Indications : Dermatosis, corticosteroid-responsive; Rhinitis, perennial allergic; Rhinitis, seasonal allergic
Pregnancy Category C
FDA Class 1C (“Little or No Therapeutic Advantage”)
FDA Pre 1990 Dec
DRUG CLASS : Corticosteroids-Inhalation/Nasal; Topical Steroids
BRAND NAMES : Atemur Mite (Germany); Cutivate (US); Flixonase (Bahamas, Barbados, Belize, Bermuda, Curacao, Guyana, Jamaica, Netherland-Antilles, Puerto-Rico, Surinam, Trinidad, Denmark, Bulgaria, France, Hungary, Russia, Italy, Turkey, Netherlands, Finland, England, Czech-Republic, Austria, Colombia, Mexico, Peru, Costa-Rica, Dominican-Republic, El-Salvador, Guatemala, Honduras, Nicaragua, Panama, Hong-Kong, Indonesia, Korea, Malaysia, Taiwan, Thailand, Israel); Flixonase Nasal Spray (New-Zealand); Flixotide (Bahamas, Barbados, Belize, Bermuda, Curacao, Guyana, Jamaica, Netherland-Antilles, Puerto-Rico, Surinam, Trinidad, Denmark, England, Finland, France, Austria, Czech-Republic, Bulgaria, Hungary, Russia, Italy, Turkey, Netherlands, Mexico, Peru, Hong-Kong, Indonesia, Korea, Philippines, Taiwan, Thailand, South-Africa, Israel); Flixotide Disk (New-Zealand); Flixotide Disks (Australia); Flixotide Inhaler (Australia); Flonase (US); Flonase Aq (US); Flovent (US); Flunase (US); Flutide (Germany, Japan); Flutivate (Germany, Norway); Zoflut (US);
(International brand names outside U.S. in italics)
COST OF THERAPY : $ 210.69 (Rhinitis; Spray; 0.05 mg/inh; 0.2 gm/day; 365 days)
Fluticasone Propionate (Inhalation)
Fluticasone propionate is a corticosteroid having the chemical name S-(fluoromethyl)6alpha,9-difluoro-11beta, 17-dihydroxy-16alpha-methyl-3-oxoandrosta-1,4-diene-17beta-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.
Inhalation Powder
Flovent Rotadisk 50 mug, 100 mug, and 250 mug contain a dry powder presentation of fluticasone propionate intended for oral inhalation only. Each double-foil Rotadisk contains four blisters. Each blister contains a mixture of 50, 100, or 250 mug 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 mug of fluticasone propionate from Flovent Rotadisk 50 mug, 100 mug, or 250 mug, respectively, when tested at a flow rate of 60 L/min for 3 seconds. In adult and adolescent patients with asthma, mean peak inspiratory flow (PIF) through the Diskhaler was 123 L/min (range, 88 to 159 L/min), and in pediatric patients 4 to 11 years of age with asthma, mean PIF was 110 L/min (range, 43 to 175 L/min).
Inhalation Aerosol
Flovent 44 mug, 110 mug, and 220 mug 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 mug of fluticasone propionate from the valve, and 44, 110, or 220 mug, respectively, of fluticasone propionate from the actuator.
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 three times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results.
The precise mechanisms of fluticasone propionate action in asthma are unknown. Inflammation is recognized as an important component in the pathogenesis of asthma. Corticosteroids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.
Though highly effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately. However, improvement following inhaled administration of fluticasone propionate can occur within 24 hours of beginning treatment, although maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer.
Pharmacokinetics
Absorption
The activity of fluticasone propionate inhalation powder and 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 powder in healthy volunteers averaged about 13.5% of the nominal dose; 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 a 1000-mug dose of fluticasone propionate inhalation powder ranged from 0.1 to 1.0 ng/ml; Peak plasma concentrations after an 880-mug inhaled dose of fluticasone propionate inhalation aerosol ranged from 0.1 to 1.0 ng/ml.
Distribution
Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. The percentage of fluticasone propionate bound to human plasma proteins averaged 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes. Fluticasone propionate is not significantly bound to human transcortin.
Metabolism
The total clearance of fluticasone propionate is high (average, 1093 ml/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17beta-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.
Additional Information for Inhalation Powder Only: In a multiple-dose drug interaction study, coadministration of fluticasone propionate (500 mug 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 mug) 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 mug twice daily. Full pharmacokinetic profiles were obtained from seven female patients and 13 male patients at these doses, and no overall differences in pharmacokinetic behavior were found.
Additional Information for Inhalation Powder Only: Plasma concentrations of fluticasone propionate were measured 20 and 40 minutes after dosing from 29 children aged 4 to 11 years who were taking either 50 or 100 mug 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-mug dose) or 154 pg/ml (100-mug dose). In a study with adults taking the 100-mug 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-mug 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 mug twice daily of fluticasone propionate inhalation powder were compared to oral fluticasone propionate, 20,000 mug given once daily, and placebo for 6 weeks. Plasma levels of fluticasone propionate were detectable in all three 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 mug 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 mug/dl for inhalation aerosol) after dosing with placebo or fluticasone propionate 220 mug twice daily. Ten percent (10%) to 16% of patients treated with fluticasone propionate at doses of 440 mug or more twice daily had an abnormal response as comparted to 29% of patients treated with prednisone.
Additional Information for Inhalation Powder Only: In clinical trials with fluticasone propionate inhalation powder, using doses up to and including 250 mug twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol <18 mug/dl) were noted in patients receiving fluticasone propionate or placebo. The incidence of abnormal tests at 500 mug twice daily was greater than placebo. In a 2-year study carried out in 64 patients randomized to fluticasone propionate 500 mug twice daily or placebo, 1 patient receiving fluticasone propionate (4%) had an abnormal response to 6-hour cosyntropin infusion at 1 year; repeat testing at 18 months and 2 years was normal. Another patient receiving fluticasone propionate (5%) had an abnormal response at 2 years. No patient on placebo had an abnormal response at 1 or 2 years.
CLINICAL STUDIES :
Inhalation Powder
Double-blind, parallel, placebo-controlled, U.S. clinical trials were conducted in 1197 adolescent and adult asthma patients to assess the efficacy and safety of fluticasone propionate inhalation powder in the treatment of asthma. Fixed doses of 50, 100, 250, and 500 mug 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 one or two blisters from the Diskhaler twice daily.
A 12-week trial tested pulmonary function for two recommended dosages of fluticasone propionate inhalation powder (100 and 250 mug twice daily) and placebo in 331 adolescent and adult asthma patients (baseline FEV1 = 2.63 L/sec) inadequately controlled on bronchodilators alone. Because this trial used predetermined criteria for lack of efficacy, which caused more patients in the placebo group to be withdrawn, pulmonary function results at Endpoint, which is the last evaluable FEV 1 result and includes most patients’ lung function data, are also considered. 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 mug twice daily was evaluated in a similar population. In this trial fluticasone propionate significantly improved pulmonary function as compared with placebo.
Another 12-week trial tested pulmonary function for two recommended dosages of fluticasone propionate inhalation powder (100 and 250 mug twice daily) and placebo in 342 adolescent and adult asthma patients (baseline FEV1 = 2.49 L/sec) already receiving daily inhaled corticosteroid therapy (
336 mug/day of beclomethasone dipropionate or 800 mug/day of triamcinolone acetonide) in addition to as-needed albuterol and theophylline (38% of all patients). Because this trial also used predetermined criteria for lack of efficacy, which caused more patients in the placebo group to be withdrawn, pulmonary function results at Endpoint are included. Pulmonary function at both 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 mug twice daily was evaluated in a similar patient population. In this trial fluticasone propionate significantly improved pulmonary function as compared with placebo.
