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Mechanism of Action
Fluticasone propionate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. In vitro assays using human lung cytosol preparations have established fluticasone propionate as a human glucocorticoid receptor agonist with an affinity 18 times greater than dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. The clinical significance of these findings is unknown.
Inflammation is 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, neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.
Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately. Individual patients will experience a variable time to onset and degree of symptom relief. 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.
Studies in patients with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone propionate. This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (less than 1%), and the minimal pharmacological activity of the only metabolite detected in man.
Serum cortisol concentrations, urinary excretion of cortisol, and urine 6-β- hydroxycortisol excretion collected over 24 hours in 24 healthy subjects following 8 inhalations of fluticasone propionate HFA 44, 110, and 220 mcg decreased with increasing dose. However, in patients with asthma treated with 2 inhalations of fluticasone propionate HFA 44, 110, and 220 mcg twice daily for at least 4 weeks, differences in serum cortisol AUC(0-12 hr) (n = 65) and 24-hour urinary excretion of cortisol (n = 47) compared with placebo were not related to dose and generally not significant. In the study with healthy volunteers, the effect of propellant was also evaluated by comparing results following the 220-mcg strength inhaler containing HFA 134a propellant with the same strength of inhaler containing CFC 11/12 propellant. A lesser effect on the HPA axis with the HFA formulation was observed for serum cortisol, but not urine cortisol and 6-betahydroxy cortisol excretion. In addition, in a crossover study of children with asthma aged 4 to 11 years (N = 40), 24-hour urinary excretion of cortisol was not affected after a 4-week treatment period with 88 mcg of fluticasone propionate HFA twice daily compared with urinary excretion after the 2-week placebo period. The ratio (95% CI) of urinary excretion of cortisol over 24 hours following fluticasone propionate HFA versus placebo was 0.987 (0.796, 1.223).
The potential systemic effects of fluticasone propionate HFA on the HPA axis were also studied in patients with asthma. Fluticasone propionate given by inhalation aerosol at dosages of 440 or 880 mcg twice daily was compared with placebo in oral corticosteroid-dependent patients with asthma (range of mean dose of prednisone at baseline: 13 to 14 mg/day) in a 16-week study. Consistent with maintenance treatment with oral corticosteroids, abnormal plasma cortisol responses to short cosyntropin stimulation (peak plasma cortisol less than 18 mcg/dL) were present at baseline in the majority of patients participating in this study (69% of patients later randomized to placebo and 72% to 78% of patients later randomized to fluticasone propionate HFA). At week 16, 8 patients (73%) on placebo compared with 14 (54%) and 13 (68%) patients receiving fluticasone propionate HFA (440 and 880 mcg twice daily, respectively) had poststimulation cortisol levels of less than 18 mcg/dL.
Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Studies using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (less than 1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed.
Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding.
The volume of distribution averaged 4.2 L/kg. The percentage of fluticasone propionate bound to human plasma proteins averages 99%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin.
The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 170-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP 3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the corticosteroid 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.
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.
Gender: No significant difference in clearance (CL/F) of fluticasone propionate was observed.
Pediatrics: A population pharmacokinetic analysis was performed for FLOVENT HFA using steady-state data from 4 controlled clinical trials and single-dose data from 1 controlled clinical trial. The combined cohort for analysis included 269 patients (161 males and 108 females) with asthma aged 6 months to 66 years who received treatment with FLOVENT HFA. Most of these subjects (n = 215) were treated with FLOVENT HFA 44 mcg given as 88 mcg twice daily. FLOVENT HFA was delivered using an AeroChamber Plus VHC with a face mask to patients aged less than 4 years. Data from adult patients with asthma following FLOVENT HFA 110 mcg given as 220 mcg twice daily (n = 15) and following FLOVENT HFA 220 mcg given as 440 mcg twice daily (n = 17) at steady state were also included. Data for 22 patients came from a single-dose crossover study of 264 mcg (6 doses of FLOVENT HFA 44 mcg) with and without AeroChamber Plus VHC in children with asthma aged 4 to 11 years.
Stratification of exposure data following FLOVENT HFA 88 mcg by age and study indicated that systemic exposure to fluticasone propionate at steady state was similar in children aged 6 to less than 12 months, children aged 1 to less than 4 years, and adults and adolescents aged 12 years and older. Exposure was lower in children aged 4 to 11 years, who did not use a VHC, as shown in Table 4.
