collect safety data.

Baseline PEF Measurements were Similar Across Treatments

Advair Diskus 500/50, 359 L/min; fluticasone propionate 500 µg, 351 L/min; and concurrent therapy, 345 L/min. Morning PEF improved significantly with Advair Diskus 500/50 compared with fluticasone propionate 500 µg over the 12 week treatment period. Improvements in morning PEF observed with Advair Diskus 500/50 were similar to improvements observed with concurrent therapy.

Onset of Action and Progression of Improvement in Asthma Control

The onset of action and progression of improvement in asthma control were evaluated in the 2 placebo-controlled US trials. Following the first dose, the median time to onset of clinically significant bronchodilatation (=15% improvement in FEV₁) in most patients was seen within 30-60 minutes. Maximum improvement in FEV₁ generally occurred within 3 hours, and clinically significant improvement was maintained for 12 hours.

Following the initial dose, predose FEV₁ relative to day 1 baseline improved markedly over the first week of treatment and continued to improve over the 12 weeks of treatment in both studies.

No diminution in the 12 hour bronchodilator effect was observed with either Advair Diskus 100/50 or Advair Diskus 250/50 as assessed by FEV₁ following 12 weeks of therapy.

Reduction in asthma symptoms, use of rescue albuterol inhalation aerosol, and improvement in morning and evening PEF also occurred within the first day of treatment with Advair Diskus, and continued to improve over the 12 weeks of therapy in both studies.

INDICATIONS AND USAGE :

Fluticasone propionate; salmeterol xinafoate is indicated for the long-term, twice-daily, maintenance treatment of asthma in patients 12 years of age and older.

Fluticasone propionate; salmeterol xinafoate is NOT indicated for the relief of acute bronchospasm.

CONTRAINDICATIONS :

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

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

WARNINGS :

Fluticasone propionate; salmeterol xinafoate should not be used for transferring patients from systemic corticosteroid therapy.

1. FLUTICASONE PROPIONATE; SALMETEROL XINAFOATE SHOULD NOT BE INITIATED IN PATIENTS DURING RAPIDLY DETERIORATING OR POTENTIALLY LIFE-THREATENING EPISODES OF ASTHMA. Serious acute respiratory events, including fatalities, have been reported both in the United States and worldwide when salmeterol, a component of Advair Diskus, has been initiated in patients with significantly worsening or acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, or previous life-threatening acute asthma exacerbations) and/or in some patients in whom asthma has been acutely deteriorating (e.g., unresponsive to usual medications; increasing need for inhaled, short-acting beta₂-agonists; increasing need for systemic corticosteroids; significant increase in symptoms; recent emergency room visits; sudden or progressive deterioration in pulmonary function). However, they have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events or simply failed to relieve the deteriorating asthma.

2. Do not use fluticasone propionate; salmeterol xinafoate to treat acute symptoms : An inhaled, short-acting beta₂-agonist, not fluticasone propionate; salmeterol xinafoate, should be used to relieve acute asthma symptoms. When prescribing fluticasone propionate; salmeterol xinafoate, the physician must also provide the patient with an inhaled, short-acting beta₂-agonist (e.g., albuterol) for treatment of symptoms that occur acutely, despite regular twice daily (morning and evening) use of fluticasone propionate; salmeterol xinafoate.

When beginning treatment with fluticasone propionate; salmeterol xinafoate, patients who have been taking oral or inhaled, short-acting beta₂-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs. For patients on fluticasone propionate; salmeterol xinafoate, short-acting, inhaled beta₂-agonists should only be used for symptomatic relief of acute asthma symptoms (see PRECAUTIONS, Information for the Patient).

3. Watch for increasing use of inhaled, short-acting beta₂-agonists, which is a marker of deteriorating asthma: Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient’s inhaled, short-acting beta₂-agonist becomes less effective, the patient needs more inhalations than usual, or the patient develops a significant decrease in PEF, these may be a marker of destabilization of asthma. In this setting, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of fluticasone propionate; salmeterol xinafoate with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than one inhalation twice daily (morning and evening) of fluticasone propionate; salmeterol xinafoate.