In the four 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 mug 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 mug twice daily and 88% of the patients on 880 mug 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 inhalation powder and inhalation aerosol formulations in this population has been conducted.
Pediatric Experience: In a 12-week, placebo-controlled clinical trial of 263 patients aged 4 to 11 years inadequately controlled on bronchodilators alone (baseline morning peak expiratory flow = 200 L/min), fluticasone propionate inhalation powder doses of 50 and 100 mug twice daily significantly improved morning peak expiratory flow (28% and 34% change from baseline at endpoint, respectively) compared to placebo (11% change). In a second placebo-controlled, 52-week trial of 325 patients aged 4 to 11 years, approximately half of whom were receiving inhaled corticosteroids at baseline, doses of fluticasone propionate inhalation powder of 50 and 100 mug 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.
Inhalation Aerosol
Double-blind, parallel, placebo-controlled, U.S. clinical trials were conducted in 1818 adolescent and adult asthma patients to assess the efficacy and/or safety of fluticasone propionate inhalation aerosol in the treatment of asthma. Fixed doses ranging from 22 to 880 mug 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, 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 two clinical trials of 660 asthmatic patients inadequately controlled on bronchodilators alone, fluticasone propionate administered by inhalation aerosol was evaluated at doses of 44 and 88 mug twice daily. Both doses of fluticasone propionate improved asthma control significantly as compared with placebo.
A 12-week trial produced results of pulmonary function tests for the recommended starting dosage of fluticasone propionate inhalation aerosol (88 mug twice daily) and placebo in asthma patients inadequately controlled on bronchodilators alone. Because this trial used predetermined criteria for lack of efficacy, which caused more patients in the placebo group to be withdrawn, pulmonary function results at Endpoint, which is the last evaluable FEV1 result and includes most patients’ lung function data, are also considered. 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 asthmatic patients already receiving daily inhaled corticosteroid therapy (doses of at least 336 mug/day of beclomethasone dipropionate) in addition to as-needed albuterol and theophylline (46% of all patients), fluticasone propionate inhalation aerosol doses of 22 to 440 mug 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).
Pulmonary function results were gathered from a 12-week clinical trial in asthma patients already receiving daily inhaled corticosteroid therapy (beclomethasone dipropionate 336 to 672 mug/day). The mean percent change from baseline in lung function results for fluticasone propionate inhalation aerosol dosages of 88, 220, and 440 mug twice daily and placebo are shown over the 12-week trial. 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 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 severe asthmatic patients requiring chronic oral prednisone therapy (average baseline daily prednisone dose was 10 mg), fluticasone propionate inhalation aerosol doses of 660 and 880 mug twice daily 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 mug twice daily and 88% of the patients on 880 mug twice daily as compared with 3% of patients on placebo). Accompanying the reduction in oral corticosteroid use, patients treated with fluticasone propionate inhalation aerosol had significantly improved lung function and fewer asthma symptoms as compared with the placebo group.
Fluticasone propionate is indicated for the maintenance treatment of asthma as prophylactic therapy (for inhalation powder, 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.
Fluticasone propionate is NOT indicated for the relief of acute bronchospasm.
Fluticasone propionate 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.
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Particular care is needed for patients who are transferred from systemically active corticosteroids to fluticasone propionate because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of HPA function. Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although fluticasone propionate inhalation powder and aerosol may provide control of asthma symptoms during these episodes, in recommended doses they supply less than normal physiological amounts of corticosteroid systemically and do NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack. |
Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to fluticasone propionate inhalation powder or aerosol. 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 or 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 complete prescribing information for IG and VZIG.) If chickenpox develops, treatment with antiviral agents may be considered.
Fluticasone propionate inhalation powder and aerosol are not to be regarded as bronchodilators and are 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 fluticasone propionate, 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 or aerosol. During such episodes, patients may require therapy with oral corticosteroids.
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 or 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 powder or 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 powder or 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 children and adolescents taking corticosteroids by any route, and weigh the benefits of corticosteroid therapy against 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.Additional Information for Inhalation Powder Only: A 52-week placebo-controlled study to assess the potential growth effects of fluticasone propionate inhalation powder at 50 and 100 mug twice daily was conducted in the U.S. in 325 prepubescent children (244 males and 81 females), 4 to 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-mug group (n = 98), and 5.66 cm/year in the 100-mug 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-mug group (n = 74), and 5.67 cm/year in the 100-mug 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.
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 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 powder or 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 tuberculous infection of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.
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).
Information for Patients
Patients being treated with fluticasone propionate 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 fluticasone propionate at regular intervals as directed. Results of clinical trials indicated significant improvement may occur within the first day or two of treatment; however, the full benefit may not be achieved until treatment has been administered for 1 to 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 fluticasone propionate inhalation powder or 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
Inhalation Powder
Fluticasone propionate demonstrated no tumorigenic potential in studies of oral doses up to 1000 mug/kg (approximately 2 times the maximum recommended daily inhalation dose in adults [and for powder approximately 10 times the maximum recommended daily inhalation dose in children on a mug/m2 basis]) for 78 weeks in the mouse or inhalation of up to 57 mug/kg (approximately ¼ the maximum recommended daily inhalation dose in adults [and for powder comparable to the maximum recommended daily inhalation dose in children] on a mug/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 rats dosed simultaneously with up to 50 mug/kg (approximately 1/5 [for powder] and ¼ [for aerosol] the maximum recommended daily inhalation dose in adults on a mug/m2 basis) 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 mug/kg, respectively, (approximately 1/10 and 1/3 [for inhalation powder; ½ for inhalation aerosol] the maximum recommended human daily inhalation dose based on a mug/m2 respectively), revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.
In the rabbit, fetal weight reduction and cleft palate were observed following subcutaneous doses of 4 mug/kg (approximately 1/30 [for inhalation powder] and 1/25 [for inhalation aerosol] the maximum recommended human daily inhalation dose based on mug/m2). However, following oral administration of up to 300 mug/kg (approximately 2 times [for inhalation powder] and 3 times [for aerosol] the maximum human daily inhalation dose based on mug/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).
Fluticasone propionate crossed the placenta (less than 0.008% of the administered dose for inhalation aerosol) following oral administration of 100 mug/kg to rats or 300 mug/kg to rabbits (approximately 1/3 and 2 times [for inhalation powder] and ½ and 3 times [for inhalation aerosol], respectively, the maximum recommended daily inhalation dose in adults on a mug/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 of 10 mug/kg tritiated drug to lactating rats (approximately 1/25 [for inhalation powder] and 1/20 [for inhalation aerosol] the maximum recommended daily inhalation dose on a mug/m2 basis) resulted in measurable radioactivity in milk (for inhalation aerosol, both plasma and milk). Because other corticosteroids are excreted in human milk, caution should be exercised when fluticasone propionate inhalation powder or aerosol is administered to a nursing woman.
Pediatric Use
Inhalation Powder: Two hundred fourteen (214) patients 4 to 11 years of age and 142 patients 12 to 16 years of age were treated with fluticasone propionate inhalation powder in U.S. clinical trials. The safety and effectiveness of fluticasone propionate 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). 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.
Inhalation Aerosol: One hundred thirty-seven (137) patients between the ages of 12 and 16 years were treated with fluticasone propionate inhalation aerosol in the U.S. pivotal clinical trials. The safety and effectiveness of fluticasone propionate 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).
Geriatric Use
One hundred seventy-three (173) [574 for inhalation aerosol] patients 65 years of age or older have been treated with fluticasone propionate inhalation powder and aerosol in U.S. and non-U.S. clinical trials. There were no differences in adverse reactions compared to those reported by younger patients.