Table 4: Systemic Exposure to Fluticasone Propionate
Following FLOVENT HFA 88 mcg Twice Daily
|Age||Valved Holding Chamber||N||AUC0-τ, pg•hr/mL (95% CI)||Cmax, pg/mL (95% CI)|
|6 to < 12 Months||Yes||17||141 (88, 227)||19 (13, 29)|
|1 to < 4 Years||Yes||164||143 (131, 157)||20 (18, 21)|
|4 to 11 Years||No||14||68 (48, 97)||11 (8, 16)|
|≥ 12 Years||No||20||149 (106, 210)||20 (15, 27)|
The lower exposure to fluticasone propionate in children aged 4 to 11 years who did not use a VHC may reflect the inability to coordinate actuation and inhalation of the metered-dose inhaler. The impact of the use of a VHC on exposure to fluticasone propionate in patients aged 4 to 11 years was evaluated in a single-dose crossover study with FLOVENT HFA 44 mcg given as 264 mcg. In this study, use of a VHC increased systemic exposure to fluticasone propionate (Table 5), possibly correcting for the inability to coordinate actuation and inhalation.
Table 5: Systemic Exposure to Fluticasone Propionate
Following a Single Dose of FLOVENT HFA 264 mcg
|Age||Valved Holding Chamber||N||AUC(0-τ), pg•hr/mL (95% CI)||Cmax, pg/mL (95% CI)|
|4 to 11 Years||Yes||22||373 (297, 468)||61 (51, 73)|
|4 to 11 Years||No||21||141 (111, 178)||23 (19, 28)|
There was a dose-related increase in systemic exposure in patients aged 12 years and older receiving higher doses of fluticasone propionate (220 and 440 mcg twice daily). The AUC0-τ in pg•hr/mL was 358 (95% CI: 272, 473) and 640 (95% CI: 477, 858), and Cmax in pg/mL was 47.3 (95% CI: 37, 61) and 87 (95% CI: 68, 112) following fluticasone propionate 220 and 440 mcg, respectively.
Hepatic and Renal Impairment: Formal pharmacokinetic studies using FLOVENT HFA have not been conducted in patients with hepatic or renal impairment. However, since fluticasone propionate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be closely monitored.
Race: No significant difference in clearance (CL/F) of fluticasone propionate in Caucasian, African-American, Asian, or Hispanic populations was observed.
Ritonavir: Fluticasone propionate is a substrate of CYP3A4. Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (less than 10 pg/mL) in most subjects, and when concentrations were detectable, peak levels (Cmax) averaged 11.9 pg/mL (range: 10.8 to 14.1 pg/mL) and AUC(0-τ) averaged 8.43 pg•hr/mL (range: 4.2 to 18.8 pg•hr/mL). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg•hr/mL (range: 1,207.1 to 5,662.0 pg^hr/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in serum cortisol AUC.
Ketoconazole: In a placebo-controlled, crossover study in 8 healthy adult volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol.
Following orally inhaled fluticasone propionate alone, AUC(2-last) averaged 1.559 ng•hr/mL (range: 0.555 to 2.906 ng•hr/mL) and AUC(2-∞) averaged 2.269 ng•hr/mL (range: 0.836 to 3.707 ng•hr/mL). Fluticasone propionate AUC(2-last) and AUC(2-∞) increased to 2.781 ng•hr/mL (range: 2.489 to 8.486 ng•hr/mL) and 4.317 ng•hr/mL (range: 3.256 to 9.408 ng•hr/mL), respectively, after coadministration of ketoconazole with orally inhaled fluticasone propionate. This increase in plasma fluticasone propionate concentration resulted in a decrease (45%) in serum cortisol AUC.
Erythromycin: In a multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.
Animal Toxicology and/or Pharmacology
Subcutaneous studies in mice and rats at 45 and 100 mcg/kg (approximately 0.1 and 0.5 times the MRHD in adults on a mg/m basis, respectively) revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.
In rabbits, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mcg/kg (approximately 0.04 times the MRHD in adults on a mg/m basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 3 times the MRHD in adults on a mg/m basis) of fluticasone propionate. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration.
Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.
