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Flovent Rotadisk (Fluticasone Propionate Inhalation) - Description and Clinical Pharmacology

 
 



DESCRIPTION

The active component of FLOVENT ROTADISK 50 mcg, FLOVENT ROTADISK 100 mcg, and FLOVENT ROTADISK 250 mcg is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl)6(alpha),9-difluoro-11(beta),17-dihydroxy- 16(alpha)-methyl-3-oxoandrosta-1,4-diene-17(beta)-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.

FLOVENT ROTADISK 50 mcg, FLOVENT ROTADISK 100 mcg, and FLOVENT ROTADISK 250 mcg contain a dry powder presentation of fluticasone propionate intended for oral inhalation only. Each double-foil ROTADISK contains 4 blisters. Each blister contains a mixture of 50, 100, or 250 mcg of microfine fluticasone propionate blended with lactose (which contains milk proteins) to a total weight of 25 mg. The contents of each blister are inhaled using a specially designed plastic device for inhaling powder called the DISKHALER. After a fluticasone propionate ROTADISK is loaded into the DISKHALER, a blister containing medication is pierced and the fluticasone propionate is dispersed into the air stream created when the patient inhales through the mouthpiece.

The amount of drug delivered to the lung will depend on patient factors such as inspiratory flow. Under standardized in vitro testing, FLOVENT ROTADISK delivers 44, 88, or 220 mcg of fluticasone propionate from FLOVENT ROTADISK 50 mcg, FLOVENT ROTADISK 100 mcg, or FLOVENT ROTADISK 250 mcg, respectively, when tested at a flow rate of 60 L/min for 3 seconds. In adult and adolescent patients with asthma, mean peak inspiratory flow (PIF) through the DISKHALER was 123 L/min (range, 88 to 159 L/min), and in pediatric patients 4 to 11 years of age with asthma, mean PIF was 110 L/min (range, 43 to 175 L/min).

CLINICAL PHARMACOLOGY

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 may contribute to their efficacy in asthma.

Though highly effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately. However, improvement following inhaled administration of fluticasone propionate can occur within 24 hours of beginning treatment, although maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer.

Pharmacokinetics: Absorption: The activity of FLOVENT ROTADISK Inhalation Powder is due to the parent drug, fluticasone propionate. 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 inhalation powder in healthy volunteers averaged about 13.5% of the nominal dose.

Peak plasma concentrations after a 1,000-mcg dose of fluticasone propionate inhalation powder ranged from 0.1 to 1.0 ng/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 averaged 91%.

Fluticasone propionate is weakly and reversibly bound to erythrocytes. Fluticasone propionate is not significantly bound to human transcortin.

Metabolism: The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17(beta)-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This metabolite had approximately 2,000 times less affinity 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.

In a multiple-dose drug interaction study, coadministration of fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.

In a drug interaction study, coadministration of fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased fluticasone propionate concentrations, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol.

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

Special Populations: Formal pharmacokinetic studies using fluticasone propionate were not carried out in any special populations. In a clinical study using fluticasone propionate inhalation powder, trough fluticasone propionate plasma concentrations were collected in 76 males and 74 females after inhaled administration of 100 and 500 mcg twice daily. Full pharmacokinetic profiles were obtained from 7 female patients and 13 male patients at these doses, and no overall differences in pharmacokinetic behavior were found.

Plasma concentrations of fluticasone propionate were measured 20 and 40 minutes after dosing from 29 children aged 4 to 11 years who were taking either 50 or 100 mcg twice daily of fluticasone propionate inhalation powder. Plasma concentration values ranged from below the limit of quantitation (25 pg/mL) to 117 pg/mL (50-mcg dose) or 154 pg/mL (100-mcg dose). In a study with adults taking the 100-mcg twice-daily dose, the plasma concentrations observed ranged from below the limit of quantitation to 73.1 pg/mL. The median fluticasone propionate plasma concentrations for the 100-mcg dose in children was 58.7 pg/mL; in adults the median plasma concentration was 39.5 pg/mL.

Drug Interactions: Fluticasone propionate is a substrate of cytochrome P450 3A4. Coadministration of fluticasone propionate and the highly potent cytochrome P450 3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (<10 pg/mL) in most subjects, and when concentrations were detectable peak levels (Cmax averaged 11.9 pg/mL [range, 10.8 to 14.1 pg/mL] and AUC(0-[tgr ]) averaged 8.43 pg·hr/mL [range, 4.2 to 18.8 pg·hr/mL]). Fluticasone propionate Cmax and AUC(0-[tgr ]) increased to 318 pg/mL (range, 110 to 648 pg/mL) and 3,102.6 pg·hr/mL (range, 1,207.1 to 5,662.0 pg·hr/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol area under the plasma concentration versus time curve (AUC).

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

In another multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.

Pharmacodynamics: To confirm that systemic absorption does not play a role in the clinical response to inhaled fluticasone propionate, a double-blind clinical study comparing inhaled and oral fluticasone propionate was conducted. Doses of 100 and 500 mcg twice daily of fluticasone propionate inhalation powder were compared to oral fluticasone propionate, 20,000 mcg given once daily, and placebo for 6 weeks. Plasma levels of fluticasone propionate were detectable in all 3 active groups, but the mean values were highest in the oral group. Both doses of inhaled fluticasone propionate were effective in maintaining asthma stability and improving lung function while oral fluticasone propionate and placebo were ineffective. This demonstrates that the clinical effectiveness of inhaled fluticasone propionate is due to its direct local effect and not to an indirect effect through systemic absorption.

