CATEGORIES: Rhinitis, allergic; Asthma; Dermatitis; Pruritus; Pregnancy Category C; FDA Approved December 1990
Drug Classes: Corticosteroids, inhalation; Corticosteroids, topical; Dermatologics
BRAND NAMES: Cutivate; Flonase; Flovent; Flovent Rotadisk
FOREIGN BRAND AVAILABILITY:
Allegro (Israel);
Atemur Mite (Germany);
Flixonase (Austria, Bulgaria, Colombia, Costa Rica, Czech Republic, Denmark, Dominican Republic, El Salvador, England, Finland, France, Guatemala, Honduras, Hong Kong, Hungary, Indonesia, Ireland, Israel, Italy, Korea, Malaysia, Mexico, Netherlands, Nicaragua, Panama, Peru, Russia, Singapore, Taiwan, Thailand, Turkey);
Flixonase 24 hour (New Zealand);
Flixonase Nasal Spray (New Zealand);
Flixotide (Austria, Bulgaria, China, Czech Republic, Denmark, England, Finland, France, Hong Kong, Hungary, Indonesia, Ireland, Israel, Italy, Korea, Mexico, Netherlands, Peru, Philippines, Russia, Singapore, South Africa, Taiwan, Thailand, Turkey);
Flixotide Disk (China, New Zealand);
Flixotide Disks (Australia);
Flixotide Inhaler (Australia);
Flixovate (France);
Flunase (Japan);
Flutide (Germany, Japan);
Flutivate (Germany, Norway);
Zoflut (India)
COST OF THERAPY:
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Note: The trade names have been used throughout this monograph for clarity.
Flovent Inhalation Aerosol
For Oral Inhalation Only
The active component of Flovent 44 μg, 110 μg, and 220 μg inhalation aerosol is fluticasone propionate, a glucocorticoid having the chemical name S-(fluoromethyl)6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate.
Fluticasone propionate is a white to off-white powder with a molecular weight of 500.6. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.
Flovent 44 μg, 110 μg, and 220 μg inhalation aerosol are pressurized, metered-dose aerosol units intended for oral inhalation only. Each unit contains a microcrystalline suspension of fluticasone propionate (micronized) in a mixture of two chlorofluorocarbon propellants (trichlorofluoromethane and dichlorodifluoromethane) with lecithin. Each actuation of the inhaler delivers 50, 125, or 250 μg of fluticasone propionate from the valve, and 44, 110, or 220 μg, respectively, of fluticasone propionate from the actuator.
Flovent Diskus
For Oral Inhalation Only
The active component of Flovent Diskus 50 μg, Flovent Diskus 100 μg, and Flovent Diskus 250 μg is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl)6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-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 Diskus 50 μg, 100 μg, and 250 μg are specially designed plastic devices containing a double-foil blister strip of a powder formulation of fluticasone propionate intended for oral inhalation only. Each blister on the double-foil strip within the device contains 50, 100, or 250 μg of microfine fluticasone propionate in 12.5 mg of formulation containing lactose. 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, Flovent Diskus delivers 47, 94, or 235 μg of fluticasone propionate from Flovent Diskus 50 μg, 100 μg, or 250 μg, respectively, when tested at a flow rate of 60 L/min for 2 seconds. In adult patients 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 82.4 L/min (range, 46.1-115.3 L/min). In children with asthma 4 and 8 years old, mean PIF through Flovent Diskus was 70 and 104 L/min, respectively (range, 48-123 L/min).
The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.
Flovent Rotadisk
For Oral Inhalation Only
For Use With the Diskhaler Inhalation Device
The active component of Flovent Rotadisk 50 μg, Flovent Rotadisk 100 μg, and Flovent Rotadisk 250 μg is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl)6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-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 μg, 100 μg, and 250 μg 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 μg of microfine fluticasone propionate blended with lactose 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 μg of fluticasone propionate from Flovent Rotadisk 50 μg, 100 μg, or 250 μg, 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, 88-159 L/min), and in pediatric patients 4-11 years of age with asthma, mean PIF was 110 L/min (range, 43-175 L/min).
Flovent Inhalation Aerosol
Fluticasone propionate is a synthetic, trifluorinated glucocorticoid 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 glucocorticoid action in asthma are unknown. Inflammation is recognized as an important component in the pathogenesis of asthma. Glucocorticoids 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 glucocorticoids may contribute to their efficacy in asthma.
Though highly effective for the treatment of asthma, glucocorticoids 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 1-2 weeks or longer after starting treatment. When glucocorticoids are discontinued, asthma stability may persist for several days or longer.