Inhalation Powder Only
In a placebo-controlled, crossover study in eight healthy volunteers, coadministration of a single dose of fluticasone propionate (1000 mug) 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 fluticasone propionate is coadministered with long-term ketoconazole and other known cytochrome P450 3A4 inhibitors.
Inhalation Powder
In TABLE 1, the incidence of common adverse experiences () is based upon six placebo-controlled clinical trials in which 1384 patients 4 years of age (520 females and 864 males) previously treated with as-needed bronchodilators and/or inhaled corticosteroids were treated with fluticasone propionate inhalation powder (doses of 50 to 500 mug twice daily for up to 12 weeks) or placebo.
TABLE 1 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% to 3% and which occurred at a greater incidence than with placebo were:
Ear, Nose, and Throat: Otitis media, tonsillitis, nasal discharge, earache, laryngitis, epistaxis, sneezing.
Eye: Conjunctivitis.
Gastrointestinal: Abdominal pain, viral gastroenteritis, gastroenteritis/colitis, abdominal discomfort.
Miscellaneous: Injury.
Mouth and Teeth: Mouth irritation.
Musculoskeletal: Sprain/strain, pain in joint, disorder/symptoms of neck, muscular soreness, aches and pains.
Neurological: Migraine, nervousness.
Respiratory: Chest congestion, acute nasopharyngitis, dyspnea, irritation due to inhalant.
Skin: Dermatitis, urticaria.
Urogenital: Dysmenorrhea, candidiasis of vagina, pelvic inflammatory disease, vaginitis/vulvovaginitis, irregular menstrual cycle.
There were no clinically relevant differences in the pattern or severity of adverse events in children compared with those reported in adults.
Fluticasone propionate inhalation aerosol (660 or 880 mug twice daily) was administered for 16 weeks to asthmatics requiring oral corticosteroids. Adverse events reported more frequently in these patients compared to patients not on oral corticosteroids included sinusitis, nasal discharge, oropharyngeal candidiasis, headache, joint pain, nausea and vomiting, muscular soreness, malaise/fatigue, and insomnia.
Observed During Clinical Practice: The following events have been identified during postapproval use of fluticasone propionate in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, causal connection to fluticasone propionate, or a combination of these factors.
Ear, Nose, and Throat: Aphonia, cough, hoarseness, laryngitis, and throat soreness and irritation.
Endocrine and Metabolic: Cushingoid features, growth velocity reduction in children/adolescents, hyperglycemia, and weight gain.
Psychiatry: Agitation, aggression, depression, and restlessness.
Respiratory: Asthma exacerbation, bronchospasm, chest tightness, dyspnea, paradoxical bronchospasm, and wheezing.
Skin: Contusions, ecchymoses, and pruritus.
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: Eosinophilic Conditions).
Inhalation Aerosol
The following incidence of common adverse experiences is based upon seven placebo-controlled U.S. 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 to 440 mug twice daily for up to 12 weeks) or placebo. (See TABLE 2.)
TABLE 2 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% to 3% and which occurred at a greater incidence than with placebo were:
Ear, Nose, and Throat: Pain in nasal sinus(es), rhinitis.
Eye: Irritation of the eye(s).
Gastrointestinal: Nausea and vomiting, diarrhea, dyspepsia and stomach disorder.
Miscellaneous: Fever.
Mouth and Teeth: Dental problem.
Musculoskeletal: Pain in joint, sprain/strain, aches and pains, pain in limb.
Neurological: Dizziness/giddiness.
Respiratory: Bronchitis, chest congestion.
Skin: Dermatitis, rash/skin eruption.
Urogenital: Dysmenorrhea.
In a 16-week study in asthmatics requiring oral corticosteroids, the effects of fluticasone propionate inhalation aerosol, 660 mug twice daily (n = 32) and 880 mug twice daily (n = 32), were compared with placebo. Adverse events (whether considered drug-related or nondrug-related by the investigator) reported by more than three patients in either fluticasone propionate group and which were more common with fluticasone propionate than placebo are shown below:
Ear, Nose, and Throat: Pharyngitis (9% and 25%); nasal congestion (19% and 22%); sinusitis (19% and 22%); nasal discharge (16% and 16%); dysphonia (19% and 9%); pain in nasal sinus(es) (13% and 0%); Candida-like oral lesions (16% and 9%); oropharyngeal candidiasis (25% and 19%).
Respiratory: Upper respiratory infection (31% and 19%); influenza (0% and 13%).
Other: Headache (28% and 34%); pain in joint (19% and 13%); nausea and vomiting (22% and 16%); muscular soreness (22% and 13%); malaise/fatigue (22% and 28%); insomnia (3% and 13%).
Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during postapproval use of fluticasone propionate in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, causal connection to fluticasone propionate, or a combination of these factors.
Ear, Nose, and Throat: Throat soreness and irritation, hoarseness, laryngitis, aphonia.
Endocrine and Metabolic: Cushingoid features, growth velocity reduction in children/adolescents, weight gain, hyperglycemia.
Psychiatry: Restlessness, agitation, aggression, depression.
Respiratory: Immediate bronchospasm, asthma exacerbation, dyspnea, wheeze, chest tightness, bronchospasm, cough.
Skin: Pruritus, contusions, ecchymoses.
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, Eosinophilic Conditions).
Chronic overdosage may result in signs/symptoms of hypercorticism (see PRECAUTIONS). Inhalation by healthy volunteers of a single dose of 4000 mug of fluticasone propionate inhalation powder or single doses of 1760 or 3520 mug of fluticasone propionate inhalation aerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at doses of 1320 mug twice daily for 7 to 15 days to healthy human volunteers was also well tolerated. Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups. The oral and subcutaneous median lethal doses in mice and rats were >1000 mg/kg (>2000 and >4100 times, respectively, the maximum recommended daily inhalation dose in adults and >9600 and >19,000 times, respectively, the maximum recommended daily inhalation dose in children on a mg/m2 basis).
Fluticasone propionate should be administered by the orally inhaled route in patients 4 years of age and older for inhalation powder and in patients 12 years of age and older for inhalation aerosol. Individual patients will experience a variable time to onset and degree of symptom relief. Generally, fluticasone propionate inhalation powder and aerosol have a relatively rapid onset of action for an inhaled corticosteroid. Improvement in asthma control following inhaled administration of fluticasone propionate can occur within 24 hours of beginning treatment, although maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.
After asthma stability has been achieved (see TABLE 3 and TABLE 4), it is always desirable to titrate to the lowest effective dose to reduce the possibility of side effects. Inhalation powder doses as low as 50 mug twice daily have been shown to be effective in some patients. For patients who do not respond adequately to the starting dose after 2 weeks of therapy, higher doses may provide additional asthma control. The safety and efficacy of fluticasone propionate when administered in excess of recommended doses have not been established.
Rinsing the mouth after inhalation is advised.
