Fluticasone Propionate and Salmeterol DISKUS 500 ug; 50 ug Powder — NDC 66993-586-97 (Billing 66993-0586-97)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Fluticasone Propionate/Salmeterol DISKUS Fluticasone Propionate/Salmeterol DISKUS contains both fluticasone propionate and salmeterol. The mechanisms of action described below for the individual components apply to Fluticasone Propionate/Salmeterol DISKUS. These drugs represent 2 different classes of medications (a synthetic corticosteroid and a LABA) that have different effects on clinical, physiologic, and inflammatory indices.

Fluticasone Propionate Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of 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 clinical significance of these findings is unknown. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation.

These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma. Inflammation is also a component in the pathogenesis of COPD. In contrast to asthma, however, the predominant inflammatory cells in COPD include neutrophils, CD8+ T-lymphocytes, and macrophages.

The effects of corticosteroids in the treatment of COPD are not well defined and ICS and fluticasone propionate when used apart from Fluticasone Propionate/Salmeterol DISKUS are not indicated for the treatment of COPD. Salmeterol Xinafoate Salmeterol is a selective LABA. In vitro studies show salmeterol to be at least 50 times more selective for beta 2 -adrenoceptors than albuterol.

Although beta 2 -adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -adrenoceptors are the predominant receptors in the heart, there are also beta 2 -adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -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 2 , 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.

12.2Pharmacodynamics Fluticasone Propionate/Salmeterol DISKUS Healthy Subjects: Cardiovascular Effects: Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four (4) trials were conducted with healthy adult subjects: (1) a single-dose crossover trial using 2 inhalations of fluticasone propionate/salmeterol DISKUS 500/50 mcg, fluticasone propionate inhalation powder 500 mcg and salmeter… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Fluticasone Propionate/Salmeterol DISKUS Fluticasone Propionate/Salmeterol DISKUS contains both fluticasone propionate and salmeterol. The mechanisms of action described below for the individual components apply to Fluticasone Propionate/Salmeterol DISKUS. These drugs represent 2 different classes of medications (a synthetic corticosteroid and a LABA) that have different effects on clinical, physiologic, and inflammatory indices.

Fluticasone Propionate Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of 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 clinical significance of these findings is unknown. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation.

These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma. Inflammation is also a component in the pathogenesis of COPD. In contrast to asthma, however, the predominant inflammatory cells in COPD include neutrophils, CD8+ T-lymphocytes, and macrophages.

The effects of corticosteroids in the treatment of COPD are not well defined and ICS and fluticasone propionate when used apart from Fluticasone Propionate/Salmeterol DISKUS are not indicated for the treatment of COPD. Salmeterol Xinafoate Salmeterol is a selective LABA. In vitro studies show salmeterol to be at least 50 times more selective for beta 2 -adrenoceptors than albuterol.

Although beta 2 -adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -adrenoceptors are the predominant receptors in the heart, there are also beta 2 -adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -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 2 , 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.

12.3Pharmacokinetics Absorption Fluticasone Propionate: Healthy Subjects: Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed.

Following administration of fluticasone propionate/salmeterol DISKUS to healthy adult subjects, peak plasma concentrations of fluticasone propionate were achieved in 1 to 2 hours. In a single‑dose crossover trial, a higher-than-recommended dose of fluticasone propionate/salmeterol DISKUS was administered to 14 healthy adult subjects. Two (2) inhalations of the following treatments were administered: fluticasone propionate/salmeterol DISKUS 500/50 mcg, fluticasone propionate inhalation powder 500 mcg and salmeterol inhalation powder 50 mcg given concurrently, and fluticasone propionate inhalation powder 500 mcg alone .

Mean peak plasma concentrations of fluticasone propionate averaged 107, 94, and 120 pg/mL, respectively, indicating no significant changes in systemic exposures of fluticasone propionate. In 15 healthy subjects, systemic exposure to fluticasone propionate from 4 inhalations of ADVAIR HFA 230/21 (fluticasone propionate 230 mcg and salmeterol 21 mcg) Inhalation Aerosol (920/84 mcg) and 2 inhalations of fluticasone propionate/salmeterol DISKUS 500/50 mcg (1,000/100 mcg) was similar between the 2 inhalers (i.e., 799 versus 832 pg•h/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•h/mL).