Pharmacokinetics
Absorption
The activity of Flovent inhalation aerosol 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 pre-systemic 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 aerosol in healthy volunteers averaged about 30% of the dose delivered from the actuator.
Peak plasma concentrations after an 880 μg inhaled dose ranged from 0.1-1.0 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, 1093 ml/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This metabolite had approximately 2000 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.
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 μg 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.
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 μg twice daily of fluticasone propionate inhalation powder were compared to oral fluticasone propionate, 20,000 μg 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 asthma patients. Fluticasone propionate given by inhalation aerosol at doses of 220, 440, 660, or 880 μg 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 less than 18 μg/dl) after dosing with placebo or 220 μg twice daily. Ten percent (10%) to 16% of patients treated with fluticasone propionate at doses of 440 μg or more twice daily had an abnormal response as compared to 29% of patients treated with prednisone.
Flovent Diskus
Mechanism of Action
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 1-2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer.
Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over recommended doses of Flovent Diskus. This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (<1%), and the minimal pharmacological activity of the only metabolite detected in man. Lung absorption does occur (see below).
Pharmacokinetics
Absorption
The activity of Flovent Diskus 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 from the Diskus device in healthy adult volunteers averages about 18%.
Peak steady-state fluticasone propionate plasma concentrations in adult patients with asthma (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. Fluticasone propionate 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 17β-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 500 μg twice daily. No overall differences in fluticasone propionate pharmacokinetics were observed.
Pediatrics
In a clinical study conducted in patients 4-11 years of age with mild to moderate asthma, fluticasone propionate concentrations were obtained in 61 patients at 20 and 40 minutes after dosing with 50 and 100 μg twice daily of fluticasone propionate inhalation powder using the Diskus. Plasma concentrations were low and ranged from undetectable (about 80% of the plasma samples) to 88 pg/ml. Mean fluticasone propionate plasma concentrations at the 2 dose levels were 5 and 8 pg/ml, respectively.
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.
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 μg twice daily of fluticasone propionate inhalation powder were compared to oral fluticasone propionate, 20,000 μg 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 asthma patients. Fluticasone propionate given by inhalation aerosol at doses of 220, 440, 660, or 880 μg 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 μg/dl) after dosing with placebo or fluticasone propionate 220 μg twice daily. For patients treated with 440, 660, and 880 μg 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 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 with the Diskhaler inhalation device 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 <35 μg/dl, 1 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.
In a placebo-controlled clinical study conducted in patients 4-11 years of age, a 30 minute cosyntropin stimulation test was performed in 41 patients after 12 weeks of dosing with 50 or 100 μg twice daily of fluticasone propionate via the Diskus device. One patient receiving fluticasone propionate via Diskus had a prestimulation plasma cortisol concentration <5 μg/dl, and 2 patients had a rise in cortisol of <7 μg/dl. However, all poststimulation values were >18 μg/dl.
Flovent Rotadisk
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 1-2 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 pre-systemic 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 1000 μg dose of fluticasone propionate inhalation powder ranged from 0.1-1.0 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, 1093 ml/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This metabolite had approximately 2000 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 μg twice daily) and erythromycin (333 mg three times daily) did not affect fluticasone propionate pharmacokinetics.
In a drug interaction study, coadministration of fluticasone propionate (1000 μg) 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 μg 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 4-11 years who were taking either 50 or 100 μg 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 μg dose) or 154 pg/ml (100 μg dose). In a study with adults taking the 100 μg 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 μg dose in children was 58.7 pg/ml; in adults the median plasma concentration was 39.5 pg/ml.
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 μg twice daily of fluticasone propionate inhalation powder were compared to oral fluticasone propionate, 20,000 μg 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 asthma patients. Fluticasone propionate given by inhalation aerosol at doses of 220, 440, 660, or 880 μg 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 μg/dl) after dosing with placebo or fluticasone propionate 220 μg twice daily. For patients treated with 440, 660, and 880 μg 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 μg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol <18 μg/dl) were noted in patients receiving fluticasone propionate or 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 randomized to fluticasone propionate 500 μg 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.
Flovent Inhalation Aerosol
Double-blind, parallel, placebo-controlled, US clinical trials were conducted in 1818 adolescent and adult patients with asthma to assess the efficacy and/or safety of Flovent inhalation aerosol in the treatment of asthma. Fixed doses ranging from 22-880 μg 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, those already maintained on daily inhaled corticosteroids, and those requiring oral corticosteroid therapy. In all efficacy trials, at all doses, measures of pulmonary function (forced expiratory volume in 1 second [FEV1] and morning peak expiratory flow rate [AM PEFR]) were statistically significantly improved as compared with placebo.