4. Do not use an inhaled, long-acting beta₂-agonist in conjunction with fluticasone propionate; salmeterol xinafoate : Patients who are receiving fluticasone propionate; salmeterol xinafoate twice daily should not use salmeterol or other long-acting inhaled beta₂-agonists for prevention of exercise-induced bronchospasm or the maintenance treatment of asthma. Additional benefit would not be gained from using supplemental salmeterol for prevention of exercise-induced bronchospasm since fluticasone propionate; salmeterol xinafoate already contains salmeterol.

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

6. Paradoxical bronchospasm : As with other inhaled asthma medications, fluticasone propionate; salmeterol xinafoate can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with fluticasone propionate; salmeterol xinafoate, it should be treated immediately with a short-acting, inhaled bronchodilator, fluticasone propionate; salmeterol xinafoate should be discontinued immediately, and alternative therapy should be instituted.

7. Immediate hypersensitivity reactions : Immediate hypersensitivity reactions may occur after administration of fluticasone propionate; salmeterol xinafoate, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm.

8. Upper airway symptoms : Symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving fluticasone propionate and salmeterol, components of fluticasone propionate; salmeterol xinafoate.

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

10. Discontinuation of systemic corticosteroids : Transfer of patients from systemic corticosteroid therapy to fluticasone propionate; salmeterol xinafoate may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, and arthritis.

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

PRECAUTIONS :

General
Cardiovascular Effects

No effect on the cardiovascular system is usually seen after the administration of inhaled fluticasone propionate; salmeterol xinafoate at recommended doses. The cardiovascular and central nervous system effects seen with all sympathomimetic drugs (e.g., increased blood pressure, heart rate, excitement) can occur after use of salmeterol, a component of fluticasone propionate; salmeterol xinafoate, and may require discontinuation of fluticasone propionate; salmeterol xinafoate. Fluticasone propionate; salmeterol xinafoate, like all medications containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines.

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

Metabolic and Other Effects

Doses of the related beta₂-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation.

Clinically significant changes in blood glucose and/or serum potassium were seen rarely during clinical studies with fluticasone propionate; salmeterol xinafoate at recommended doses.

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

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

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with these drugs should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear in a small number of patients, particularly at higher doses. If such changes occur, the dose of fluticasone propionate should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients (see , Pediatric Use). Patients should be maintained on the lowest strength of fluticasone propionate; salmeterol xinafoate that effectively controls their asthma.

The long-term effects of fluticasone propionate; salmeterol xinafoate in human subjects are not fully known. In particular, the effects resulting from chronic use of fluticasone propionate on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown. Some patients have received inhaled fluticasone propionate on a continuous basis for periods of 3 years or longer. In clinical studies with patients treated for 2 years with inhaled fluticasone propionate, no apparent differences in the type or severity of adverse reactions were observed after long- versus short-term treatment.

Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported following the inhaled administration of corticosteroids, including fluticasone propionate, a component of fluticasone propionate; salmeterol xinafoate.

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

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

Eosinophilic Conditions

In rare cases, patients on inhaled fluticasone propionate, a component of fluticasone propionate; salmeterol xinafoate, may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established (see ADVERSE REACTIONS).

Information for the Patient

Patients being treated with fluticasone propionate; salmeterol xinafoate should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

It is important that patients understand how to use the Diskus inhalation device appropriately and how it should be used in relation to other asthma medications they are taking. Patients should be given the following information:

Patients should use fluticasone propionate; salmeterol xinafoate at regular intervals as directed. Results of clinical trials indicate significant improvement may occur within the first 30 minutes of taking the first dose; however, the full benefit may not be achieved until treatment has been administered for 1 week or longer. The patient should not exceed the prescribed dosage and should contact the physician if symptoms do not improve or if the condition worsens.
The bronchodilation from a single dose of fluticasone propionate; salmeterol xinafoate may last up to 12 hours or longer. The recommended dosage (1 inhalation twice daily, morning and evening) should not be exceeded. Patients who are receiving fluticasone propionate; salmeterol xinafoate twice daily should not use salmeterol or other long-acting inhaled beta₂-agonists for prevention of exercise-induced bronchospasm or maintenance treatment of asthma.
Fluticasone propionate; salmeterol xinafoate is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta₂-agonist such as albuterol (the physician should provide the patient with such medication and instruct the patient in how it should be used).

