FLOVENT

Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C₂₅H₃₁F₃O₅S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

FLOVENT HFA 44 mcg Inhalation Aerosol, FLOVENT HFA 110 mcg Inhalation Aerosol, and FLOVENT HFA 220 mcg Inhalation Aerosol are pressurized metered-dose aerosol units fitted with a counter. FLOVENT HFA is intended for oral inhalation only. Each unit contains a microcrystalline suspension of fluticasone propionate (micronized) in propellant HFA-134a (1,1,1,2-tetrafluoroethane). It contains no other excipients.

After priming, each actuation of the inhaler delivers 50, 125, or 250 mcg of fluticasone propionate in 60 mg of suspension (for the 44-mcg product) or in 75 mg of suspension (for the 110- and 220-mcg products) from the valve. Each actuation delivers 44, 110, or 220 mcg of fluticasone propionate from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the device and inspiration through the delivery system.

Each 10.6-g canister (44 mcg) and each 12-g canister (110 and 220 mcg) provides 120 inhalations.

FLOVENT HFA should be primed before using for the first time by releasing 4 test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well for 5 seconds and releasing 1 test spray into the air away from the face.

This product does not contain any chlorofluorocarbon (CFC) as the propellant.

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

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 h)} (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 post-stimulation cortisol levels of less than 18 mcg/dL.

12.3 Pharmacokinetics

Absorption: 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.

Distribution: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg.

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

Metabolism: The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-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.

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

Special Populations: 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 mask to patients aged younger 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 younger than 12 months, children aged 1 to younger 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.

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.

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 AUC_0-τ in pg•h/mL was 358 (95% CI: 272, 473) and 640 (95% CI: 477, 858), and C_max 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.

Drug Interactions: 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 (C_max) averaged 11.9 pg/mL (range: 10.8 to 14.1 pg/mL) and AUC_(0-τ) averaged 8.43 pg•h/mL (range: 4.2 to 18.8 pg•h/mL). Fluticasone propionate C_max and AUC_(0-τ) increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg•h/mL (range: 1,207.1 to 5,662.0 pg•h/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•h/mL (range: 0.555 to 2.906 ng•h/mL) and AUC_(2-∞) averaged 2.269 ng•h/mL (range: 0.836 to 3.707 ng•h/mL). Fluticasone propionate AUC_(2-last) and AUC_(2-∞) increased to 2.781 ng•h/mL (range: 2.489 to 8.486 ng•h/mL) and 4.317 ng•h/mL (range: 3.256 to 9.408 ng•h/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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 2 and 10 times the MRHD for adults and children aged 4 to 11 years, respectively, on a mg/m² basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 0.3 times and approximately equivalent to the MRHD for adults and children aged 4 to 11 years, respectively, on a mg/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 in vivo mouse micronucleus test.

No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 0.2 times the MRHD for adults on a mg/m² basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg.

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology: Subcutaneous studies in mice and rats at 45 and 100 mcg/kg (approximately 0.1 and 0.5 times the MRHD for adults on a mg/m² 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 for adults on a mg/m² basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 3 times the MRHD for adults on a mg/m² basis) of fluticasone propionate. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see Clinical Pharmacology (12.3)].

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 (T_max) 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 metered-dose inhalers.

14 CLINICAL STUDIES

14.1 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.

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 pre-specified 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%, 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.

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.

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.

14.2 Pediatric Patients Aged 4 to 11 Years

A 12-week clinical trial conducted in 241 pediatric patients with asthma was supportive 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 (8.4)].

16 HOW SUPPLIED/STORAGE AND HANDLING

Flovent HFA 44 mcg Inhalation Aerosol is supplied in 10.6-g pressurized aluminum canisters containing 120 metered inhalations in boxes of 1 with patient instructions (NDC 0173-0718-20).

Flovent HFA 110 mcg Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered inhalations in boxes of 1 with patient instructions (NDC 0173-0719-20).

Flovent HFA 220 mcg Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered inhalations in boxes of 1 with patient instructions (NDC 0173-0720-20).

Each canister is fitted with a counter and a dark orange oral actuator with a peach strapcap. The dark orange actuator supplied with FLOVENT HFA should not be used with any other product canisters, and actuators from other products should not be used with a FLOVENT HFA canister.

The correct amount of medication in each inhalation cannot be assured after the counter reads 000, even though the canister is not completely empty and will continue to operate. The inhaler should be discarded when the counter reads 000.

Keep out of reach of children. Avoid spraying in eyes.

Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw into fire or incinerator.