The recommended starting dose and the highest recommended dose of fluticasone propionate, based on prior anti-asthma therapy, are listed in TABLE 3 for inhalation powder and TABLE 4 for inhalation aerosol.
| Previous Therapy |
Recommended Starting Dose
|
Highest Recommended Dose
|
|
|---|---|---|---|
| Adults and Adolescents | |||
| Bronchodilators alone |
100 mug twice daily
|
500 mug twice daily
|
|
| Inhaled corticosteroids |
100-250 mug twice daily*
|
500 mug twice daily
|
|
Oral corticosteroids |
1000 mug twice daily
|
1000 mug twice daily
|
|
| Children 4 to 11 Years | |||
| Bronchodilators alone |
50 mug twice daily
|
100 mug twice daily
|
|
| Inhaled corticosteroids |
50 mug twice daily
|
100 mug twice daily
|
|
|
* Starting doses above 100 mug twice daily for adults and adolescents and 50 mug twice daily for children 4 to 11 years of age may be considered for patients with poorer asthma control or those who have previously required doses of inhaled corticosteroids that are in the higher range for that specific agent. NOTE: In all patients, it is desirable to titrate to the lowest effective dose once asthma stability is achieved.
|
|||
|
For Patients Currently Receiving Chronic Oral Corticosteroid Therapy: Prednisone should be reduced no faster than 2.5 mg/day on a weekly basis, beginning after at least 1 week of therapy with fluticasone propionate inhalation powder. Patients should be carefully monitored for signs of asthma instability, including serial objective measures of airflow, and for signs of adrenal insufficiency (see WARNINGS). Once prednisone reduction is complete, the dosage of fluticasone propionate should be reduced to the lowest effective dosage. |
|||
|
This dosing recommendation is based on clinical data from a study conducted using fluticasone propionate inhalation aerosol. No clinical trials have been conducted in patients on oral corticosteroids using the inhalation powder formulation; no direct assessment of the clinical comparability of equal nominal doses for the inhalation powder and inhalation aerosol formulations in this population has been conducted. |
|||
| Previous Therapy |
Recommended Starting Dose
|
Highest Recommended Dose
|
|---|---|---|
| Bronchodilators alone |
88 mug twice daily
|
440 mug twice daily
|
| Inhaled corticosteroids |
88-220 mug twice daily*
|
440 mug twice daily
|
| Oral corticosteroids |
880 mug twice daily
|
880 mug twice daily
|
|
* Starting doses above 88 mug twice daily may be considered for patients with poorer asthma control or those who have previously required doses of inhaled corticosteroids that are in the higher range for that specific agent. NOTE: In all patients, it is desirable to titrate to the lowest effective dose once asthma stability is achieved.
|
||
|
For Patients Currently Receiving Chronic Oral Corticosteroid Therapy: Prednisone should be reduced no faster than 2.5 mg/day on a weekly basis, beginning after at least 1 week of therapy with fluticasone propionate inhalation aerosol. Patients should be carefully monitored for signs of asthma instability, including serial objective measures of airflow, and for signs of adrenal insufficiency (see WARNINGS). Once prednisone reduction is complete, the dosage of fluticasone propionate should be reduced to the lowest effective dosage. |
||
Geriatric Use: In studies where geriatric patients (65 years of age or older, see PRECAUTIONS) have been treated with fluticasone propionate inhalation powder or aerosol, efficacy and safety did not differ from that in younger patients. Consequently, no dosage adjustment is recommended.
Directions for Use: Illustrated Patient’s Instructions for Use accompany each package of Flovent Rotadisk and Flovent Inhalation Aerosol.
HOW SUPPLIED :
Inhalation Powder
Flovent Rotadisk is available in 50 mug, 100 mug, and 250 mug strengths.
Storage: Store at controlled room temperature, 20-25°C (68-77°F) in a dry place. Keep out of reach of children. Do not puncture any fluticasone propionate Rotadisk blister until taking a dose using the Diskhaler.
Use the Rotadisk blisters within 2 months after opening of the moisture-protective foil overwrap or before the expiration date, whichever comes first. Place the sticker provided with the product on the tube and enter the 2-month use date on the sticker.
Inhalation Aerosol
Flovent 44 mug: Each actuation of the inhaler delivers 44 mug of fluticasone propionate from the actuator.
Flovent 110 mug: Each actuation of the inhaler delivers 110 mug of fluticasone propionate from the actuator.
Flovent 220 mug: Each actuation of the inhaler delivers 220 mug of fluticasone propionate from the actuator.
Flovent canisters are for use with Flovent inhalation aerosol actuators only. The actuators should not be used with other aerosol medications.
The correct amount of medication in each inhalation cannot be assured after 60 inhalations from the 7.9-g canister or 120 inhalations from the 13-g canister even though the canister is not completely empty. The canister should be discarded when the labeled number actuations has been used.
Storage: Store between 2-30°C (36-86°F). Store canister with nozzle end down. Protect from freezing temperatures and direct sunlight.
Avoid spraying in eyes. Contents under pressure. Do not puncture or incinerate. Do not store at temperatures above 120°F. Keep out of reach of children. For best results, the canister should be at room temperature before use. Shake well before using.
Note: The statement below is required by the Federal Government’s Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs).
Warning: Contains trichlorofluoromethane and dichlorodifluoromethane, substances which harm public health and environment by destroying ozone in the upper atmosphere.
A notice similar to the above warning has been placed in the patient information leaflet of this product pursuant to EPA regulations.
Fluticasone Propionate (Intranasal)
Fluticasone propionate is a synthetic corticosteroid with the chemical name of S-fluoromethyl 6alpha,9alpha-difluoro-11beta-hydroxy-16alpha-methyl-3-oxo-17alpha-propionyloxyandrosta -1, 4-diene-17beta-carbothioate.
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.
Fluticasone propionate nasal spray 50 mug is an aqueous suspension of microfine fluticasone propionate for topical administration to the nasal mucosa by means of a metering, atomizing spray pump. Flonase nasal spray also contains microcrystalline cellulose and carboxymethylcellulose sodium, dextrose, 0.02% w/w benzalkonium chloride, polysorbate 80, and 0.25% w/w phenylethyl alcohol, and has a pH between 5 and 7.
It is necessary to prime the pump before first use or after a period of non-use (1 week or more). After initial priming (6 actuations), each actuation delivers 50 mug of fluticasone propionate in 100 mg of formulation through the nasal adapter. Each bottle of Flonase nasal spray provides 120 metered sprays. After 120 metered sprays, the amount of fluticasone propionate delivered per actuation may not be consistent and the unit should be discarded.
Fluticasone propionate is a synthetic, trifluorinated corticosteroid with anti-inflammatory activity. In vitro dose response studies on a cloned human glucocorticoid receptor system involving binding and gene expression afforded 50% responses at 1.25 and 0.17 nM concentrations, respectively. Fluticasone propionate was threefold to fivefold more potent than dexamethasone in these assays. Data from the McKenzie vasoconstrictor assay in man also support its potent glucocorticoid activity.
In preclinical studies, fluticasone propionate revealed progesterone-like activity similar to the natural hormone. However, the clinical significance of these findings in relation to the low plasma levels (see Pharmacokinetics) is not known.
The precise mechanism through which fluticasone propionate affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. In seven trials in adults, fluticasone propionate nasal spray has decreased nasal mucosal eosinophils in 66% (35% for placebo) of patients and basophils in 39% (28% for placebo) of patients. The direct relationship of these findings to long-term symptom relief is not known.
Fluticasone propionate nasal spray, like other corticosteroids, is an agent that does not have an immediate effect on allergic symptoms. A decrease in nasal symptoms has been noted in some patients 12 hours after initial treatment with fluticasone propionate nasal spray. Maximum benefit may not be reached for several days. Similarly, when corticosteroids are discontinued, symptoms may not return for several days.
Absorption: The activity of fluticasone propionate nasal spray is due to the parent drug, fluticasone propionate. Indirect calculations indicate that fluticasone propionate delivered by the intranasal route has absolute bioavailability averaging less than 2%. After intranasal treatment of patients with allergic rhinitis for 3 weeks, fluticasone propionate plasma concentrations were above the level of detection (50 pg/ml) only when recommended doses were exceeded and then only in occasional samples at low plasma levels. Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration. Studies using oral dosing of radiolabeled drug have demonstrated that fluticasone propionate is highly extracted from plasma and absorption is low. Oral bioavailability is negligible, and the majority of the circulating radioactivity is due to an inactive metabolite.