Similar results were observed for peak fluticasone propionate plasma concentrations (186 and 182 pg/mL from ADVAIR HFA and fluticasone propionate/salmeterol DISKUS, respectively, and 307 pg/mL from the fluticasone propionate CFC inhalation aerosol). Absolute bioavailability of fluticasone propionate was 5.3% and 5.5% following administration of ADVAIR HFA and fluticasone propionate/salmeterol DISKUS, respectively. Subjects with Asthma and COPD: Peak steady-state fluticasone propionate plasma concentrations in adult subjects with asthma (N = 11) ranged from undetectable to 266 pg/mL after a 500-mcg twice-daily dose of fluticasone propionate inhalation powder using the DISKUS inhaler.

The mean fluticasone propionate plasma concentration was 110 pg/mL. Full pharmacokinetic profiles were obtained from 9 female and 16 male subjects with asthma given fluticasone propionate inhalation powder 500 mcg twice daily using the DISKUS inhaler and from 14 female and 43 male subjects with COPD given 250 or 500 mcg twice daily. No overall differences in fluticasone propionate pharmacokinetics were observed.

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

Salmeterol Xinafoate: Healthy Subjects: Salmeterol xinafoate, an ionic salt, dissociates in solution so that the salmeterol and 1-hydroxy-2-naphthoic acid (xinafoate) moieties are absorbed, distributed, metabolized, and eliminated independently. Salmeterol acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Following admini… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Fluticasone Propionate/Salmeterol DISKUS Healthy Subjects: Cardiovascular Effects: Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four (4) trials were conducted with healthy adult subjects: (1) a single-dose crossover trial using 2 inhalations of fluticasone propionate/salmeterol DISKUS 500/50 mcg, fluticasone propionate inhalation powder 500 mcg and salmeterol inhalation powder 50 mcg given concurrently, or fluticasone propionate inhalation powder 500 mcg given alone, (2) a cumulative-dose trial using 50 to 400 mcg of salmeterol inhalation powder given alone or as fluticasone propionate/salmeterol DISKUS 500/50 mcg, (3) a repeat-dose trial for 11 days using 2 inhalations twice daily of fluticasone propionate/salmeterol DISKUS 250/50 mcg, fluticasone propionate inhalation powder 250 mcg, or salmeterol inhalation powder 50 mcg, and (4) a single‑dose trial using 5 inhalations of fluticasone propionate/salmeterol DISKUS 100/50 mcg, fluticasone propionate inhalation powder 100 mcg alone, or placebo.

In these trials 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 DISKUS, concurrently with fluticasone propionate from separate inhalers, or as salmeterol alone. The systemic pharmacodynamic effects of salmeterol were not altered by the presence of fluticasone propionate in fluticasone propionate/salmeterol DISKUS. The potential effect of salmeterol on the effects of fluticasone propionate on the HPA axis was also evaluated in these trials.

Hypothalamic-Pituitary-Adrenal Axis Effects: No significant differences across treatments were observed in 24-hour urinary cortisol excretion and, where measured, 24-hour plasma cortisol AUC. The systemic pharmacodynamic effects of fluticasone propionate were not altered by the presence of salmeterol in fluticasone propionate/salmeterol DISKUS in healthy subjects. Subjects with Asthma: Adult and Adolescent Subjects: Cardiovascular Effects: In clinical trials with fluticasone propionate/salmeterol DISKUS in adult and adolescent subjects aged 12 years and older with asthma, no significant differences were observed in the systemic pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given alone or as fluticasone propionate/salmeterol DISKUS.

In 72 adult and adolescent subjects with asthma given either fluticasone propionate/salmeterol DISKUS 100/50 mcg or fluticasone propionate/salmeterol DISKUS 250/50 mcg, continuous 24-hour electrocardiographic monitoring was performed after the first dose and after 12 weeks of therapy, and no clinically significant dysrhythmias were noted. Hypothalamic-Pituitary-Adrenal Axis Effects: In a 28-week trial in adult and adolescent subjects with asthma, fluticasone propionate/salmeterol DISKUS 500/50 mcg twice daily was compared with the concurrent use of salmeterol inhalation powder 50 mcg plus fluticasone propionate inhalation powder 500 mcg from separate inhalers or fluticasone propionate inhalation powder 500 mcg alone.

No significant differences across treatments were observed in serum cortisol AUC after 12 weeks of dosing or in 24-hour urinary cortisol excretion after 12 and 28 weeks. In a 12-week trial in adult and adolescent subjects with asthma, fluticasone propionate/salmeterol DISKUS 250/50 mcg twice daily was compared with fluticasone propionate inhalation powder 250 mcg alone, salmeterol inhalation powder 50 mcg alone, and placebo. For most subjects, the ability to increase cortisol production in response to stress, as assessed by 30-minute cosyntropin stimulation, remained intact with fluticasone propionate/salmeterol DISKUS.