The physician should be notified immediately if any of the following situations occur, which may be a sign of seriously worsening asthma:

• Patients should be cautioned regarding common adverse cardiovascular effects, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
• When patients are prescribed fluticasone propionate; salmeterol xinafoate, other inhaled drugs and asthma medications should be used only as directed by the physician.
• Fluticasone propionate; salmeterol xinafoate should not be used with a spacer device.
• If you are pregnant or nursing, contact your physician about the use of fluticasone propionate; salmeterol xinafoate.

  Effective and safe use of fluticasone propionate; salmeterol xinafoate includes an understanding of the way that it should be used:

  	Never exhale into the Diskus.
  	Never attempt to take the Diskus apart.
  	Always activate and use the Diskus in a level, horizontal position.
  	Never wash the mouthpiece or any part of the Diskus. KEEP IT DRY.
  	Always keep the Diskus in a dry place.
  	Discard 1 month after removal from the moisture-protective foil overwrap pouch or after every blister has been used (when the dose indicator reads “0”), whichever comes first.

• Patients should be warned to avoid exposure to chickenpox or measles and, if they are exposed, to consult their physicians without delay.
• For the proper use of fluticasone propionate; salmeterol xinafoate and to attain maximum improvement, the patient should read and follow carefully the accompanying Patient’s Instructions for Use.

Carcinogenesis, Mutagenesis, and Impairment of Fertility
Fluticasone Propionate

Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1000 µg/kg (approximately 4 times the maximum recommended daily inhalation dose in adults on a µg/m² basis) for 78 weeks or in rats at inhalation doses up to 57 µg/kg (less than the maximum recommended daily inhalation dose in adults on a µg/m² basis) for 104 weeks.

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

No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at subcutaneous doses up to 50 µg/kg (less than the maximum recommended daily inhalation dose in adults on a µg/m² basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 µg/kg.

Salmeterol

In an 18 month carcinogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 20 times the maximum recommended daily inhalation dose in adults based on comparison of the plasma area under the curves ([AUCs]) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and cysts in the ovaries. The incidence of leiomyosarcomas was not statistically significant. No tumors were seen at 0.2 mg/kg (approximately 3 times the maximum recommended daily inhalation doses in adults based on comparison of the AUCs).

In a 24 month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 60 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). No tumors were seen at 0.21 mg/kg (approximately 20 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in male and female rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 180 times the maximum recommended daily inhalation dose in adults on a mg/m² basis).

Pregnancy Category C
Fluticasone Propionate; Salmeterol Xinafoate
Teratogenic Effects

From the reproduction toxicity studies in mice and rats, no evidence of enhanced toxicity was seen using combinations of fluticasone propionate and salmeterol compared to toxicity data from the components administered separately. In mice combining 150 µg/kg subcutaneously of fluticasone propionate (less than the maximum recommended daily inhalation dose in adults on a µg/m² basis) with 10 mg/kg orally of salmeterol (approximately 450 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) were teratogenic. Cleft palate, fetal death, increased implantation loss and delayed ossification was seen. These observations are characteristic of glucocorticoids. No developmental toxicity was observed at combination doses up to 40 µg/kg subcutaneously of fluticasone propionate (less than the maximum recommended daily inhalation dose in adults on a µg/m² basis) and up to 1.4 mg/kg orally of salmeterol (approximately 65 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). In rats, no teratogenicity was observed at combination doses up to 30 µg/kg subcutaneously of fluticasone propionate (less than the maximum recommended daily inhalation dose in adults on a µg/m² basis) and up to 1 mg/kg of salmeterol (approximately 90 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). Combining 100 µg/kg subcutaneously of fluticasone propionate (less than the maximum recommended daily inhalation dose in adults on a µg/m² basis) with 10 mg/kg orally of salmeterol (approximately 900 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) produced maternal toxicity, decreased placental weight, decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone. There are no adequate and well-controlled studies with fluticasone propionate; salmeterol xinafoate in pregnant women. Fluticasone propionate; salmeterol xinafoate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Fluticasone Propionate

Subcutaneous studies in the mouse and rat at 45 and 100 µg/kg (less than or equivalent to the maximum recommended daily inhalation dose in adults on a µg/m² basis), respectively, revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.