Distribution: Following intravenous administration, the initial dispostion 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% with no obvious concentration relationship. Fluticasone propionate is weakly and reversibly bound to erythrocytes and freely equilibrates between erythrocytes and plasma. Fluticasone propionate is not significantly bound to human transcortin.
Metabolism: The total blood 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 17beta-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This inactive metabolite had approximately 2000 times less affinity than the parent drug for the clucocorticoid 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 orally inhaled fluticasone propionate (500 mug twice daily) and erythromycin (333 mg three times daily) did not affect fluticasone propionate pharmacokinetics.
In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1000 mug, 5 times the maximum daily intranasal dose) 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.
Fluticasone propionate was not studied in any special populations, and no gender-specific pharmacokinetic data have been obtained.
In a trial to evaluate the potential systemic and topical effects of fluticasone propionate nasal spray on allergic rhinitis symptoms, the benefits of comparable drug blood levels produced by fluticasone propionate nasal spray and oral fluticasone propionate were compared. The doses used were 200 mug of fluticasone propionate nasal spray, the nasal spray vehicle (plus oral placebo), and 5 and 10 mg of oral fluticasone propionate (plus nasal spray vehicle) per day for 14 days. Plasma levels were undetectable in the majority of patients after intranasal dosing, but present at low levels in the majority after oral dosing. Fluticasone propionate nasal spray was significantly more effective in reducing symptoms of allergic rhinitis than either the oral fluticasone propionate or the nasal vehicle. This trial demonstrated that the therapeutic effect of fluticasone propionate nasal spray can be attributed to the topical effects of fluticasone propionate.
In another trial, the potential systemic effects of fluticasone propionate nasal spray on the hypothalamic-pituitary-adrenal (HPA) axis were also studied in allergic patients. Fluticasone propionate nasal spray given as 200 mug once daily or 400 mug twice daily was compared with placebo or oral prednisone 7.5 or 15 mg given in the morning. Fluticasone propionate nasal spray at either dose for 4 weeks did not affect the adrenal response to 6-hour cosyntropin stimulation, while both doses of oral prednisone significantly reduced the response to cosyntropin.
Adult patients may be started on 200-mug once-a-day regimen (two 50-mug sprays in each nostril once a day). An alternative 200-mug/day dosage regimen can be given as 100 mug twice daily (one 50-mug spray in each nostril twice a day).
Individual patients will experience a variable time to onset and different degree of symptom relief. In 4 randomized, double-blind, placebo-controlled, parallel group allergic rhinitis studies and 2 studies of patients in an outdoor “park” setting (park studies), a decrease in nasal symptoms in treated subjects compared to placebo was shown to occur as soon as 12 hours after treatment with a 200-mug dose of fluticasone propionate nasal spray. Maximum effect may take several days. Patients who have responded may be able to be maintained (after 4 to 7 days) on 100 mug per day (one spray in each nostril once daily).
Pediatric patients 4 years of age and older should be started with 100 mug (one spray in each nostril once-a-day). Treatment with 200 mug (two sprays in each nostril once daily or one spray in each nostril twice daily) should be reserved for pediatric patients not adequately responding to 100 mug daily. Once adequate control is achieved, the dosage may be decreased to 100 mug (one spray in each nostril) daily.
Maximum total daily doses should not exceed two sprays in each nostril (total dose, 200 mug per day). There is no evidence that exceeding the recommended dose is more effective.
A total of 13, randomized, double-blind, parallel, multicenter, vehicle-controlled clinical trials were conducted in the United States in adults and pediatric patients (4 years of age and older) with seasonal of perennial allergic rhinitis. The trials included 2633 adults (1439 men and 1194 women) with mean age of 37 years (range, 18 to 79). A total of 440 adolescents (405 boys and 35 girls), mean age of 14 (range, 12 to 17), and 500 children (325 boys and 175 girls), mean age of 9 (range, 4 to 11) were also studied. The overall racial distribution was 89% white, 4% black, and 7% other. These trials evaluated the total nasal symptoms scores (TNSS) that included rhinorrhea, nasal obstruction, sneezing, and nasal itching in known allergic patients who were treated for 2 to 24 weeks. Subjects treated with fluticasone propionate nasal spray exhibited significantly greater decreases in TNSS than vehicle placebo-treated patients. Nasal mucosal basophils and eosinophils were also reduced at the end of treatment in adult studies; however, the clinical significance of this decrease is not known.
There were no significant differences between fluticasone propionate regimens whether administered as a single daily dose of 200 mug (two 50-mug sprays in each nostril) or as 100 mug (one 50-mug spray in each nostril) twice daily in six clinical trials. A clear dose response could not be identified in clinical trials. In one trial, 200 mug/day was slightly more effective than 50 mug/day during the first few days of treatment, thereafter, no difference was seen.
Three randomized, double-blind, parallel, vehicle-controlled trials were conducted in 1191 patients with perennial nonallergic rhinitis. These trials evaluated the patient-rated total nasal symptom scores (nasal obstruction, postnasal drip, rhinorrhea) in patients treated for 28 days of double-blind therapy and in one of the three trials for 6 months of open-label treatment. Two of these trials demonstrated that patients treated with fluticasone propionate nasal spray at a dose of 100 mug twice daily exhibited statistically significant decreases in total nasal symptom scores compared with patients treated with vehicle.
Fluticasone propionate nasal spray is indicated for the management of the nasal symptoms of seasonal and perennial allergic and nonallergic rhinitis in adults and pediatric patients 4 years of age and older.
Safety and effectiveness of fluticasone propionate nasal spray in children below 4 years of age have not been adequately established.
Fluticasone propionate nasal spray is contraindicated in patients with a hypersensitivity to any of its ingredients.
The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency, and in addition some patients may experience symptoms of withdrawal, e.g., joint and/or muscular pain, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their symptoms.
The concomitant use of intranasal corticosteroids with other inhaled corticosteroids could increase the risk of signs or symptoms of hypercorticism and/or suppression of the HPA axis.
Patients who are on immunosuppressant drugs are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in patients on immunosuppressant doses of corticosteroids. In such patients 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 prescribing informatio for complete VZIG and IG information.) If chickenpox develops, treatment with antiviral agents may be considered.
General: Rarely, immediate hypersensitivity reactions or contact dermatitis may occur after the administration of fluticasone propionate nasal spray. Rare instances of wheezing, nasal septum perforation, cataracts, glaucoma and increased intraocular pressure have been reported following the intranasal application of corticosteroids, including fluticasone propionate.
Use of excessive doses of corticosteroids may lead to signs or symptoms of hypercorticism, suppression of HPA function, and/or reduction of growth velocity in children or teenagers. Physicians should closely follow the growth of children and adolescents taking corticosteroids, by any route, and weigh the benefits of corticosteroid therapy against the possibility of growth suppression if growth appears slowed.
Although systemic effects have been minimal with recommended doses of fluticasone propionate nasal spray, potential risk increases with larger doses. Therefore, larger than recommended doses of fluticasone propionate nasal spray should be avoided.
When used at higher than recommended doses, or in rare individuals at recommended doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of fluticasone propionate nasal spray should be discontinued slowly consistent with accepted procedures for discontinuing oral corticosteroid therapy.
In clinical studies with fluticasone propionate administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred only rarely. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of treatment with fluticasone propionate nasal spray. Patients using fluticasone propionate nasal spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa.
Fluticasone propionate nasal spray should be used with caution, if at all, in patients with active or quiescent tuberculous infection; untreated local or systemic fungal or bacterial, or systemic viral infections or parasitic infection; or ocular herpes simplex.
Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until healing has occurred.
Information for the Patient: Patients being treated with fluticasone propionate nasal spray 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 be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay.