One subject (3%) who received fluticasone propionate/salme… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Asthma Adult and Adolescent Subjects Aged 12 Years and Older In clinical trials comparing fluticasone propionate/salmeterol DISKUS with its individual components, improvements in most efficacy endpoints were greater with fluticasone propionate/salmeterol DISKUS than with the use of either fluticasone propionate or salmeterol alone. In addition, clinical trials showed similar results between fluticasone propionate/salmeterol DISKUS and the concurrent use of fluticasone propionate plus salmeterol at corresponding doses from separate inhalers.

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

Trial 1: Clinical Trial with Fluticasone Propionate/Salmeterol DISKUS 100/50 mcg: This placebo-controlled, 12-week, U.S. trial compared fluticasone propionate/salmeterol DISKUS 100/50 mcg with its individual components, fluticasone propionate 100 mcg and salmeterol 50 mcg. The trial was stratified according to baseline asthma maintenance therapy; subjects were using either ICS (n = 250) (daily doses of beclomethasone dipropionate 252 to 420 mcg; flunisolide 1,000 mcg; fluticasone propionate inhalation aerosol 176 mcg; or triamcinolone acetonide 600 to 1,000 mcg) or salmeterol (n = 106).

Baseline FEV 1 measurements were similar across treatments: fluticasone propionate/salmeterol DISKUS 100/50 mcg,

2.17 L; fluticasone propionate 100 mcg,

2.11 L; salmeterol,

2.13 L; and placebo,

2.15L. Predefined withdrawal criteria for lack of efficacy, an indicator of worsening asthma, were utilized for this placebo-controlled trial. Worsening asthma was defined as a clinically important decrease in FEV 1 or PEF, increase in use of VENTOLIN (albuterol, USP) Inhalation Aerosol, increase in night awakenings due to asthma, emergency intervention or hospitalization due to asthma, or requirement for asthma medication not allowed by the protocol.

As shown in Table 4 , statistically significantly fewer subjects receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg were withdrawn due to worsening asthma compared with fluticasone propionate, salmeterol, and placebo. Table 4. Percent of Subjects Withdrawn due to Worsening Asthma in Subjects Previously Treated with Either Inhaled Corticosteroids or Salmeterol (Trial 1) Fluticasone Propionate/ Salmeterol DISKUS 100/50 mcg (n = 87) Fluticasone Propionate 100 mcg (n = 85) Salmeterol 50 mcg (n = 86) Placebo (n = 77) 3% 11% 35% 49% The FEV 1 results are displayed in Figure 1.

Because this trial used predetermined criteria for worsening asthma, which caused more subjects in the placebo group to be withdrawn, FEV 1 results at Endpoint (last available FEV 1 result) are also provided. Subjects receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg had significantly greater improvements in FEV 1 (0.51 L, 25%) compared with fluticasone propionate 100 mcg (0.28 L, 15%), salmeterol (0.11 L, 5%), and placebo (0.01 L, 1%). These improvements in FEV 1 with fluticasone propionate/salmeterol DISKUS were achieved regardless of baseline asthma maintenance therapy (ICS or salmeterol).

Figure 1. Mean Percent Change from Baseline in FEV 1 in Subjects with Asthma Previously Treated with Either Inhaled Corticosteroids or Salmeterol (Trial 1) The effect of fluticasone propionate/salmeterol DISKUS 100/50 mcg on morning and evening PEF endpoints is shown in Table 5 . Table 5.

Peak Expiratory Flow Results for Subjects with Asthma Previously Treated with Either Inhaled Corticosteroids or Salmeterol (Trial… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Fluticasone Propionate Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 5 and 10 times the MRHDID for adults and children, respectively, on a mcg/m 2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than and approximately equivalent to the MRHDID for adults and children, respectively, on a mcg/m 2 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 in vivo mouse micronucleus test. Fertility and reproductive performance were unaffected in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 0.5 times the MRHDID for adults on a mcg/m 2 basis). Salmeterol In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1,400 mcg/kg and above (approximately 20 times the MRHDID for adults and children based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts.

No tumors were seen at 200 mcg/kg (approximately 3 times the MRHDID for adults and children 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 680 mcg/kg and above (approximately 66 and 35 times the MRHDID for adults and children, respectively, on a mcg/m 2 basis). No tumors were seen at 210 mcg/kg (approximately 20 and 10 times the MRHDID for adults and children, respectively, on a mcg/m 2 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. Fertility and reproductive performance were unaffected in male and female rats at oral doses up to 2,000 mcg/kg (approximately 195 times the MRHDID for adults on a mcg/m 2 basis).

13.2Animal Toxicology and/or Pharmacology Preclinical Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown.