Fluticasone Propionate and Salmeterol 113 ug; 14 ug Powder, Metered — NDC 0093-3608-82 (Billing 00093-3608-82)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action This product contains both fluticasone propionate and salmeterol. The mechanisms of action described below for the individual components apply to this combination product. 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 humans 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, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation.

These anti-inflammatory actions of corticosteroids contribute to their efficacy in the treatment of asthma. Salmeterol : 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 hyperresponsiveness.

12.2Pharmacodynamics Hypothalamic Pituitary Adrenal Axis Effects (HPA) There are no HPA data from controlled trials of the Fluticasone Propionate/Salmeterol MDPI in healthy subjects or subjects with asthma. Cardiovascular Effects and Effects on Potassium and Glucose Fluticasone Propionate/Salmeterol MDPI in Healthy Subjects There were no clinical trials conducted with Fluticasone Propionate/Salmeterol MDPI that assessed cardiovascular (CV) effects in healthy subjects. Other Fluticasone Propionate and Salmeterol Dry Powder Inhaler (DPI) Products in Healthy Subjects Since systemic pharmacodynamic effects of salmeterol are not normally seen at the maximum approved salmeterol dosage, higher doses were used to produce measurable effects.

Four trials were conducted with healthy adult subjects to assess CV effects: Single‑dose crossover trial using 2 inhalations of fluticasone propionate and salmeterol DPI (500 mcg/50 mcg) (two times the maximum approved salme… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action This product contains both fluticasone propionate and salmeterol. The mechanisms of action described below for the individual components apply to this combination product. 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 humans 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, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation.

These anti-inflammatory actions of corticosteroids contribute to their efficacy in the treatment of asthma. Salmeterol : 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 hyperresponsiveness.

12.3Pharmacokinetics Absorption Fluticasone Propionate: Fluticasone Propionate/Salmeterol MDPI acts locally in the lung; therefore, plasma levels may not predict therapeutic effect. Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate was 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 was systemically absorbed.

After administration of 232 mcg/14 mcg Fluticasone Propionate/Salmeterol MDPI to patients aged 12 years and older with persistent asthma in a clinical trial, the mean C max value of fluticasone propionate was 66 pg/mL with a median t max value of approximately 2 hours. Salmeterol: After administration of 232 mcg/14 mcg Fluticasone Propionate/Salmeterol MDPI to patients aged 12 years and older with persistent asthma, the mean C max values of salmeterol was 60 pg/mL. The median t max was 5 minutes.

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

4.2L/kg. The percentage of fluticasone propionate bound to human plasma proteins averages 99%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin.

Salmeterol: Volume of distribution data are not available for salmeterol. The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol. Elimination Fluticasone Propionate: Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours.

Terminal half-life estimates of fluticasone propionate following oral inhalation administration of Fluticasone Propionate/Salmeterol MDPI were approximately 10.8 hours. Metabolism The total clearance of fluticasone propionate is high (average, 1,093 mL/minute), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in humans is the 17β carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway.

This metabolite has less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in humans. Excretion 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.

Salmeterol : Terminal half-life estimates for salmeterol for Fluticasone Propionate/Salmeterol MDPI were approximately 12.6 hours. The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (greater than 99%) and has a long elimination half-life of 11 days.

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

Excretion In 2 healthy adult subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. Specific Populations A population pharmacokinetic analysis was performed for fluticasone propionate and salmeterol util… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Hypothalamic Pituitary Adrenal Axis Effects (HPA) There are no HPA data from controlled trials of the Fluticasone Propionate/Salmeterol MDPI in healthy subjects or subjects with asthma. Cardiovascular Effects and Effects on Potassium and Glucose Fluticasone Propionate/Salmeterol MDPI in Healthy Subjects There were no clinical trials conducted with Fluticasone Propionate/Salmeterol MDPI that assessed cardiovascular (CV) effects in healthy subjects. Other Fluticasone Propionate and Salmeterol Dry Powder Inhaler (DPI) Products in Healthy Subjects Since systemic pharmacodynamic effects of salmeterol are not normally seen at the maximum approved salmeterol dosage, higher doses were used to produce measurable effects.

Four trials were conducted with healthy adult subjects to assess CV effects: Single‑dose crossover trial using 2 inhalations of fluticasone propionate and salmeterol DPI (500 mcg/50 mcg) (two times the maximum approved salmeterol dosage for that DPI per dosing interval), fluticasone propionate DPI 500 mcg and salmeterol DPI 50 mcg given concurrently, or fluticasone propionate DPI 500 mcg given alone, Cumulative dose trial using 50 to 400 mcg of salmeterol DPI (1 time to 8 times the maximum approved salmeterol dosage per dosing interval for that DPI, respectively) given alone, or fluticasone propionate and salmeterol DPI (500 mcg/50 mcg), Repeat‑dose trial for 11 days using 2 inhalations twice daily of fluticasone propionate and salmeterol DPI (250 mcg/50 mcg) (two times the maximum approved salmeterol dosage for that DPI per dosing interval), fluticasone propionate DPI 250 mcg, or salmeterol DPI 50 mcg, and Single-dose trial using 5 inhalations of fluticasone propionate and salmeterol DPI (100 mcg/50 mcg) (five times the maximum approved salmeterol dosage for that DPI per dosing interval), fluticasone propionate DPI 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 and salmeterol DPI, 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 the fluticasone propionate and salmeterol DPI product. Other Salmeterol Products in Subjects with Asthma: Inhaled salmeterol, like other beta‑adrenergic agonist drugs, can produce dose‑related CV effects and effects on blood glucose and/or serum potassium [see Warnings and Precautions ( 5.11 , 5.17 )] .