Patients should use fluticasone propionate nasal spray at regular intervals as directed since its effectiveness depends on its regular use. A decrease in nasal symptoms may occur as soon as 12 hours after starting therapy with fluticasone propionate nasal spray. Results in several clinical trials indicate statistically significant improvement within the first day or two of treatment; however, the full benefit of fluticasone propionate nasal spray may not be achieved until treatment has been administered for several days. The patient should not increase the prescribed dosage but should contact the physician if symptoms do not improve or if the condition worsens. For the proper use of the nasal spray and to attain maximum improvement, the patient should read and follow carefully the accompanying patient’s instructions.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1000 mug/kg (approximately 20 times the maximum recommended daily intranasal dose in adults and approximately 10 times the maximum recommended daily intranasal dose in children on a mug/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mug/kg (approximately 2 times the maximum recommended daily intranasal dose in adults and approximately equivalent to the maximum recommended daily intranasal dose in children on a mug/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 mug/kg (approximately 2 times the maximum recommended daily intranasal dose in adults on a mug/m2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mug/kg.
Pregnancy, Teratogenic Effects, Pregnancy Category C: Subcutaneous studies in the mouse and rat at 45 and 100 mug/kg, respectively (approximately equivalent to and 4 times the maximum recommended daily intranasal dose in adults on a mug/m2 basis, respectively) revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele cleft palate, and retarded cranial ossification.
In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mug/kg (less than the maximum recommended daily intranasal dose in adults on a mug/m2 basis).
However, no teratogenic effects were reported at oral doses up to 300 mug/kg (approximately 25 times the maximum recommended daily intranasal dose in adults on a mug/m2 basis) of fluticasone propionate to the rabbit. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration (see CLINICAL PHARMACOLOGY).
Fluticasone propionate crossesd the placenta following oral administration of 100 mug/kg to rats or 300 mug/kg to rabbits (approximately 4 and 25 times, respectively, the maximum recommended daily intranasal dose in adults on a mug/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. When tritiated fluticasone propionate was administered to rats at a subcutaneous dose of 10 mug/kg (less than the maximum recommended daily intranasal dose in adults on a mug/m2 basis), radioactivity was excreted in the milk. Because other corticosteroids are excreted in human milk, caution should be exercised when fluticasone propionate nasal spray is administered to a nursing woman.
Pediatric Use: Five hundred (500) patients aged 4 to 11 years of age and 440 patients aged 12 to 17 years were studied in U.S. clinical trials with fluticasone propionate nasal spray. The safety and effectiveness of fluticasone propionate nasal spray in children below 4 years of age have not been established.
Oral and, to a less clear extent, inhaled and intranasal corticosteroids have been shown to have the potential to cause a reduction in growth velocity in children and adolescents with extended use. 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 (see PRECAUTIONS).
Geriatric Use: A limited number of patients above 60 years of age (n = 275) have been treated with fluticasone propionate nasal spray in U.S. and non-U.S. clinical trials. While the number of patients is too small to permit separate analysis of efficacy and safety, the adverse reactions reported in this population were similar to those reported by younger patients.
In a placebo-controlled, crossover study in eight healthy volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1000 mug, 5 times the maximum daily intranasal dose) 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. No drug interaction studies have been conducted with fluticasone propionate nasal spray; however, care should be exercised when fluticasone propionate is coadministered with long-term ketoconazole and other known cytochrome P450 3A4 inhibitors.
In controlled U.S. studies, more than 3300 patients with seasonal allergic, perennial allergic, or perennial nonallergic rhinitis received treatment with intranasal fluticasone propionate. In general, adverse reactions in clinical studies have been primarily associated with irritation of the nasal mucous membranes, and the adverse reactions were reported with approximately the same frequency by patients treated with the vehicle itself. The complaints did not usually interfere with treatment. Less than 2% of patients in clinical trials discontinued because of adverse events; this rate was similar for vehicle placebo and active comparators.
Systemic corticosteroid side effects were not reported during controlled clinical studies up to 6 months’ duration with fluticasone propionate nasal spray. If recommended doses are exceeded, however, or if individuals are particularly sensitive, or taking fluticasone propionate nasal spray in conjunction with administration of other corticosteroids, symptoms of hypercorticism e.g., Cushing’s syndrome, could occur.
The following incidence of common adverse reactions (>3%, where incidence in fluticasone propionate-treated subjects exceeded placebo) is based upon seven controlled clinical trials in which 536 patients (57 girls and 108 boys aged 4 to 11 years, 137 female and 234 male adolescents and adults) were treated with fluticasone propionate nasal spray 200 mug once daily over 2 to 4 weeks and two controlled clinical trials in which 246 patients (119 female and 127 male adolescents and adults) were treated with fluticasone propionate nasal spray 200 mug once daily over 6 months (see TABLE 1). Also included in the table are adverse events from two studies in which 167 children (45 girls and 122 boys aged 4 to 11 years) were treated with fluticasone propionate nasal spray 100 mug once daily for 2 to 4 weeks.
3% but 1% of patients and that were more common with fluticasone propionate (with uncertain relationship to treatment) included: Blood in nasal mucus, runny nose, abdominal pain, diarrhea, fever, flu-like symptoms, aches and pains, dizziness, bronchitis.Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during postapproval use of fluticasone propionate in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, causal connection to fluticasone propionate, occurrence during clinical trials, or a combination of these factors.
General: Hypersensitivity reactions, including angioedema, skin rash, edema of the face and tongue, pruritus, urticaria, bronchospasm, wheezing, dyspnea, and anaphylaxis/anaphylactoid reactions, which in rare instances were severe.
Ear, Nose, and Throat: Alteration or loss of sense of taste and/or smell and, rarely, nasal septal perforation, nasal ulcer, sore throat, throat irritation and dryness, cough, hoarseness, and voice changes.
Eye: Dryness and irritation, conjunctivitis, blurred vision, glaucoma, increased intraocular pressure, and cataracts.
Chronic overdosage with fluticasone propionate nasal spray may result in signs/symptoms of hypercorticism (see PRECAUTIONS). Intranasal administration of 2 mg (10 times the recommended dose) of fluticasone propionate twice daily for 7 days to healthy human volunteers was well tolerated. Single oral doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported. Repeat oral doses up to 80 mg daily for 10 days in volunteers and repeat oral doses up to 10 mg daily for 14 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups. Acute overdosage with this dosage form is unlikely since one bottle of fluticasone propionate nasal spray contains approximately 8 mg of fluticasone propionate.
The oral and subcutaneous median lethal doses in mice and rats were >1000 mg/kg (>20,000 and >41,000 times, respectively, the maximum recommended daily intranasal dose in adults and >10,000 and >20,000 times, respectively, the maximum recommended daily intranasal dose in children on a mg/m2 basis).
Patients should use fluticasone propionate nasal spray at regular intervals as directed since its effectiveness depends on its regular use.
Adults: The recommended starting dosage in adults is two sprays (50 mug of fluticasone propionate each) in each nostril once-a-day (total daily dose, 200 mug). The same dosage divided into 100 mug given twice-a-day (e.g., 8 a.m. and 8 p.m.) is also effective. After the first few days, patients may be able to reduce their dosage to 100 mug (one spray in each nostril) once daily for maintenance therapy.
Adolescents and Children (4 Years of Age and Older): Patients should be started with 100 mug (one spray in each nostril once-a-day). Patients not adequately responding to 100 mug may use 200 mug (two sprays in each nostril). Once adequate control is achieved, the dosage should be decreased to 100 mug (one spray in each nostril) daily.
The maximum total daily dosage should not exceed two sprays in each nostril (200 mug per day). (See Individualization Of Dosage and CLINICAL STUDIES.)