In 2 clinical trials of 660 patients with asthma inadequately controlled on bronchodilators alone, fluticasone propionate administered by inhalation aerosol was evaluated at doses of 44 and 88 μg twice daily. Both doses of fluticasone propionate improved asthma control significantly as compared with placebo.
Results of pulmonary function tests for the recommended starting dosage of fluticasone propionate inhalation aerosol (88 μg twice daily) and placebo from a 12 week trial in patients with asthma inadequately controlled on bronchodilators alone 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. Pulmonary function improved significantly with fluticasone propionate compared with placebo by the second week of treatment, and this improvement was maintained over the duration of the trial.
In clinical trials of 924 patients with asthma already receiving daily inhaled corticosteroid therapy (doses of at least 336 μg/day of beclomethasone dipropionate) in addition to as-needed albuterol and theophylline (46% of all patients), fluticasone propionate inhalation aerosol doses of 22-440 μg twice daily were also evaluated. All doses of fluticasone propionate were efficacious when compared to placebo on major endpoints including lung function and symptom scores. Patients treated with fluticasone propionate were also 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 PEFR, albuterol use, and nighttime awakenings due to asthma).
The results of pulmonary function from a 12 week clinical trial in patients with asthma already receiving daily inhaled corticosteroid therapy (beclomethasone dipropionate 336-672 μg/day) show the mean percent change from baseline in lung function results for fluticasone propionate inhalation aerosol dosages of 88, 220, and 440 μg twice daily and placebo over the 12 week trial. This trial also used predetermined criteria for lack of efficacy, which caused more patients in the placebo group to be withdrawn. Pulmonary function improved significantly with fluticasone propionate compared with placebo by the first week of treatment, and the improvement was maintained over the duration of the trial. Analysis of the endpoint results that adjusted for differential withdrawal rates indicated that pulmonary function significantly improved with fluticasone propionate compared with placebo treatment. Similar improvements in lung function were seen in the other two trials in patients treated with inhaled corticosteroids at baseline.
In a clinical trial of 96 patients with severe asthma requiring chronic oral prednisone therapy (average baseline daily prednisone dose was 10 mg), twice-daily doses of 660 and 880 μg of Flovent inhalation aerosol were 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 μg twice daily and 88% of the patients on 880 μg twice daily as compared with 3% of patients on placebo). Accompanying the reduction in oral corticosteroid use, patients treated with Flovent inhalation aerosol had significantly improved lung function and fewer asthma symptoms as compared with the placebo group.
Flovent Diskus
Four double-blind, parallel, placebo-controlled, US clinical trials were conducted in 1036 adolescent and adult patients (≥12 years of age) with asthma to assess the efficacy and safety of Flovent Diskus. These studies included fixed doses of 100, 250, and 500 μg twice daily 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 bronchodilators alone, and those already maintained on daily inhaled corticosteroids. All doses were delivered by inhalation of the contents of 1 or 2 blisters from the Diskus twice daily.
Trials were conducted that showed results of pulmonary function tests (mean percent change from baseline in FEV1 prior to AM dose) for 3 recommended dosages of fluticasone propionate inhalation powder (100, 250, and 500 μg twice daily) and placebo from the four 12 week trials in adolescents and adults. These trials 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. Pulmonary function at recommended dosages of fluticasone propionate improved significantly compared with placebo by the first week of treatment, and improvement was maintained for up to 1 year or more.
In all efficacy trials, measures of pulmonary function (FEV1) and morning peak expiratory flow rate (AM PEFR) were statistically significantly improved as compared with placebo at all twice-daily doses. Patients on all fluticasone propionate dosages were also significantly 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 PEFR, albuterol use and nighttime awakenings due to asthma) compared with placebo.
In a clinical trial of 111 patients with severe asthma requiring chronic oral prednisone therapy (average baseline daily prednisone dose was 14 mg), fluticasone propionate given by inhalation powder at doses of 500 and 1000 μg twice daily was evaluated. Both doses enabled a statistically significantly larger percentage of patients to wean successfully from oral prednisone as compared with placebo (75% of the patients on 500 μg twice daily and 89% of the patients on 1000 μg twice daily as compared with 9% 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.