In animals and humans, propellant HFA-134a was found to be rapidly absorbed and rapidly eliminated, with an elimination half-life of 3 to 27 minutes in animals and 5 to 7 minutes in humans. Time to maximum plasma concentration (Tmax) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation.
Propellant HFA-134a is devoid of pharmacological activity except at very high doses in animals (i.e., 380 to 1,300 times the maximum human exposure based on comparisons of AUC values), primarily producing ataxia, tremors, dyspnea, or salivation. These events are similar to effects produced by the structurally related CFCs, which have been used extensively in metereddose inhalers.
Adult and Adolescent Patients Aged 12 Years and Older
Three randomized, double-blind, parallel-group, placebo-controlled, US clinical trials were conducted in 980 adult and adolescent patients (aged 12 years and older) with asthma to assess the efficacy and safety of FLOVENT HFA in the treatment of asthma. Fixed dosages of 88, 220, and 440 mcg twice daily (each dose administered as 2 inhalations of the 44-, 110-, and 220-mcg strengths, respectively) and 880 mcg twice daily (administered as 4 inhalations of the 220-mcg strength) were compared with placebo to provide information about appropriate dosing to cover a range of asthma severity. Patients in these studies included those inadequately controlled with bronchodilators alone (Study 1), those already receiving inhaled corticosteroids (Study 2), and those requiring oral corticosteroid therapy (Study 3). In all 3 studies, patients (including placebo-treated patients) were allowed to use VENTOLIN® (albuterol, USP) Inhalation Aerosol as needed for relief of acute asthma symptoms. In Studies 1 and 2, other maintenance asthma therapies were discontinued.
Study 1 enrolled 397 patients with asthma inadequately controlled on bronchodilators alone. FLOVENT HFA was evaluated at dosages of 88, 220, and 440 mcg twice daily for 12 weeks. Baseline FEV1 values were similar across groups (mean 67% of predicted normal). All 3 dosages of FLOVENT HFA demonstrated a statistically significant improvement in lung function as measured by improvement in AM pre-dose FEV1 compared with placebo. This improvement was observed after the first week of treatment, and was maintained over the 12- week treatment period.
At Endpoint (last observation), mean change from baseline in AM pre-dose percent predicted FEV1 was greater in all 3 groups treated with FLOVENT HFA (9.0% to 11.2%) compared with the placebo group (3.4%). The mean differences between the groups treated with FLOVENT HFA 88, 220, and 440 mcg and the placebo group were statistically significant, and the corresponding 95% confidence intervals were (2.2%, 9.2%), (2.8%, 9.9%), and (4.3%, 11.3%), respectively.
Figure 1 displays results of pulmonary function tests (mean percent change from baseline in FEV1 prior to AM dose) for the recommended starting dosage of FLOVENT HFA (88 mcg twice daily) and placebo from Study 1. This trial used predetermined criteria for lack of efficacy (indicators of worsening asthma), resulting in withdrawal of more patients in the placebo group. Therefore, pulmonary function results at Endpoint (the last evaluable FEV1 result, including most patients' lung function data) are also displayed.
Figure 1: A 12-Week Clinical Trial in Patients Aged 12
Years and Older Inadequately Controlled on Bronchodilators Alone: Mean Percent
Change From Baseline in FEV1 Prior to AM Dose (Study 1)
In Study 2, FLOVENT HFA at dosages of 88, 220, and 440 mcg twice daily was evaluated over 12 weeks of treatment in 415 patients with asthma who were already receiving an inhaled corticosteroid at a daily dose within its recommended dose range in addition to as-needed albuterol. Baseline FEV1 values were similar across groups (mean 65% to 66% of predicted normal). All 3 dosages of FLOVENT HFA demonstrated a statistically significant improvement in lung function, as measured by improvement in FEV1, compared with placebo. This improvement was observed after the first week of treatment and was maintained over the 12- week treatment period. Discontinuations from the study for lack of efficacy (defined by a prespecified decrease in FEV1 or PEF, or an increase in use of VENTOLIN or nighttime awakenings requiring treatment with VENTOLIN) were lower in the groups treated with FLOVENT HFA (6% to 11%) compared with placebo (50%).