Fluticasone propionate nasal spray is not recommended for children under 4 years of age.
Directions for Use: Illustrated patient’s instructions for proper use accompany each package of Flonase nasal spray.
HOW SUPPLIED:
Flonase nasal spray 50 mug provides 120 acutations. Each actuation delivers 50 mug of fluticasone propionate in 100 mg of formulation through the nasal adapter. The bottle should be discarded when the labeled number of actuations has been reached even though the bottle is not completely empty.
Storage: Store between 4-30°C (39-86°F).
Fluticasone Propionate (Topical)
Cutivate cream (0.05%) and Cutivate ointment (0.005%) each contain fluticasone propionate [(6alpha,11beta,16alpha,17alpha)-6,9,-difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy)androsta-1,4-diene-17-carbothioic acid, S-fluoromethyl ester], a synthetic fluorinated corticosteroid, for topical dermatologic use. The topical corticosteroids constitute a class of primarily synthetic steroids used as anti-inflammatory and antipruritic agents.
Chemically, fluticasone propionate is C25H31F3O5S.
Fluticasone propionate has a molecular weight of 500.6. It is a white to off-white powder and is insoluble in water.
Cream: Each gram of Cutivate cream contains fluticasone propionate 0.5 mg in a base of propylene glycol, mineral oil, cetostearyl alcohol, Ceteth-20, isopropyl myristate, dibasic sodium phosphate, citric acid, purified water, and imidurea as preservative.
Ointment: Each gram of Cutivate ointment contains fluticasone propionate 0.05 mg in a base of propylene glycol, sorbitan sesquioleate, microcrystalline wax, and liquid paraffin.
Like other topical corticosteroids, fluticasone propionate has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.
Additional Information for Fluticasone Propinate Cream Only: Fluticasone propinate is lipophilic and has a strong affinity for the glucocorticoid receptor. It has weak affinity for the progesterone receptor, and virtually no affinity for the mineralocorticoid, estrogen, or androgen receptors. The therapeutic potency of glucocorticoids is related to the half-life of the glucocorticoid-receptor complex. The half-life of the fluticasone propionate-glucocorticoid receptor complex is approximately 10 hours.
Studies performed with fluticasone propionate cream and fluticasone propionate ointment indicate that they are in the medium range of potency as compared with other topical corticosteroids.
Cream
Absorption: The activity of fluticasone propionate cream is due to the parent drug, fluticasone propionate. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusive dressing enhances penetration. Topical corticosteroids can be absorbed from nornal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption.
In a human study of 12 healthy males receiving 12.5 g of 0.05% fluticaseon propionate cream twice daily for 3 weeks, plasma levels were generally below the level of quantification (0.05 ng/ml). In another study of six healthy males administered 25 g of 0.05% fluticasone propionate cream under occlusion for 5 days, plasma levels of fluticasone ranged from 0.07 to 0.39 ng/ml.
In an animal study using radiolabeled 0.05% fluticasone propionate cream and ointment preparations, rats received a topical dose of 1 g/kg for a 24 hour period. Total recovery of radioactivity was approximately 80% at the end of 7 days. The majority of the dose (73%) was recovered in the skin at the application site. Approximately 5% of the dose was absorbed systematically from the surface of the application site. Less than 1% of the dose was recovered through the skin. Absorption from the skin continued for the duration of the study (7 days), indicating a long retention time at the application site.
Distribution: Following intravenous administration of 1 mg fluticasone propionate in healthy volunteers, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The apparent volume of distribution averaged 4.2 L/kg (range 2.3 to 16.7 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: No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone propionate incubated in a human skin homogenate. The total blood clearance of systemically absorbed fluticasone propionate averages 1093 ml/min (range 618 to 1702 ml/min) after a 1-mg intravenous dose, with renal clearance accounting for less than 0.02% of the total. Fluticasone propionate is metabolized in the liver by cytochrome P450 3A4-mediated hydrolysis of the 5-fluoromethyl carbothioate grouping. This transformation occurs in one metabolic step to produce the inactive 17-beta-carboxylic acid metabolite, the only known metabolite detected in man. This metabolite has 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 dose of 1 mg in healthy volunteers, fluticasone propionate showed polyexponential kinetics and had an average terminal half-life of 7.2 hours (range 3.2 to 11.2 hours).
Ointment
The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusive dressing with hydrocortisone for up to 24 hours has not been demonstrated to increase penetration; however, occlusion of hydrocortisone for 96 hours markedly enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption.
Cream
Psoriasis Studies
In two vehicle-controlled studies, fluticasone propionate cream applied twice daily was significantly more effective than the vehicle in the treatment of moderate to severe psoriasis. The investigator’s global evaluation after 28 days of treatment is shown in TABLE 1.
The clinical signs of psoriasis were scored on a scale of 0 = absent, 1 = mild, 2 = moderate, and 3 = severe. The mean improvements over baseline in the clinical signs at the end of treatment are shown in TABLE 2.
Atopic Dermatitis Studies
In two controlled 28-day studies, fluticasone propionate cream once daily was equivalent to fluticasone propionate cream twice daily in the treatment of moderate to severe eczema. The investigator’s global evaluation after 28 days of treatment is shown in TABLE 3.
The clinical signs and symptoms of atopic dermatitis were scored on a scale of 0 = absent, 1 = mild, 2 = moderate, and 3 = severe. The mean improvements over baseline at the end of treatment are shown in TABLE 4.
Fluticasone propionate cream and ointment are medium potency corticosteroids indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.
Additional Information for Cream Only: Fluticasone propionate cream may be used with caution in pediatric patients 3 months of age or older. The safety and efficacy of drug use for longer than 4 weeks in this population have not been established. The safety and efficacy of fluticasone propionate cream in pediatric patients below 3 months of age have not been established.
Fluticasone propionate cream and ointment are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.
Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal from treatment. Manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment.
Patients applying a potent topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free cortisol tests.
If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid (with fluticasone propionate ointment; steroid for fluticasone propionate cream). Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur, requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products.
Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios (see PRECAUTIONS, Pediatric Use).
If irritation develops, fluticasone propionate cream or ointment should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing.
If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of fluticasone propionate cream or ointment should be discontinued until the infection has been adequately controlled.
Fluticasone propionate cream and ointment should not be used in the presence of preexisting skin atrophy and should not be used where the infection is present at the treatment site. Fluticasone propionate cream and ointment should not be used in the treatment of rosacea and perioral dermatitis.
Cream: Fluticasone propionate cream, 0.05% caused depression of A.M. plasma cortisol levels in one of six adult patients when used daily for 7 days in patients with psoriasis or eczema involving at least 30% of the body surface. After 2 days of treatment, this patient developed a 60% decrease from pretreatment values in the A.M. plasma cortisol level.
There was some evidence of corresponding decrease in 24-hour urinary free cortisol levels. The A.M. plasma cortisol level remained slightly depressed for 48 hours but recovered by day 6 of treatment.
Fluticasone propionate cream, 0.05%, caused HPA axis suppression in two of 43 pediatric patients, ages 2 and 5 years old, who were treated for 4 weeks covering at least 35% of the body surface area. Follow-up testing 12 days after treatment discontinuation, available for 1 of the 2 subjects, demonstrated a normally responsive HPA axis (see PRECAUTIONS, Pediatric Use). Fluticasone propionate cream, 0.05% may cause local cutaneous adverse reactions (see ADVERSE REACTIONS
Ointment: Fluticasone propionate ointment, 0.05% (a concentration 10 times that of fluticasone propionate ointment, 0.005%) suppressed 24-hour urinary free cortisol levels in two of six patients when used at a dose of 30 g/day for a week in patients with psoriasis or atopic eczema. In a second study, fluticasone propionate ointment, 0.05% caused depression of A.M. plasma cortisol levels in three of 12 normal volunteers when applied at doses of 50 g/day for 21 days. Morning plasma levels returned to normal levels within the first week upon discontinuation of fluticasone propionate. In this study there was no corresponding decrease in 24-hour urinary free cortisol levels.