Pediatric Experience
A 12 week, placebo-controlled clinical trial was conducted in 437 patients (177 on fluticasone propionate via Diskus) aged 4-11 years, approximately half of whom were receiving inhaled corticosteroids at baseline. In this study, doses of fluticasone propionate inhalation powder 50 and 100 μg twice daily significantly improved FEV1 (15% and 18% change from baseline at Endpoint, respectively) compared to placebo (7% change). Morning peak expiratory flow rate was also significantly improved with doses of fluticasone propionate 50 and 100 μg twice daily (26% and 27% change from baseline at Endpoint, respectively) compared to placebo (14% change). In this study, patients on active treatment were significantly less likely to discontinue treatment due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and patient recorded variables such as AM PEFR, albuterol use, and nighttime awakenings due to asthma).
Two other 12 week placebo-controlled clinical trials were conducted in 504 pediatric patients with asthma, approximately half of whom were receiving inhaled corticosteroids at baseline. In these studies, fluticasone propionate inhalation powder was efficacious at doses of 50 and 100 μg twice daily when compared to placebo on major endpoints including lung function and symptom scores. Pulmonary function improved significantly compared with placebo by the first week of treatment, and patients treated with fluticasone propionate were also less likely to discontinue study participation due to asthma deterioration. One hundred ninety-two (192) patients received fluticasone propionate for up to 1 year during an open-label extension. Data from this open-label extension suggested that lung function improvements could be maintained up to 1 year.
Flovent Rotadisk
Double-blind, parallel, placebo-controlled, US clinical trials were conducted in 1197 adolescent and adult asthma patients to assess the efficacy and safety of Flovent Rotadisk in the treatment of asthma. Fixed doses of 50, 100, 250, and 500 μg twice daily were compared to placebo to provide information about appropriate dosing to cover a range of asthma severity. Asthmatic patients 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 PEFR]) 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.
A trial of pulmonary function tests for 2 recommended dosages of fluticasone propionate inhalation powder (100 and 250 μg twice daily) and placebo from a 12 week trial in 331 adolescent and adult asthma patients (baseline FEV1 = 2.63 L/sec) inadequately controlled on bronchodilators alone was conducted. 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. Pulmonary function at both fluticasone propionate dosages 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 μg twice daily was evaluated in a similar population. In this trial fluticasone propionate significantly improved pulmonary function as compared with placebo.
A trial of pulmonary function tests for 2 recommended dosages of fluticasone propionate inhalation powder (100 and 250 μg twice daily) and placebo from a 12 week trial in 342 adolescent and adult asthma patients (baseline FEV1 = 2.49 L/sec) already receiving daily inhaled corticosteroid therapy (≥336 μg/day of beclomethasone dipropionate or ≥800 μg/day of triamcinolone acetonide) in addition to as-needed albuterol and theophylline (38% of all patients) was conducted 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 fluticasone propionate dosages 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 μg twice daily was evaluated in a similar patient population. In this trial fluticasone propionate significantly improved pulmonary function as compared with placebo.
In the 4 trials described above, all dosages of fluticasone propionate 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 PEFR, albuterol use, and nighttime awakenings due to asthma).
In a clinical trial of 96 severe asthmatic patients 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 μg 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 μg twice daily and 88% of the patients on 880 μg 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 4-11 years inadequately controlled on bronchodilators alone (baseline morning peak expiratory flow = 200 L/min), fluticasone propionate inhalation powder doses of 50 and 100 μg 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 4-11 years, approximately half of whom were receiving inhaled corticosteroids at baseline, doses of fluticasone propionate inhalation powder of 50 and 100 μg 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.
Flovent Inhalation Aerosol
Flovent inhalation aerosol is indicated for the maintenance treatment of asthma as prophylactic therapy. It is also indicated for patients requiring oral corticosteroid therapy for asthma. Many of these patients may be able to reduce or eliminate their requirement for oral corticosteroids over time.
Flovent inhalation aerosol is NOT indicated for the relief of acute bronchospasm.
Flovent Diskus
Flovent Diskus is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients 4 years of age and older. It is also indicated for patients requiring oral corticosteroid therapy for asthma. Many of these patients may be able to reduce or eliminate their requirement for oral corticosteroids over time.
Flovent Diskus is NOT indicated for the relief of acute bronchospasm.
Flovent Rotadisk
Flovent Rotadisk is indicated for the maintenance treatment of asthma as prophylactic therapy in patients 4 years of age and older. It is also indicated for patients requiring oral corticosteroid therapy for asthma. Many of these patients may be able to reduce or eliminate their requirement for oral corticosteroids over time.
Flovent Rotadisk is NOT indicated for the relief of acute bronchospasm.
Flovent Inhalation Aerosol
Flovent inhalation aerosol 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.
Flovent Diskus
Flovent Diskus 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.
Flovent Rotadisk
Flovent Rotadisk 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.