In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 µg/kg (less than the maximum recommended daily inhalation dose in adults on a µg/m² basis). However, no teratogenic effects were reported at oral doses up to 300 µg/kg (approximately 5 times the maximum recommended daily inhalation dose in adults on a µg/m² basis) of fluticasone propionate. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration (see CLINICAL PHARMACOLOGY).

Fluticasone propionate crossed the placenta following administration of a subcutaneous dose of 100 µg/kg to mice (less than the maximum recommended daily inhalation dose in adults on a µg/m² basis) administration of a subcutaneous or an oral dose of 100 µg/kg to rats (approximately equivalent to the maximum recommended daily inhalation dose in adults on a µg/m² basis) and an oral dose of 300 µg/kg administered to rabbits (approximately 5 times the maximum recommended daily inhalation dose in adults on a µg/m² basis).

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

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

Salmeterol

No teratogenic effects occurred in rats at oral doses up to 2 mg/kg (approximately 180 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). In pregnant Dutch rabbits administered oral doses of 1 mg/kg and above (approximately 50 times the maximum recommended daily inhalation dose in adults based on comparison of the AUCs), salmeterol exhibited fetal toxic effects characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No significant effects occurred at an oral dose of 0.6 mg/kg (approximately 20 times the maximum recommended daily inhalation dose in adults based on comparison of the AUCs).

New Zealand White rabbits were less sensitive since only delayed ossification of the frontal bones was seen at an oral dose of 10 mg/kg (approximately 1800 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). Extensive use of other beta-agonists has provided no evidence that these class effects in animals are relevant to their use in humans. There are no adequate and well-controlled studies with salmeterol in pregnant women. Salmeterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Salmeterol xinafoate crossed the placenta following oral administration of 10 mg/kg to mice and rats (approximately 450 and 900 times, respectively, the maximum recommended daily inhalation dose in adults on a mg/m² basis).

Labor and Delivery

There are no well-controlled human studies that have investigated effects of fluticasone propionate; salmeterol xinafoate on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of fluticasone propionate; salmeterol xinafoate for management of asthma during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Nursing Mothers

Plasma levels of salmeterol, a component of fluticasone propionate; salmeterol xinafoate, after inhaled therapeutic doses are very low. In rats, salmeterol xinafoate is excreted in the milk. There are no data from controlled trials on the use of salmeterol by nursing mothers. It is not known whether fluticasone propionate, a component of Advair Diskus, is excreted in human breast milk; however, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of 10 µg/kg tritiated fluticasone propionate (less than the maximum recommended daily inhalation dose in adults on a µg/m² basis) resulted in measurable radioactivity in milk.

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

Caution should be exercised when fluticasone propionate; salmeterol xinafoate is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of fluticasone propionate; salmeterol xinafoate in children under 12 years of age has not been established. In one 12 week study, 257 patients 4-11 years inadequately controlled using inhaled corticosteroids were randomized to fluticasone propionate; salmeterol xinafoate 100/50 or concurrent therapy with fluticasone propionate inhalation powder 100 µg plus salmeterol inhalation powder 50 µg twice daily. The pattern of adverse events reported in patients 4-11 years of age was similar to that seen in patients 12 years of age and older treated with fluticasone propionate; salmeterol xinafoate.

Controlled clinical studies have shown that orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.

Inhaled corticosteroids, including fluticasone propionate, a component of fluticasone propionate; salmeterol xinafoate, may cause a reduction in growth velocity in children and adolescents (see PRECAUTIONS). The growth of pediatric patients receiving orally inhaled corticosteroids, including fluticasone propionate; salmeterol xinafoate, should be monitored. If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect of corticosteroids should be considered. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained. To minimize the systemic effects of orally inhaled corticosteroids, including fluticasone propionate; salmeterol xinafoate, each patient should be titrated to the lowest strength that effectively controls his/her asthma (see DOSAGE AND ADMINISTRATION).