Patients using topical corticosteroids should receive the following information and instructions:
1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes.
2. This medication should not be used for any disorder other than that for which it was prescribed.
3. The treated skin area should not be bandaged or otherwise covered or wrapped so as to be occlusive unless directed by the physician.
4. Patients should report to their physician any signs of local adverse reactions.
Additional Information for Cream Only:
5. Parents of pediatric patients should be advised not to use this medication in the treatment of diaper dermatitis. Fluticasone propionate cream should not be applied in the diaper areas as diapers or plastic pants may constitute occlusive dressing (see DOSAGE AND ADMINISTRATION).
6. This medication should not be used on the face, underarms, or groin areas unless directed by a physician.
7. As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, contact the physician.
The following tests may be helpful in evaluating patients for HPA axis suppression:
ACTH stimulation test.
A.M. plasma cortisol test.
Urinary free cortisol test.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Two 18-month studies were performed in mice to evaluate the carcinogenic potential of fluticasone propionate when given topically (as an 0.05% ointment) and orally. No evidence of carcinogenicity was found in either study.
Fluticasone propionate was not mutagenic in the standard Ames test, E. coli fluctuation test, S. cerevisiae gene conversion test, or Chinese Hamster ovarian cell assay. It was not clastogenic in mouse micronucleus or cultured human lymphocyte tests.
In a fertility and general reproductive performance study in rats, fluticasone propionate administered subcutaneously to females at up to 50 mug/kg per day and to males at up to 100 mug/kg per day (later reduced to 50 mug/kg per day) had no effect upon mating performance or fertility. In fluticasone propionate cream, 0.05%, these doses are approximately 15 and 30 times, and in fluticasone propionate ointment, 0.005%, these doses are approximately 150 and 300 times, respectively, the human systemic exposure following use of the recommended human topical dose of fluticasone propionate cream, 0.05% and fluticasone propionate ointment, 0.005%, assuming human percutaneous absorption of approximately 3% and the use in a 70-kg person of 15 g/day.
Pregnancy, Teratogenic Effects, Pregnancy Category C
Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. Teratology studies in the mouse demonstrated fluticasone propionate to be teratogenic (cleft palate) when administered subcutaneously in doses of 45 mug/kg per day and 150 mug/kg per day. This dose is approximately 14 and 45 times, respectively, the human topical dose of fluticasone propionate cream, 0.05% and is approximately 140 and 450 times, respectively, the human topical dose of fluticasone propionate ointment, 0.005%. There are no adequate and well-controlled studies in pregnant women. Fluticasone propionate cream, and ointment, should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when fluticasone propionate cream, or ointment, is administered to a nursing woman.
HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.
Cream
Fluticasone propionate cream may be used with caution in pediatric patients as young as 3 months of age. The safety and efficacy of drug use for longer than 4 weeks in this population have not been established. The safety and efficacy of fluticasone propionate cream in pediatric patients below 3 months of age have not been established.
Fluticasone propionate cream, 0.05%, caused HPA axis suppression in two of 43 pediatric patients, ages 2 and 5 years old, who were treated for 4 weeks covering at least 35% of the body surface area. Follow-up testing 12 days after treatment discontinuation, available for one of the two subjects, demonstrated a normally responsive HPA axis (see ADVERSE REACTIONS). Adverse effects including striae have been reported with use of topical corticosteroids in pediatric patients.
Ointment
Safety and effectiveness in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA axis suppression and Cushing’s syndrome when they are treated with topical corticosteroids. They are therefore also at greater risk of adrenal insufficiency during or after withdrawal of treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in pediatric patients.
In controlled clinical trials (of twice daily administration for fluticasone propionate cream), the total incidence of adverse reactions associated with the use of fluticasone propionate cream, 0.05% and ointment, 0.005% was approximately 4%. These adverse reactions were usually mild, self-limiting, and for fluticasone propionate cream consisted primarily of pruritus, dryness, numbness of fingers, and burning. These events occurred in 2.9%, 1.2%, 1.0%, and 0.6% of patients, respectively. For fluticasone propionate ointment, the adverse reactions consisted primarily of pruritus, burning, hypertrichosis, increased erythema, hives, irritation, and lightheadedness. Each of these events occurred individually in less than 1% of patients.
The following additional local adverse reactions have been reported infrequently with topical corticosteroids including fluticasone propionate and they may occur more frequently with the use of occlusive dressings and higher potency corticosteroids. These reactions are listed in an approximately decreasing order of occurrence: irritation (dryness for ointment), folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae and miliaria. Also, there are reports of the development of pustular psoriasis from chronic plaque psoriasis following reduction or discontinuation of potent topical corticosteroid products.
Additional Information for Cream Only: Two clinical studies compared once to twice daily administration of fluticasone propionate cream for the treatment of moderate to severe eczema. The local drug-related adverse events for the 491 patients enrolled in both studies are shown in TABLE 5. In the study enrolling both adult and pediatric patients, the incidence of local adverse events in the 119 pediatric patients ages 1 to 12 years was comparable to the 140 patients ages 13 to 62 years.
Fifty-one pediatric patients ages 3 months to 5 years, with moderate to severe eczema, were enrolled in an open-label HPA axis safety study. Fluticasone propionate cream was applied twice daily for 3 to 4 weeks over an arithmetic mean body surface area of 64% (range 35-95%). The mean morning cortisol levels with standard deviations before treatment (pre-stimulation mean value = 13.76 ± 6.94 mug/dl, post-stimulation mean value = 30.53 ± 7.23 mug/dl) and at end treatment (pre-stimulation mean value = 12.32 ± 6.92 mug/dl, post-stimulation mean value = 28.84 ± 7.16 mug/dl) showed little change. In 2 of 43 (4.7%) patients with end-treatment results, peak cortisol levels following cosyntropin stimulation testing were 18 mug/dl indicating adrenal suppression. Follow-up testing after treatment discontinuation, available for one of the two subjects, demonstrated a normally responsive HPA axis. Local drug-related adverse events were: transient burning, resolving the same day it was reported; transient urticaria, resolving the same day it was reported; erythematous rash; dusky erythema, resolving within one month after cessation of fluticasone propionate cream; and telangiectasia resolving within 3 months after stopping fluticasone propionate cream (see TABLE 6).
Topically applied fluticasone propionate cream or ointment can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS).
Cream
Fluticasone propionate cream may be used in adult and pediatric patients 3 months of age or older. Safety and efficacy of fluticasone propionate in pediatric patients for more than 4 weeks of use have not been established (see PRECAUTIONS, Pediatric Use). The safety and efficacy of fluticasone propionate cream in pediatric patients below 3 months of age have not been established.
Atopic Dermatitis: Apply a thin film of fluticasone propionate cream to the affected skin areas once or twice daily. Rub in gently.
Other Corticosteroid-Responsive Dermatoses: Apply a thin film of fluticasone propionate cream to the affected skin areas twice daily. Rub in gently.
As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary.
Fluticasone propionate cream should not be used with occlusive dressings. Fluticasone propionate cream should not be applied in the diaper area, as diapers or plastic pants may constitute occlusive dressings.
Ointment
Apply a thin film of fluticasone propionate ointment to the affected skin areas twice daily. Rub in gently.
HOW SUPPLIED:
Storage: Store between 2-30°C (36-86°F).