The potential systemic effects of inhaled fluticasone propionate on the hypothalamic-pituitary-adrenal (HPA) axis were also studied in patients with asthma. Fluticasone propionate given by inhalation aerosol at doses of 220, 440, 660, or 880 mcg twice daily was compared with placebo or oral prednisone 10 mg given once daily for 4 weeks. For most patients, the ability to increase cortisol production in response to stress, as assessed by 6-hour cosyntropin stimulation, remained intact with inhaled fluticasone propionate treatment. No patient had an abnormal response (peak serum cortisol <18 mcg/dL) after dosing with placebo or fluticasone propionate 220 mcg twice daily. For patients treated with 440, 660, and 880 mcg twice daily, 10%, 16%, and 12%, respectively, had an abnormal response as compared to 29% of patients treated with prednisone.

In clinical trials with fluticasone propionate inhalation powder, using doses up to and including 250 mcg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol <18 mcg/dL) were noted in patients receiving fluticasone propionate or placebo. The incidence of abnormal tests at 500 mcg twice daily was greater than placebo. In a 2-year study carried out in 64 patients randomized to fluticasone propionate 500 mcg twice daily or placebo, 1 patient receiving fluticasone propionate (4%) had an abnormal response to 6-hour cosyntropin infusion 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.

CLINICAL TRIALS

Double-blind, parallel-group, placebo-controlled, US clinical trials were conducted in 1,197 adolescent and adult patients with asthma to assess the efficacy and safety of FLOVENT ROTADISK in the treatment of asthma. Fixed doses of 50, 100, 250, and 500 mcg twice daily were compared to placebo to provide information about appropriate dosing to cover a range of asthma severity. Patients with asthma included in these studies were those not adequately controlled with beta-agonists alone, and those already maintained on daily inhaled corticosteroids. In these efficacy trials, at all doses, measures of pulmonary function (forced expiratory volume in 1 second [FEV1] and morning peak expiratory flow rate [AM PEF]) were statistically significantly improved as compared with placebo. All doses were delivered by inhalation of the contents of 1 or 2 blisters from the DISKHALER twice daily.

Figure 1 displays results of pulmonary function tests for 2 recommended dosages of FLOVENT ROTADISK (100 and 250 mcg twice daily) and placebo from a 12-week trial in 331 adolescent and adult patients with asthma (baseline FEV1= 2.63 L/sec) inadequately controlled on bronchodilators alone. Because this trial used predetermined criteria for lack of efficacy, which caused more patients in the placebo group to be withdrawn, pulmonary function results at Endpoint, which is the last evaluable FEV1 result and includes most patients' lung function data, are also provided. Pulmonary function at both dosages of FLOVENT ROTADISK improved significantly compared with placebo by the first week of treatment, and this improvement was maintained over the duration of the trial.

In a second clinical study of 75 patients, 500 mcg twice daily was evaluated in a similar population. In this trial FLOVENT ROTADISK significantly improved pulmonary function as compared with placebo.

Figure 2 displays results of pulmonary function tests for 2 recommended dosages of FLOVENT ROTADISK (100 and 250 mcg twice daily) and placebo from a 12-week trial in 342 adolescent and adult patients with asthma (baseline FEV1= 2.49 L/sec) already receiving daily inhaled corticosteroid therapy (>/=336 mcg/day of beclomethasone dipropionate or >/=800 mcg/day of triamcinolone acetonide) in addition to as-needed albuterol and theophylline (38% of all patients). Because this trial also used predetermined criteria for lack of efficacy, which caused more patients in the placebo group to be withdrawn, pulmonary function results at Endpoint are included. Pulmonary function at both dosages of FLOVENT ROTADISK improved significantly compared with placebo by the first week of treatment and the improvement was maintained over the duration of the trial.

In a second clinical study of 139 patients, treatment with 500 mcg twice daily was evaluated in a similar patient population. In this trial FLOVENT ROTADISK significantly improved pulmonary function as compared with placebo.

In the 4 trials described above, all dosages of FLOVENT ROTADISK were efficacious; however, at higher dosages, patients were less likely to discontinue study participation due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and patient-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma).

In a clinical trial of 96 patients with severe asthma requiring chronic oral prednisone therapy (average baseline daily prednisone dose was 10 mg), fluticasone propionate given by inhalation aerosol at doses of 660 and 880 mcg twice daily was evaluated. Both doses enabled a statistically significantly larger percentage of patients to wean successfully from oral prednisone as compared with placebo (69% of the patients on 660 mcg twice daily and 88% of the patients on 880 mcg twice daily as compared with 3% of patients on placebo). Accompanying the reduction in oral corticosteroid use, patients treated with fluticasone propionate had significantly improved lung function and fewer asthma symptoms as compared with the placebo group. These data were obtained from a clinical study using fluticasone propionate inhalation aerosol; no direct assessment of the clinical comparability of equal nominal doses for the FLOVENT ROTADISK and FLOVENT Inhalation Aerosol formulations in this population has been conducted.

Pediatric Experience: In a 12-week, placebo-controlled clinical trial of 263 patients aged 4 to 11 years inadequately controlled on bronchodilators alone (baseline morning peak expiratory flow = 200 L/min), fluticasone propionate inhalation powder doses of 50 and 100 mcg twice daily significantly improved morning peak expiratory flow (28% and 34% change from baseline at Endpoint, respectively) compared to placebo (11% change). In a second placebo-controlled, 52-week trial of 325 patients aged 4 to 11 years, approximately half of whom were receiving inhaled corticosteroids at baseline, doses of fluticasone propionate inhalation powder of 50 and 100 mcg twice daily improved lung function by the first week of treatment, and the improvement continued over 1 year compared to placebo. In both studies, patients on active treatment were significantly less likely to discontinue treatment due to lack of efficacy.

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