Store at 25°C (77°F); excursions permitted from 15° to 30°C (59° to 86°F). Store the inhaler with the mouthpiece down. For best results, the inhaler should be at room temperature before use. SHAKE WELL BEFORE USING.

FLOVENT HFA does not contain CFCs as the propellant.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information and Instructions for Use).

17.1 Oral Candidiasis

Patients should be advised that localized infections with Candida albicans have occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while still continuing therapy with FLOVENT HFA, but at times therapy with FLOVENT HFA may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised.

17.2 Status Asthmaticus and Acute Asthma Symptoms

Patients should be advised that FLOVENT HFA is not a bronchodilator and is not intended for use as rescue medication for acute asthma exacerbations. Acute asthma symptoms should be treated with an inhaled, short-acting beta₂-agonist such as albuterol. Patients should be instructed to contact their physicians immediately if there is deterioration of their asthma.

17.3 Immunosuppression

Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and if they are exposed to consult their physicians without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.

17.4 Hypercorticism and Adrenal Suppression

Patients should be advised that FLOVENT HFA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to FLOVENT HFA.

17.5 Hypersensitivity Reactions, Including Anaphylaxis

Patients should be advised that hypersensitivity reactions including anaphylaxis, angioedema, urticaria, and bronchospasm may occur after administration of FLOVENT HFA. Patients should discontinue FLOVENT HFA if such reactions occur.

17.6 Reduction in Bone Mineral Density

Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk.

17.7 Reduced Growth Velocity

Patients should be informed that orally inhaled corticosteroids, including FLOVENT HFA, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route.

17.8 Ocular Effects

Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered.

17.9 Use Daily for Best Effect

Patients should use FLOVENT HFA at regular intervals as directed. Individual patients will experience a variable time to onset and degree of symptom relief and the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer. Patients should not increase the prescribed dosage but should contact their physicians if symptoms do not improve or if the condition worsens. Patients should be instructed not to stop use of FLOVENT HFA abruptly. Patients should contact their physicians immediately if they discontinue use of FLOVENT HFA.

DISKUS, FLOVENT, ROTADISK, and VENTOLIN are registered trademarks of the GSK group of companies. The other brands listed are trademarks of their respective owners and are not trademarks of the GSK group of companies. The makers of these brands are not affiliated with and do not endorse GlaxoSmithKline or its products.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2014, the GSK group of companies. All rights reserved.

FLH:6PI

PHARMACIST—DETACH HERE AND GIVE LEAFLET TO PATIENT

Patient Information

FLOVENT^® [flō′ vent] HFA 44 mcg

(fluticasone propionate 44 mcg)

Inhalation Aerosol

FLOVENT^® HFA 110 mcg

(fluticasone propionate 110 mcg)

Inhalation Aerosol

FLOVENT^® HFA 220 mcg

(fluticasone propionate 220 mcg)

Inhalation Aerosol

FOR ORAL INHALATION ONLY

Read this leaflet carefully before you start to use FLOVENT HFA Inhalation Aerosol.

Keep this leaflet because it has important summary information about FLOVENT HFA. This leaflet does not contain all the information about your medicine. If you have any questions or are not sure about something, you should ask your doctor or pharmacist.

Read the new leaflet that comes with each refill of your prescription because there may be new information.

What is FLOVENT HFA?

FLOVENT HFA contains a medicine called fluticasone propionate, which is a synthetic corticosteroid. Corticosteroids are natural substances found in the body that help fight inflammation. Corticosteroids are used to treat asthma because they reduce airway inflammation.

FLOVENT HFA is used to treat asthma in patients 4 years and older. When inhaled regularly, FLOVENT HFA also helps to prevent symptoms of asthma.

FLOVENT HFA comes in 3 strengths. Your doctor has prescribed the one that is best for your condition.

Who should not use FLOVENT HFA?

Do not use FLOVENT HFA if you:

• •are allergic to any of the ingredients in FLOVENT HFA or other inhaled corticosteroids. See “What are the ingredients in FLOVENT HFA?” below.
• •have an acute asthma attack or status asthmaticus. FLOVENT HFA is not a bronchodilator and should not be used to give you fast relief from your breathing problems during an asthma attack. Always use a short-acting bronchodilator (rescue medicine), such as albuterol inhaler, during a sudden asthma attack. You must take FLOVENT HFA at regular times as recommended by your doctor, and not as an emergency medicine.

What should I tell my doctor before taking FLOVENT HFA?