Flovent Inhalation Aerosol
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Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to fluticasone propionate inhalation aerosol. In a trial of 96 patients, prednisone reduction was successfully accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during transfer to inhaled fluticasone propionate. Successive reduction of prednisone dose was allowed only when lung function, symptoms, and as-needed beta-agonist use were better than or comparable to that seen before initiation of prednisone dose reduction. Lung function (FEV1 or AM PEFR), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.
Transfer of patients from systemic corticosteroid therapy to fluticasone propionate inhalation aerosol may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, and arthritis.
Persons who are on 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 on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects 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.
Fluticasone propionate inhalation aerosol is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.
As with other inhaled asthma medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with Flovent inhalation aerosol, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with Flovent inhalation aerosol should be discontinued and alternative therapy instituted.
Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with fluticasone propionate inhalation aerosol. During such episodes, patients may require therapy with oral corticosteroids.
Flovent Diskus
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Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to fluticasone propionate inhalation powder. In a clinical trial of 111 patients, prednisone reduction was successfully accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during transfer to inhaled fluticasone propionate. Successive reduction of prednisone dose was allowed only when lung function, symptoms, and as-needed beta-agonist use were better than or comparable to that seen before initiation of prednisone dose reduction. Lung function (FEV1 or AM PEFR), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.
Transfer of patients from systemic corticosteroid therapy to fluticasone propionate inhalation powder may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.
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.
Fluticasone propionate inhalation powder is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.
As with other inhaled asthma medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with Flovent Diskus, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with Flovent Diskus should be discontinued and alternative therapy instituted.
Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with fluticasone propionate inhalation powder. During such episodes, patients may require therapy with oral corticosteroids.
Flovent Rotadisk
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Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to fluticasone propionate inhalation powder. In a clinical trial of 96 patients, prednisone reduction was successfully accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during transfer to inhaled fluticasone propionate. Successive reduction of prednisone dose was allowed only when lung function, symptoms, and as-needed beta-agonist use were better than or comparable to that seen before initiation of prednisone dose reduction. Lung function (FEV1 or AM PEFR), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.
Transfer of patients from systemic corticosteroid therapy to fluticasone propionate inhalation powder may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, and arthritis.
Persons who are on 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 on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects 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.
Fluticasone propionate inhalation powder is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.
As with other inhaled asthma medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with Flovent Rotadisk, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with inhaled fluticasone propionate should be discontinued and alternative therapy instituted.
Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with fluticasone propionate inhalation powder. During such episodes, patients may require therapy with oral corticosteroids.
Flovent Inhalation Aerosol
General
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 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 inhalation aerosol 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 inhalation aerosol.
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, fluticasone propionate inhalation aerosol should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.
A reduction of growth velocity in children or teenagers may occur as a result of inadequate control of chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians should closely follow the growth of adolescents taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression if an adolescent's growth appears slowed.
The long-term effects of fluticasone propionate 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 fluticasone propionate inhalation aerosol on a continuous basis for periods of 3 years or longer. In clinical studies with patients treated for nearly 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.
In clinical studies with inhaled fluticasone propionate, 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 inhalation aerosol, but at times therapy with fluticasone propionate may need to be interrupted.
Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection 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 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, Flovent Inhalation Aerosol).
Information for the Patient
Patients being treated with Flovent inhalation aerosol 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.
Patients should use Flovent inhalation aerosol at regular intervals as directed. Results of clinical trials indicated significant improvement may occur within the first day or 2 of treatment; however, the full benefit may not be achieved until treatment has been administered for 1-2 weeks or longer. The patient should not increase the prescribed dosage but should contact the physician if symptoms do not improve or if the condition worsens.
After inhalation, rinse the mouth with water without swallowing.
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 Flovent inhalation aerosol 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 demonstrated no tumorigenic potential in studies of oral doses up to 1000 μg/kg (approximately 2 times the maximum human daily inhalation dose based on μg/m2) for 78 weeks in the mouse or inhalation of up to 57 μg/kg (approximately ¼ the maximum human daily inhalation dose based on μg/m2) for 104 weeks in the rat.
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 when administered at high doses by the oral or subcutaneous routes. Furthermore, the compound did not delay erythroblast division in bone marrow.
No evidence of impairment of fertility was observed in reproductive studies conducted in rats dosed subcutaneously with doses up to 50 μg/kg (approximately ¼ the maximum human daily inhalation dose based on μg/m2) in males and females. However, prostate weight was significantly reduced in rats.