Geriatric Use

Of the total number of patients in clinical studies of fluticasone propionate; salmeterol xinafoate, 44 were 65 years of age or older and 3 were 75 years of age or older. No overall differences in safety were observed between these patients and younger patients, and other reported clinical experience, including studies of the individual components, has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. As with other products containing beta₂-agonists, special caution should be observed when using fluticasone propionate; salmeterol xinafoate in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta₂-agonists. Based on available data for fluticasone propionate; salmeterol xinafoate or its active components, no adjustment of dosage of fluticasone propionate; salmeterol xinafoate in geriatric patients is warranted.

DRUG INTERACTIONS :

Fluticasone propionate; salmeterol xinafoate has been used concomitantly with other drugs, including short-acting beta₂-agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma, without adverse drug reactions. No formal drug interaction studies have been performed with fluticasone propionate; salmeterol xinafoate.

Short-acting beta₂-agonists : In clinical trials, the mean daily need for additional beta₂-agonist use in 166 patients using fluticasone propionate; salmeterol xinafoate was approximately 1.3 inhalations per day, and ranged from 0-9 inhalations per day. Five percent (5%) of the fluticasone propionate; salmeterol xinafoate patients in these trials averaged 6 or more inhalations per day over the course of the 12 week trials. No observed increase in frequency of cardiovascular events was noted among patients who averaged 6 or more inhalations per day.
Methylxanthines : The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving fluticasone propionate; salmeterol xinafoate has not been completely evaluated. In clinical trials, 39 patients receiving fluticasone propionate; salmeterol xinafoate 100/50, 250/50, or 500/50 twice daily concurrently with a theophylline product had adverse event rates similar to those in 304 patients receiving fluticasone propionate; salmeterol xinafoate without theophylline. Similar results were observed in patients receiving salmeterol 50 µg plus fluticasone propionate 500 µg twice daily concurrently with a theophylline product (n=39) or without theophylline (n=132).
Fluticasone propionate nasal spray : In patients taking fluticasone propionate; salmeterol xinafoate in clinical trials, no difference in the profile of adverse events or HPA axis effects was noted between patients taking fluticasone propionate nasal spray, 50 µg concurrently (n=46) and those who were not (n=130).
Monoamine oxidase inhibitors and tricyclic antidepressants : Fluticasone propionate; salmeterol xinafoate should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of fluticasone propionate; salmeterol xinafoate, on the vascular system may be potentiated by these agents.
Beta-adrenergic receptor blocking agents : Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of fluticasone propionate; salmeterol xinafoate, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
Diuretics : The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics.
Ketoconazole and other inhibitors of cytochrome P450 : In a placebo-controlled, crossover study in 8 healthy volunteers, coadministration of a single dose of fluticasone propionate (1000 µg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased mean fluticasone propionate concentrations, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. This interaction may be due to an inhibition of cytochrome P450 3A4 by ketoconazole, which is also the route of metabolism of fluticasone propionate. Care should be exercised when fluticasone propionate; salmeterol xinafoate is coadministered with long-term ketoconazole and other known cytochrome P450 3A4 inhibitors.

ADVERSE REACTIONS :

The incidence of common adverse experiences in TABLE 3A and TABLE 3B are based upon 2 placebo-controlled, 12 week, US clinical studies (Studies 1 and 2). A total of 705 adolescent and adult patients (349 females and 356 males) previously treated with salmeterol or inhaled corticosteroids were treated twice daily with fluticasone propionate; salmeterol xinafoate (100/50 or 250/50 µg doses), fluticasone propionate inhalation powder (100 or 250 µg doses), salmeterol inhalation powder 50 µg, or placebo.

TABLE 3A and TABLE 3B includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in either of the groups receiving fluticasone propionate; salmeterol xinafoate and were more common than in the placebo group. In considering these data, differences in average duration of exposure should be taken into account.

These adverse reactions were mostly mild to moderate in severity. Rare cases of immediate and delayed hypersensitivity reactions, including rash and other rare events of angioedema and bronchospasm, have been reported.