Tell your doctor if you:

• •have liver problems.
• •have been exposed to chickenpox or measles.
• •have any other medical conditions.
• •are pregnant or planning to become pregnant. It is not known if FLOVENT HFA will harm your unborn baby.
• •are breastfeeding a baby. It is not known if FLOVENT HFA passes into your breast milk.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. FLOVENT HFA may affect the way other medicines work, and other medicines may affect how FLOVENT HFA works. Especially, tell your doctor if you take:

• •a medicine containing ritonavir (commonly used to treat HIV infection or AIDS). The anti-HIV medicines NORVIR^® (ritonavir capsules) Soft Gelatin, NORVIR (ritonavir oral solution), and KALETRA^® (lopinavir/ritonavir) tablets contain ritonavir.
• •any other corticosteroid medicines.
• •ketoconazole (NIZORAL^®), an antifungal medicine.

How should I use FLOVENT HFA?

1. It is important that you inhale each dose as your doctor has prescribed. The prescription label provided by your pharmacist will usually tell you what dose to take and how often. If it doesn’t or if you aren’t sure, ask your doctor or pharmacist. DO NOT inhale more doses or use your FLOVENT HFA more often than your doctor has prescribed.

2. It may take 1 to 2 weeks or longer for this medicine to work, and it is very important that you use it regularly. Do not stop taking FLOVENT HFA, even if you are feeling better, unless your doctor tells you to.

3. If you miss a dose, just take your next scheduled dose when it is due. Do not double the dose.

4. Your doctor may prescribe additional medicine (such as fast-acting bronchodilators) for emergency relief if a sudden asthma attack occurs. Contact your doctor if:

• •an asthma attack does not respond to the additional medicine or
• •you need more of the additional medicine than usual.

5. If you also use another medicine by inhalation, you should ask your doctor for instructions on when to use it while you are also using FLOVENT HFA.

6. Children should use FLOVENT HFA with an adult’s help, as instructed by the child’s healthcare provider. A valved holding chamber (a kind of spacer) and mask may be used to deliver FLOVENT HFA to young patients.

What should I avoid while taking FLOVENT HFA?

If you have not had or not been vaccinated against chickenpox, measles, or active tuberculosis, you should stay away from people who are infected.

What are the possible side effects of FLOVENT HFA?

FLOVENT HFA can cause serious side effects, including:

• • fungal infections (thrush) in your mouth and throat. Tell your doctor if you have any redness or white-colored coating in your mouth.
• • decreased ability to fight infections. Symptoms of infection may include: fever, pain, aches, chills, feeling tired, nausea and vomiting. Tell your doctor about any signs of infection while you use FLOVENT HFA.
• • decreased adrenal function (adrenal insufficiency). Symptoms of decreased adrenal function include tiredness, weakness, nausea and vomiting, and low blood pressure. Decreased adrenal function can lead to death.
• • allergic reaction (anaphylaxis). Call your doctor and stop FLOVENT HFA right away if you have any symptoms of an allergic reaction:
  • •swelling of the face, throat and tongue
  • •hives
  • •rash
  • •breathing problems
• • lower bone mineral density. This may be a problem for people who already have a higher chance of low bone density (osteoporosis).
• • slow growth in children. The growth of children using FLOVENT HFA should be checked regularly.
• • eye problems including glaucoma and cataracts. Tell your doctor about any vision changes while using FLOVENT HFA. Your doctor may tell you to have your eyes checked.
• • increased wheezing (bronchospasm). Increased wheezing can happen right away after using FLOVENT HFA. Always have a rescue inhaler with you to treat sudden wheezing.

Tell your doctor right away if you have any of the serious side effects listed above or if you have worsening lung symptoms.

The most common side effects of FLOVENT HFA include:

• •a cold or upper respiratory tract infection
• •throat irritation
• •headache
• •fever
• •diarrhea
• •ear infection

Tell your doctor if you have any side effects that bother you or that do not go away. These are not all the possible side effects of FLOVENT HFA. For more information ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or 1-800-332-1088.

How should I store FLOVENT HFA?

Store FLOVENT HFA at room temperature between 59°and 86°F (15°-30°C). Store the inhaler with the mouthpiece down. For best results, the inhaler should be at room temperature before use.

Keep FLOVENT HFA and all medicines out of the reach of children.

This Patient Information leaflet summarizes the most important information about FLOVENT HFA. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or doctor for information about FLOVENT HFA that is written for health professionals. You can also contact the company that makes FLOVENT HFA (toll free) at 1-888-825-5249.

What are the ingredients in FLOVENT HFA?

Active ingredient: fluticasone propionate (micronized)

Inactive ingredient: propellant HFA-134a

Instructions for Use

The parts of your FLOVENT HFA

There are 2 main parts to your FLOVENT HFA inhaler—the metal canister that holds the medicine and the dark orange plastic actuator that sprays the medicine from the canister (see Figure 1).