Pregnancy, Teratogenic Effects, Pregnancy Category C
Subcutaneous studies in the mouse and rat at 45 and 100 μg/kg, respectively (approximately 1/10 and 1/2 the maximum human daily inhalation dose based on μg/m2, respectively), revealed fetal toxicity characteristic of potent glucocorticoid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.
In the rabbit, fetal weight reduction and cleft palate were observed following subcutaneous doses of 4 μg/kg (approximately 1/25 the maximum human daily inhalation dose based on μg/m2). However, following oral administration of up to 300 μg/kg (approximately 3 times the maximum human daily inhalation dose based on μg/m2) of fluticasone propionate to the rabbit, there were no maternal effects nor increased incidence of external, visceral, or skeletal fetal defects. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration (see CLINICAL PHARMACOLOGY, Flovent Inhalation Aerosol).
Less than 0.008% of the administered dose crossed the placenta following oral administration of 100 μg/kg to rats or 300 μg/kg to rabbits (approximately ½ and 3 times the maximum human daily inhalation dose based on μg/m2, respectively).
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 glucocorticoids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from glucocorticoids than humans. In addition, because there is a natural increase in glucocorticoid production during pregnancy, most women will require a lower exogenous glucocorticoid dose and many will not need glucocorticoid treatment during pregnancy.
Nursing Mothers
It is not known whether fluticasone propionate is excreted in human breast milk. Subcutaneous administration of 10 μg/kg tritiated drug to lactating rats (approximately 1/20 the maximum human daily inhalation dose based on μg/m2) resulted in measurable radioactivity in both plasma and milk. Because glucocorticoids are excreted in human milk, caution should be exercised when fluticasone propionate inhalation aerosol is administered to a nursing woman.
Pediatric Use
One hundred thirty-seven (137) patients between the ages of 12 and 16 years were treated with fluticasone propionate inhalation aerosol in the US pivotal clinical trials. The safety and effectiveness of Flovent inhalation aerosol in children below 12 years of age have not been established. Oral corticosteroids have been shown to cause a reduction in growth velocity in children and teenagers with extended use. If a child or teenager on any corticosteroid appears to have growth suppression, the possibility that they are particularly sensitive to this effect of corticosteroids should be considered (see PRECAUTIONS, Flovent Inhalation Aerosol).
Geriatric Use
Five hundred seventy-four (574) patients 65 years of age or older have been treated with fluticasone propionate inhalation aerosol in US and non-US clinical trials. There were no differences in adverse reactions compared to those reported by younger patients.
Flovent Diskus
General
Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients (see Pediatric Use).
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 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 inhalation powder 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 inhalation powder.
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, fluticasone propionate inhalation powder should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.
The long-term effects of fluticasone propionate 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.
In clinical studies with inhaled fluticasone propionate, 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 inhalation powder, but at times therapy with fluticasone propionate 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 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, Flovent Diskus).
Information for the Patient
Patients being treated with Flovent Diskus 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:
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1000 μg/kg (approximately 2 times the maximum recommended daily inhalation dose in adults and approximately 10 times the maximum recommended daily inhalation dose in children 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 and approximately equal to the maximum recommended daily inhalation dose in children 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.
Pregnancy, Teratogenic Effects, Pregnancy Category C
Subcutaneous studies in the mouse and rat at 45 and 100 μg/kg, respectively, (less than the maximum recommended daily inhalation dose in adults on a μg/m2 basis) 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 3 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, Flovent Diskus).
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), a subcutaneous or an oral dose of 100 μg/kg to rats (less than the maximum recommended daily inhalation dose in adults on a μg/m2 basis), and an oral dose of 300 μg/kg to rabbits (approximately 3 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.
Nursing Mothers
It is not known whether fluticasone propionate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of 10 μg/kg of tritiated fluticasone propionate (less than the maximum recommended daily inhalation dose in adults on a μg/m2 basis) resulted in measurable radioactivity in the milk. Since there are no data from controlled trials on the use of Flovent Diskus by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue Flovent Diskus, taking into account the importance of Flovent Diskus to the mother.
Pediatric Use
Five hundred twenty (520) patients 4-11 years of age and 66 patients 12-16 years of age were treated with Flovent Diskus in US pivotal clinical trials. The safety and effectiveness of Flovent Diskus in children below 4 years of age have not been established.
Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm/year (range, 0.3-1.8 cm/year) and appears to depend upon the dose and duration of exposure. The specific growth effects of inhaled fluticasone propionate have also been studied in a controlled clinical trial (see data below). This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for "catch-up" growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The growth of children and adolescents receiving orally inhaled corticosteroids, including Flovent Diskus, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including Flovent Diskus, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.