Other adverse effects that occurred in the groups receiving fluticasone propionate; salmeterol xinafoate in these studies with an incidence of 1-3% and that occurred at a greater incidence than with placebo were:

Blood and Lymphatic : Lymphatic signs and symptoms.
Cardiovascular : Palpitations.
Drug Interaction, Overdose, and Trauma : Muscle injuries, fractures, wounds and lacerations, contusions and hematomas, burns.
Ear, Nose, and Throat : Rhinorrhea/post nasal drip; ear, nose and throat infections; ear signs and symptoms; nasal signs and symptoms; nasal sinus disorders; rhinitis; sneezing; nasal irritation; blood in nasal mucosa.
Eye : Keratitis and conjunctivitis, viral eye infections, eye redness.
Gastrointestinal : Dental discomfort and pain, gastrointestinal signs and symptoms, gastrointestinal infections, gastroenteritis, gastrointestinal disorders, oral ulcerations, oral erythema and rashes, constipation, appendicitis, oral discomfort and pain.
Hepatobiliary Tract and Pancreas : Abnormal liver function tests.
Lower Respiratory : Lower respiratory signs and symptoms, pneumonia, lower respiratory infections.
Musculoskeletal : Arthralgia and articular rheumatism; muscle stiffness, tightness, and rigidity; bone and cartilage disorders.
Neurology : Sleep disorders, tremors, hypnagogic effects, compressed nerve syndromes.
Non-Site Specific : Allergies and allergic reactions, congestion, viral infections, pain, chest symptoms, fluid retention, bacterial infections, wheeze and hives, unusual taste.
Skin : Viral skin infections, urticaria, skin flakiness and acquired ichthyosis, disorders of sweat and sebum, sweating.

The incidence of common adverse experiences reported in Study 3, a 28 week, non-US clinical study of 503 patients previously treated with inhaled corticosteroids who were treated twice daily with fluticasone propionate; salmeterol xinafoate 500/50, fluticasone propionate inhalation powder 500 µg and salmeterol inhalation powder 50 µg used concurrently, or fluticasone propionate inhalation powder 500 µg was similar to the incidences reported in TABLE 3A and TABLE 3B.

Observed During Clinical Practice

In addition to adverse events reported from clinical trials, the following events have been identified during postapproval use of fluticasone propionate; salmeterol xinafoate, fluticasone propionate, and/or salmeterol. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to fluticasone propionate; salmeterol xinafoate, fluticasone propionate, and/or salmeterol.

In extensive US and worldwide postmarketing experience with salmeterol, a component of fluticasone propionate; salmeterol xinafoate, serious exacerbations of asthma, including some that have been fatal, have been reported. In most cases, these have occurred in patients with severe asthma and/or in some patients in whom asthma has been acutely deteriorating (see WARNINGS), but they have also occurred in a few patients with less severe asthma. It was not possible from these reports to determine whether salmeterol contributed to these events or simply failed to relieve the deteriorating asthma.

Cardiovascular : Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), ventricular tachycardia.
Ear, Nose, and Throat : Aphonia, earache, paranasal sinus pain, throat soreness and irritation.
Endocrine and Metabolic : Cushing syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism, hyperglycemia, weight gain.
Gastrointestinal : Abdominal pain, dyspepsia, xerostomia.
Musculoskeletal : Back pain, cramps, muscle spasm, myositis.
Neurology : Paresthesia, restlessness.
Non-Site Specific : Immediate and delayed hypersensitivity reaction, pallor.
Psychiatry : Agitation, aggression, depression.
Respiratory : Chest congestion, chest tightness, dyspnea, immediate bronchospasm, influenza, paradoxical bronchospasm, tracheitis, wheezing, reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.
Skin : Contact dermatitis, contusions, ecchymoses, photodermatitis.
Urogenital : Dysmenorrhea, irregular menstrual cycle, pelvic inflammatory disease, vaginal candidiasis, vaginitis, vulvovaginitis.
Eosinophilic Conditions : In rare cases, patients on inhaled fluticasone propionate, a component of Advair Diskus, may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. While fluticasone propionate; salmeterol xinafoate should not be used for transferring patients from systemic corticosteroid therapy, physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established (see PRECAUTIONS, General, Eosinophilic Conditions).

OVERDOSAGE :

Fluticasone Propionate; Salmeterol Xinafoate

No deaths occurred in rats given combinations of salmeterol and fluticasone propionate at acute inhalation doses of 3.6 and 1.9 mg/kg, respectively (approximately 320 and 15 times the maximum recommended daily inhalation dose in adults on a mg/m² basis).