The canister has a counter to show how many sprays of medicine you have left. The number shows through a window in the back of the actuator. The counter starts at 124. The number will count down by 1 each time you spray the inhaler. The counter will stop counting at 000.

Never try to change the numbers or take the counter off the metal canister. The counter cannot be reset, and it is permanently attached to the canister.

The mouthpiece of the actuator is covered by a cap. A strap on this cap keeps it attached to the actuator.

Do not use the actuator with a canister of medicine from any other inhaler. And do not use a FLOVENT HFA canister with an actuator from any other inhaler.

Using your FLOVENT HFA

• •The inhaler should be at room temperature before you use it.
• • Priming the inhaler:
  Before you use FLOVENT HFA for the first time, you must prime the inhaler so that you will get the right amount of medicine when you use it. To prime the inhaler, take the cap off the mouthpiece and shake the inhaler well for 5 seconds. Then spray the inhaler into the air away from your face. Avoid spraying in eyes. Shake and spray the inhaler like this 3 more times to finish priming it. The counter should now read 120.
  You must prime the inhaler again if you have not used it in more than 7 days or if you drop it. Take the cap off the mouthpiece and shake the inhaler well for 5 seconds. Then spray it 1 time into the air away from your face.
• •If a child needs help using the inhaler, an adult should help the child use the inhaler with or without a valved holding chamber, which may also be attached to a mask. The adult should follow the instructions that came with the valved holding chamber. An adult should watch a child use the inhaler to be sure it is used correctly.

Read the following 7 steps before using FLOVENT HFA and follow them at each use. If you have any questions, ask your doctor or pharmacist.

• 1. Take the cap off the mouthpiece of the actuator (see Figure 2).
  Look inside the mouthpiece for foreign objects, and take out any you see.
  Make sure the canister fits firmly in the actuator.
  Shake the inhaler well for 5 seconds.
• 2.Hold the inhaler with the mouthpiece down (see Figure 2). Breathe out through your mouth and push as much air from your lungs as you can. Put the mouthpiece in your mouth and close your lips around it.

• 1.Push the top of the canister all the way down while you breathe in deeply and slowly through your mouth (see Figure 3).
  Right after the spray comes out, take your finger off the canister. After you have breathed in all the way, take the inhaler out of your mouth and close your mouth.

• 1. Hold your breath as long as you can, up to 10 seconds. Then breathe normally.
• 2. Wait about 30 seconds and shake the inhaler well for 5 seconds. Repeat steps 2 through 4.
•  After you finish taking this medicine, rinse your mouth with water. Spit out the water. Do not swallow it.
• 3.Put the cap back on the mouthpiece after each time you use the inhaler. Make sure it snaps firmly into place.

Cleaning your FLOVENT HFA

Clean the inhaler at least once a week after your evening dose. It is important to keep the canister and plastic actuator clean so the medicine will not build-up and block the spray.

• 1.Take the cap off the mouthpiece. The strap on the cap will stay attached to the actuator. Do not take the canister out of the plastic actuator.
• 2.Use a clean cotton swab dampened with water to clean the small circular opening where the medicine sprays out of the canister. Gently twist the swab in a circular motion to take off any medicine (see Figure 4). Repeat with a new swab dampened with water to take off any medicine still at the opening.
• 3.Wipe the inside of the mouthpiece with a clean tissue dampened with water. Let the actuator air-dry overnight.
• 4.Put the cap back on the mouthpiece after the actuator has dried.

Replacing your FLOVENT HFA

• • When the counter reads 020, you should refill your prescription or ask your doctor if you need a refill of your prescription.
• • When the counter reads 000, throw the inhaler away. You should not keep using the inhaler because you will not receive the right amount of medicine.
• • Do not use the inhaler after the expiration date, which is on the packaging it comes in.
•  This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

FLOVENT is a registered trademark of the GSK group of companies. The other brands listed are trademarks of their respective owners and are not trademarks of the GSK group of companies. The makers of these brands are not affiliated with and do not endorse GlaxoSmithKline or its products.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2014, the GSK group of companies. All rights reserved.

May 2014

FLH:4PIL

Principal Display Panel

NDC 0173-0718-20

Flovent^® HFA 44 mcg

(fluticasone propionate 44 mcg)

Inhalation Aerosol

For oral inhalation with FLOVENT HFA actuator only.

Attention Pharmacist: Dispense with enclosed “Patient Information.”

See prescribing information for dosage information.

R_x only

With Dose Counter

Net Wt. 10.6g

120 Metered Actuations

Made in UK

©2013, GlaxoSmithKline

10000000120650 Rev. 9/13