A 52 week, placebo-controlled study to assess the potential growth effects of fluticasone propionate inhalation powder at 50 and 100 μg twice daily was conducted in the US in 325 prepubescent children (244 males and 81 females) 4-11 years of age. The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n=76), 6.07 cm/year in the 50 μg group (n=98), and 5.66 cm/year in the 100 μg group (n=89). An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data. A separate subset analysis of children who remained prepubertal during the study revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n=57), 5.91 cm/year in the 50 μg group (n=74), and 5.67 cm/year in the 100 μg group (n=79). The clinical significance of these growth data is not certain. In children 8.5 years of age, the mean age of children in this study, the range for expected growth velocity is: Boys: 3rd percentile = 3.8 cm/year, 50th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; Girls: 3rd percentile = 4.2 cm/year, 50th percentile = 5.7 cm/year, and 97th percentile = 7.3 cm/year.
Geriatric Use
Of the total number of patients in clinical studies of Flovent Diskus, 152 were 65 years of age or older and 4 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 has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on available data for Flovent Diskus, no adjustment of dosage of Flovent Diskus in geriatric patients is warranted.
Flovent Rotadisk
General
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 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 inhalation powder 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 inhalation powder.
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, fluticasone propionate inhalation powder should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.
A reduction of growth velocity in children or adolescents may occur as a result of poorly controlled asthma or from the therapeutic use of corticosteroids, including inhaled corticosteroids. A 52 week placebo-controlled study to assess the potential growth effects of fluticasone propionate inhalation powder at 50 and 100 μg twice daily was conducted in the US in 325 prepubescent children (244 males and 81 females), 4-11 years of age. The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n=76), 6.07 cm/year in the 50 μg group (n=98), and 5.66 cm/year in the 100 μg group (n=89). An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data. A separate subset analysis of children who remained prepubertal during the study revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n=57), 5.91 cm/year in the 50 μg group (n=74), and 5.67 cm/year in the 100 μg group (n=79). The clinical significance of these growth data is not certain. In children 8.5 years of age, the mean age of children in this study, the range for expected growth velocity is: Boys: 3rd percentile = 3.8 cm/year, 50th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; Girls: 3rd percentile = 4.2 cm/year, 50th percentile = 5.7 cm/year, and 97th percentile = 7.3 cm/year. The effects of long-term treatment of children with inhaled corticosteroids, including fluticasone propionate, on final adult height are not known. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route, and weigh the benefits of corticosteroid therapyagainst the possibility of growth suppression if growth appears slowed. Patients should be maintained on the lowest dose of inhaled corticosteroid that effectively controls their asthma.
The long-term effects of fluticasone propionate 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.
In clinical studies with inhaled fluticasone propionate, 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 inhalation powder, but at times therapy with fluticasone propionate may need to be interrupted.
Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous 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 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, Flovent Rotadisk).
Information for the Patient
Patients being treated with Flovent Rotadisk 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.
Patients should use Flovent Rotadisk at regular intervals as directed. Results of clinical trials indicated significant improvement may occur within the first day or 2 of treatment; however, the full benefit may not be achieved until treatment has been administered for 1-2 weeks or longer. The patient should not increase the prescribed dosage but should contact the physician if symptoms do not improve or if the condition worsens.
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 Flovent Rotadisk inhalation powder 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 demonstrated no tumorigenic potential in mice at oral doses up to 1000 μg/kg (approximately 2 times the maximum recommended daily inhalation dose in adults and approximately 10 times the maximum recommended daily inhalation dose in children on a μg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 μg/kg (approximately ¼ the maximum recommended daily inhalation dose in adults and comparable to the maximum recommended daily inhalation dose in children 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 when administered at high doses by the oral or subcutaneous routes. Furthermore, the compound did not delay erythroblast division in bone marrow.
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 (approximately 1/5 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.
Pregnancy, Teratogenic Effects, Pregnancy Category C
Subcutaneous studies in the mouse and rat at 45 and 100 μg/kg, respectively, (approximately 1/10 and 1/3, respectively, the maximum recommended daily inhalation dose in adults on a μg/m2 basis) 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 (approximately 1/30 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 2 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, Flovent Rotadisk).
Fluticasone propionate crossed the placenta following oral administration of 100 μg/kg to rats or 300 μg/kg to rabbits (approximately 1/3 and 2 times, respectively, 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.
Nursing Mothers
It is not known whether fluticasone propionate is excreted in human breast milk. Subcutaneous administration to lactating rats of 10 μg/kg tritiated fluticasone propionate (approximately 1/25 the maximum recommended daily inhalation dose in adults on a μg/m2 basis) resulted in measurable radioactivity in milk. Because other corticosteroids are excreted in human milk, caution should be exercised when fluticasone propionate inhalation powder is administered to a nursing woman.