Fluticasone Propionate

Chronic overdosage with fluticasone propionate may result in signs/symptoms of hypercorticism (see PRECAUTIONS). Inhalation by healthy volunteers of a single dose of 4000 µg of fluticasone propionate inhalation powder or single doses of 1760 or 3520 µg of fluticasone propionate inhalation aerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at doses of 1320 µg twice daily for 7-15 days to healthy human volunteers was also well tolerated. Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups. The oral and subcutaneous median lethal doses in mice and rats were >1000 mg/kg (>4300 and >8700 times, respectively, the maximum recommended daily inhalation dose in adults on a mg/m² basis).

Salmeterol

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

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

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

No deaths were seen in rats given salmeterol at an inhalation dose of 2.9 mg/kg (approximately 250 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) and in dogs at an inhalation dose of 0.7 mg/kg (approximately 200 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). By the oral route, no deaths occurred in mice at 150 mg/kg (approximately 6500 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) and in rats at 1000 mg/kg (approximately 86,000 times the maximum recommended daily inhalation dose in adults on a mg/m² basis).

DOSAGE AND ADMINISTRATION :

Advair Diskus is available in 3 strengths, Advair Diskus 100/50, Advair Diskus 250/50, and Advair Diskus 500/50, containing 100, 250, and 500 µg of fluticasone propionate, respectively, and 50 µg of salmeterol per inhalation. Advair Diskus should be administered by the orally inhaled route only (see Patient’s Instructions for Use).

For patients 12 years of age and older, the dosage is 1 inhalation twice daily (morning and evening, approximately 12 hours apart).

The recommended starting doses for fluticasone propionate; salmeterol xinafoate are based upon patients’ current asthma therapy.

The maximum recommended dose is fluticasone propionate; salmeterol xinafoate 500/50 twice daily.

For all patients it is desirable to titrate to the lowest effective strength after adequate asthma stability is achieved.

Advair Diskus should be administered twice daily every day. More frequent administration (more than twice daily) or a higher number of inhalations (more than 1 inhalation twice daily) of the prescribed strength of Advair Diskus is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. The safety and efficacy of Advair Diskus when administered in excess of recommended doses have not been established.

If symptoms arise in the period between doses, an inhaled, short-acting beta₂-agonist should be taken for immediate relief.

Patients who are receiving Advair Diskus twice daily should not use salmeterol for prevention of exercise-induced bronchospasm, or for any other reason.

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

For patients who do not respond adequately to the starting dose after 2 weeks of therapy, replacing the current strength of Advair Diskus with a higher strength may provide additional asthma control.

If a previously effective dosage regimen of Advair Diskus fails to provide adequate control of asthma, the therapeutic regimen should be reevaluated and additional therapeutic options, e.g., replacing the current strength of Advair Diskus with a higher strength, adding additional inhaled corticosteroid, or initiating oral corticosteroids, should be considered.

Rinsing the mouth after inhalation is advised.

Geriatric Use

In studies where geriatric patients (65 years of age or older, see PRECAUTIONS, Geriatric Use) have been treated with Advair Diskus, efficacy and safety did not differ from that in younger patients. Based on available data for Advair Diskus and its active components, no dosage adjustment is recommended.

HOW SUPPLIED :

Advair Diskus 100/50 is supplied as a disposable, purple-colored device containing 60 blisters. The DISKUS inhalation device is packaged within a purple-colored, plastic-coated, moisture-protective foil pouch.
Advair Diskus 250/50 is supplied as a disposable, purple-colored device containing 60 blisters. The DISKUS inhalation device is packaged within a purple-colored, plastic-coated, moisture-protective foil pouch.
Advair Diskus 500/50 is supplied as a disposable, purple-colored device containing 60 blisters. The DISKUS inhalation device is packaged within a purple-colored, plastic-coated, moisture-protective foil pouch.

Storage : Store at controlled room temperature, 20-25°C (68-77°F) in a dry place away from direct heat or sunlight. Keep out of reach of children. The DISKUS inhalation device is not reusable. The device should be discarded 1 month after removal from the moisture-protective foil overwrap pouch or after every blister has been used (when the dose indicator reads “0”), whichever comes first. Do not attempt to take the device apart.