At Endpoint (last observation), mean change from baseline in AM pre-dose percent predicted FEV1 was greater in all 3 groups treated with FLOVENT HFA (2.2% to 4.6%) compared with the placebo group (-8.3%). The mean differences between the groups treated with FLOVENT HFA 88, 220, and 440 mcg and the placebo group were statistically significant, and the corresponding 95% confidence intervals were (7.1%, 13.8%), (8.2%, 14.9%), and (9.6%, In Study 2, FLOVENT HFA at dosages of 88, 220, and 440 mcg twice daily was 16.4%), respectively.
Figure 2 displays the mean percent change from baseline in FEV1 from Week 1 through Week 12. This study also used predetermined criteria for lack of efficacy, resulting in withdrawal of more patients in the placebo group; therefore, pulmonary function results at Endpoint are also displayed.
Figure 2: A 12-Week Clinical Trial in Patients Aged 12
Years and Older Already Receiving Daily Inhaled Corticosteroids: Mean Percent
Change From Baseline in FEV1 Prior to AM Dose (Study 2)
In both studies, use of VENTOLIN, AM and PM PEF, and asthma symptom scores showed numerical improvement with FLOVENT HFA compared with placebo.
Study 3 enrolled 168 patients with asthma requiring oral prednisone therapy (average baseline daily prednisone dose ranged from 13 to 14 mg). FLOVENT HFA at dosages of 440 and 880 mcg twice daily was evaluated over a 16-week treatment period. Baseline FEV1 values were similar across groups (mean 59% to 62% of predicted normal). Over the course of the study, patients treated with either dosage of FLOVENT HFA required a statistically significantly lower mean daily oral prednisone dose (6 mg) compared with placebo-treated patients (15 mg). Both dosages of FLOVENT HFA enabled a larger percentage of patients (59% and 56% in the groups treated with FLOVENT HFA 440 and 880 mcg, respectively, twice daily) to eliminate oral prednisone as compared with placebo (13%) (see Figure 3). There was no efficacy advantage of FLOVENT HFA 880 mcg twice daily compared with 440 mcg twice daily. Accompanying the reduction in oral corticosteroid use, patients treated with either dosage of FLOVENT HFA had statistically significantly improved lung function, fewer asthma symptoms, and less use of VENTOLIN Inhalation Aerosol compared with the placebo-treated patients.
Figure 3: A 16-Week Clinical Trial in Patients Aged 12
Years and Older Requiring Chronic Oral Prednisone Therapy: Change in
Maintenance Prednisone Dose
Two long-term safety studies (Study 4 and Study 5) of ≥ 6 months' duration were conducted in 507 adult and adolescent patients with asthma. Study 4 was designed to monitor the safety of 2 doses of FLOVENT HFA, while Study 5 compared fluticasone propionate HFA with fluticasone propionate CFC. Study 4 enrolled 182 patients who were treated daily with low to high doses of inhaled corticosteroids, beta-agonists (short-acting [as needed or regularly scheduled] or long-acting), theophylline, inhaled cromolyn or nedocromil sodium, leukotriene receptor antagonists, or 5-lipoxygenase inhibitors at baseline. FLOVENT HFA at dosages of 220 and 440 mcg twice daily was evaluated over a 26-week treatment period in 89 and 93 patients, respectively. Study 5 enrolled 325 patients who were treated daily with moderate to high doses of inhaled corticosteroids, with or without concurrent use of salmeterol or albuterol, at baseline. Fluticasone propionate HFA at a dosage of 440 mcg twice daily and fluticasone propionate CFC at a dosage of 440 mcg twice daily were evaluated over a 52-week treatment period in 163 and 162 patients, respectively. Baseline FEV1 values were similar across groups (mean 81% to 84% of predicted normal). Throughout the 52-week treatment period, asthma control was maintained with both formulations of fluticasone propionate compared with baseline. In both studies, none of the patients were withdrawn due to lack of efficacy.
Pediatric Patients Aged 4 to 11 Years
A 12-week clinical trial conducted in 241 pediatric patients with asthma was supportive Two long-term safety studies (Study 4 and Study 5) of > 6 months' duration were of efficacy but inconclusive due to measurable levels of fluticasone propionate in 6/48 (13%) of the plasma samples from patients randomized to placebo. Efficacy in patients aged 4 to 11 years is extrapolated from adult data with FLOVENT HFA and other supporting data [see Use in Specific Populations].
Last reviewed on RxList: 8/23/2013
This monograph has been modified to include the generic and brand name in many instances.
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