The CV effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol occurred with similar frequency, and are of similar type and severity, as those noted following albuterol administration. The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in subjects with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/minute, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/minute).

Adult and adolescent subjects receiving 50 mcg doses of salmeterol MDPI (N=60) underwent continuous electrocardiographic monitoring during two 12‑hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted. Concomitant Use of Fluticasone Propionate/Salmeterol MDPI With Other Respiratory Medications: Short-Acting Beta 2 ‑Agonists: In clinical trials in subjects with asthma, the mean daily need for albuterol by 166 adult and adolescent subjects aged 12 years and older using another fluticasone propionate/salmeterol DPI product was approximately 1.3 inhalations/day and ranged from 0 to 9 inhalations/day (0 to about 4.5 times the maximum approved salmeterol dosage for that DPI per dosing interval).

Five… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES The safety and efficacy of Fluticasone Propionate/Salmeterol Multidose Dry Powder Inhaler (FS MDPI) were evaluated in 3004 patients with asthma. The development program included 2 confirmatory trials of 12 weeks duration, a 26 week safety trial and three dose-ranging trials. The efficacy of Fluticasone Propionate/Salmeterol MDPI is based primarily on the dose-ranging trials and the confirmatory trials described below.

14.1Dose-Ranging Studies in Patients with Asthma Six doses of fluticasone propionate ranging from 16 mcg to 434 mcg (expressed as metered doses) administered twice daily via MDPI were evaluated in 2 randomized, double-blind, placebo-controlled 12 week trials in patients with asthma. Trial 201 was conducted in patients whose asthma was uncontrolled at baseline and had been treated by short-acting beta 2 -agonist alone or in combination with non-corticosteroid asthma medication. Low dose inhaled corticosteroids (ICS)-treated patients may have been included after a minimum of 2 weeks washout.

This trial contained an open-label active comparator fluticasone propionate inhalation powder 100 mcg administered twice daily. Trial 202 was conducted in patients whose asthma was uncontrolled at baseline and had been treated with high dose ICS with or without a LABA. This study contained an open-label active comparator fluticasone propionate inhalation powder 250 mcg twice daily.

The trials were dose-ranging trials of fluticasone propionate MDPI not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority/inferiority to fluticasone propionate inhalation powder. The metered doses for fluticasone MDPI (16, 28, 59, 118, 225, 434 mcg) used in Trial 201 and Trial 202 (see Figure 1) are slightly different from the metered doses for the comparator products (fluticasone inhalation powder) and the Phase 3 investigational products which are the basis of the proposed commercial labeled claim (55, 113, 232 mcg for fluticasone).

The changes in doses between Phase 2 and 3 resulted from optimization of the manufacturing process. Figure 1: Baseline Adjusted Least Square Mean Change in Trough Morning FEV 1 (L) over 12 weeks (FAS) a FAS = full analysis set; a Trials were not designed to provide comparative effectiveness data and should not be interpreted as superiority/inferiority to fluticasone propionate inhalation powder The efficacy and safety of four doses of salmeterol xinafoate were evaluated in a double blind, 6-period crossover study compared with single dose fluticasone propionate MDPI and open label fluticasone propionate/salmeterol 100 mcg/50 mcg dry powder inhaler (DPI) as comparator in patients with persistent asthma.

The trials were dose-ranging trials of the salmeterol component of Fluticasone Propionate/Salmeterol MDPI and not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority/inferiority to fluticasone propionate/salmeterol inhalation powder. The salmeterol doses studied were 6.8 mcg, 13.2 mcg, 26.8 mcg and 57.4 mcg in combination with fluticasone propionate 118 mcg delivered by MDPI (expressed as metered dose). The metered doses for salmeterol (6.8, 13.2, 26.8, 57.4 mcg) used in this study are slightly different from the metered doses for the comparator products (fluticasone/salmeterol inhalation powder) and the Phase 3 investigational products which are the basis of the proposed commercial labeled claim (55, 113, 232 mcg for fluticasone and 14 mcg for salmeterol).

The phase 3 and commercial products were optimized to better match the strengths to the comparators. Plasma for pharmacokinetic characterization was obtained at each dosing period. Fluticasone propionate/salmeterol xinafoate MDPI 118 mcg/13.2 mcg had similar clinical efficacy with lower systemic exposure when compared to the 50 mcg of salmeterol in fluticasone propionate/salmeterol 100 mcg/50 mcg dry powder inhaler (Figure 2).

Figure 2:… [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 1000 mcg/kg (approximately 10 times the MRHDID for adults on a mcg/m 2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately equivalent to the MRHDID for adults 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 equivalent to 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 1400 mcg/kg and above (approximately 240 times the MRHDID on a mcg/m 2 basis) 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 35 times the MRHDID on a mcg/m 2 basis).

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 240 times the MRHDID on a mcg/m 2 basis). No tumors were seen at 210 mcg/kg (approximately 75 times the MRHDID 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 2000 mcg/kg (approximately 690 times the MRHDID for adults on a mcg/m 2 basis).

13.2Animal Toxicology and/or Pharmacology 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.