Pediatric Use
Two hundred fourteen (214) patients 4-11 years of age and 142 patients 12-16 years of age were treated with fluticasone propionate inhalation powder in US clinical trials. The safety and effectiveness of Flovent Rotadisk inhalation powder in children below 4 years of age have not been established.
Inhaled corticosteroids, including fluticasone propionate, may cause a reduction in growth in children and adolescents (see PRECAUTIONS, Flovent Rotadisk). If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that they are particularly sensitive to this effect of corticosteroids should be considered. Patients should be maintained on the lowest dose of inhaled corticosteroid that effectively controls their asthma.
Geriatric Use
Safety data have been collected on 280 patients (Flovent Diskus n=83, Flovent Rotadisk n=197) 65 years of age or older and 33 patients (Flovent Diskus n=14, Flovent Rotadisk n=19) 75 years of age or older who have been treated with fluticasone propionate inhalation powder in US and non-US clinical trials. There were no differences in adverse reactions compared to those reported by younger patients. In addition, there were no apparent differences in efficacy between patients 65 years of age or older and younger patients. Fifteen (15) patients 65 years of age or older and 1 patient 75 years of age or older were included in the efficacy evaluation of US clinical studies.
Flovent Diskus
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 Flovent is coadministered with long-term ketoconazole and other known cytochrome P450 3A4 inhibitors.
Flovent Rotadisk
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 the cytochrome P450 3A4 isoenzyme system by ketoconazole, which is also the route of metabolism of fluticasone propionate. Care should be exercised when Flovent is coadministered with long-term ketoconazole and other known cytochrome P450 3A4 inhibitors.
Flovent Inhalation Aerosol
The incidence of common adverse experiences in TABLE 1 is based upon 7 placebo-controlled US clinical trials in which 1243 patients (509 female and 734 male adolescents and adults previously treated with as-needed bronchodilators and/or inhaled corticosteroids) were treated with fluticasone propionate inhalation aerosol (doses of 88-440 μg twice daily for up to 12 weeks) or placebo.
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TABLE 1 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of over 3% in the combined fluticasone propionate inhalation aerosol groups 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, with ≤2% of patients discontinuing the studies because of adverse events. Rare cases of immediate and delayed hypersensitivity reactions, including urticaria and rash and other rare events of angioedema and bronchospasm, have been reported.
Systemic glucocorticoid side effects were not reported during controlled clinical trials with fluticasone propionate inhalation aerosol. If recommended doses are exceeded, however, or if individuals are particularly sensitive, symptoms of hypercorticism, e.g., Cushing's syndrome, could occur.
Other adverse events that occurred in these clinical trials using fluticasone propionate inhalation aerosol with an incidence of 1-3% and which occurred at a greater incidence than with placebo were:
In a 16 week study in patients with asthma requiring oral corticosteroids, the effects of fluticasone propionate inhalation aerosol, 660 μg twice daily (n=32) and 880 μg twice daily (n=32), were compared with placebo.
Adverse events (whether considered drug-related or nondrug-related by the investigator) reported by more than 3 patients in either fluticasone propionate group and which were more common with fluticasone propionate than placebo are:
Observed During Clinical Practice
In addition to adverse experiences reported from clinical trials, the following experiences have been identified during postapproval use of fluticasone propionate. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These experiences have been chosen for inclusion due to either their seriousness, frequency of reporting, causal connection to fluticasone propionate, or a combination of these factors.
Eosinophilic Conditions
In rare cases, patients on inhaled fluticasone propionate 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 PRECAUTIONS, Flovent Inhalation Aerosol, Eosinophilic Conditions).
Flovent Diskus
The incidence of common adverse experiences in TABLE 2 is based upon 7 placebo-controlled US clinical trials in which 1176 pediatric, adolescent, and adult patients (466 females and 710 males) previously treated with as-needed bronchodilators and/or inhaled corticosteroids were treated with fluticasone propionate inhalation powder (doses of 50-500 μg twice daily for up to 12 weeks) or placebo.
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TABLE 2 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of over 3% in any of the fluticasone propionate inhalation powder groups 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, with <2% of patients discontinuing the studies because of adverse events. Rare cases of immediate and delayed hypersensitivity reactions, including rash and other rare events of angioedema and bronchospasm, have been reported.
Other adverse events that occurred in these clinical trials using fluticasone propionate inhalation powder with an incidence of 1-3% and that occurred at a greater incidence than with placebo were: