FLOVENT HFA (fluticasone propionate HFA) Inhalation Aerosol

PRESCRIBING INFORMATION 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 FLOVENT® HFA 44 mcg (fluticasone propionate HFA 44 mcg) Inhalation Aerosol FLOVENT® HFA 110 mcg (fluticasone propionate HFA 110 mcg) Inhalation Aerosol FLOVENT® HFA 220 mcg (fluticasone propionate HFA 220 mcg) Inhalation Aerosol For Oral Inhalation Only DESCRIPTION The active component of FLOVENT HFA 44 mcg Inhalation Aerosol, FLOVENT HFA 110 mcg Inhalation Aerosol, and FLOVENT HFA 220 mcg Inhalation Aerosol is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9-difluoro-11β,17- dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure: 22 23 24 25 26 27 28 29 30 31 32 33 Fluticasone propionate is a white to off-white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. FLOVENT HFA 44 mcg Inhalation Aerosol, FLOVENT HFA 110 mcg Inhalation Aerosol, and FLOVENT HFA 220 mcg Inhalation Aerosol are pressurized, metered-dose aerosol units 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 1 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 110- and 220-mcg products) from the valve and 44, 110, or 220 mcg, respectively, 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 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 and releasing 1 test spray into the air away from the face. This product does not contain any chlorofluorocarbon (CFC) as the propellant. CLINICAL PHARMACOLOGY 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 corticosteroid 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, 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 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 (<1%), and the minimal pharmacological activity of the only metabolite detected in man. Preclinical: 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 area under the plasma concentration versus time curve [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. 2 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 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 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. 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 (<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. Systemic exposure as measured by AUC in healthy subjects (N = 24) who received 8 inhalations, as a single dose, of fluticasone propionate HFA using the 44-, 110-, and 220-mcg strengths increased proportionally with dose. The geometric means (95% CI) of AUC0-24 hr for the 44-, 110-, and 220-mcg strengths were 488 (362, 657); 1,284 (904; 1,822); and 2,495 (1,945; 3,200) pg•hr/mL, respectively, and the geometric means of Cmax were 126 (108, 148), 254 (202, 319), and 421 (338, 524) pg/mL, respectively. Systemic exposure from fluticasone propionate HFA 220 mcg was 30% lower than that from the CFC-propelled fluticasone propionate inhaler. Systemic exposure was measured in subjects with asthma who received 2 inhalations of fluticasone propionate HFA 44 mcg (n = 20), 110 mcg (n = 15), or 220 mcg (n = 17) twice daily for at least 4 weeks. The geometric means (95% CI) of AUC0-12 hr for the 44-, 110-, and 220-mcg strengths were 76 (33, 175), 298 (191, 464), and 601 (431, 838) pg•hr/mL, respectively. Cmax occurred in about 1 hour, and the geometric means were 25 (18, 36), 61 (46, 81), and 103 (73, 145) pg/mL, respectively. Distribution: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. The percentage of fluticasone propionate bound to human plasma proteins averages 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes 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 cytochrome P450 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. 3 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 Special Populations: Hepatic Impairment: Since fluticasone propionate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be closely monitored. Pediatric: Two pharmacokinetic studies evaluated the systemic exposure to fluticasone propionate at steady state in children with asthma aged 4 to 11 years following inhalation of fluticasone propionate HFA. In an open-label, multiple-dose, 2-period crossover study, 13 children aged 4 to 11 years received 88 mcg of fluticasone propionate HFA twice daily for 7.5 days in one period and 88 mcg of CFC-propelled fluticasone propionate twice daily for 7.5 days in the other period. The geometric means (95% CI) of AUC(last) were 28 pg•hr/mL (10, 80) following fluticasone propionate HFA and 65 pg•hr/mL (27, 153) following CFC-propelled fluticasone propionate, indicating that systemic exposure was 55% lower using fluticasone propionate HFA. The geometric means (95% CI) of Cmax were 15.1 pg/mL (8.5, 27) following fluticasone propionate HFA and 20.4 pg/mL (13, 32) following CFC-propelled fluticasone propionate; indicating that Cmax was 26% lower using fluticasone propionate HFA. Tmax was similar for both treatments. AUClast and Cmax in this pediatric population were 37% and 60%, respectively, of those in adult patients receiving the same dose. In a second open-label, single-dose, 2-period crossover study, 21 children with asthma aged 5 to 11 years received 264 mcg of fluticasone propionate HFA administered with and without an AeroChamber Plus™ Valved Holding Chamber (VHC). The geometric means (95% CI) of AUClast were 261 pg•hr/mL (252, 444) with the use of the VHC and 40 pg•hr/mL (16, 208) without the VHC. The geometric means (95% CI) of Cmax were 52 pg/mL (46, 70) with the VHC and 19 pg/mL (17, 41) without the VHC. The median Tmax was 1 hour with or without the VHC. Therefore, systemic exposure was higher with the VHC in these pediatric patients with asthma. Gender: Systemic exposure for 19 male and 33 female subjects with asthma from 2 inhalations of CFC-propelled fluticasone propionate 44, 110, and 220 mcg twice daily was similar. Other: Formal pharmacokinetic studies using fluticasone propionate have not been conducted in other special populations. Drug Interactions: Fluticasone propionate is a substrate of cytochrome P450 3A4. Coadministration of fluticasone propionate and the highly potent cytochrome P450 3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (<10 pg/mL) in most subjects, and when concentrations were detectable, peak levels (Cmax) averaged 11.9 pg/mL (range, 10.8 to 14.1 pg/mL) and AUC(0-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 4 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol AUC. Caution should be exercised when other potent cytochrome P450 3A4 inhibitors are coadministered with fluticasone propionate. In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased plasma fluticasone propionate exposure and reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol. In another multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics. Similar definitive studies with fluticasone propionate HFA were not performed, but results should be independent of the formulation and drug delivery device. 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 subjects 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) concentrations (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 hypothalamic-pituitary-adrenal (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 subjects 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 <18 mcg/dL) were present at baseline in the majority of subjects 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 subjects (73%) on placebo compared to 14 (54%) and 13 (68%) subjects receiving fluticasone propionate HFA (440 and 880 mcg b.i.d., respectively) had post-stimulation cortisol levels of <18 mcg/dL. 5 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 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 fluticasone propionate powder and oral fluticasone propionate was conducted. Fluticasone propionate inhalation powder in dosages of 100 and 500 mcg twice daily was compared to oral fluticasone propionate 20,000 mcg once daily and placebo for 6 weeks. Plasma levels of fluticasone propionate were detectable in all 3 active groups, but the mean values were highest in the oral group. Both dosages 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. CLINICAL TRIALS Adolescent and Adult Patients: Three randomized, double-blind, parallel-group, placebo-controlled clinical trials were conducted in the US in 980 adolescent and adult patients (≥12 years of age) 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 significantly improved asthma control as measured by improvement in AM pre-dose FEV1 compared with placebo. Pulmonary function (AM pre-dose FEV1) improved significantly with FLOVENT HFA compared with placebo after the first week of treatment, and this improvement 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 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 6 (indicators of worsening asthma), resulting in withdrawal of more patients in the placebo group. Therefore, pulmonary function results at Endpoint (the last evaluable FEV 230 231 232 233 234 235 236 237 1 result, including most patients’ lung function data) are also displayed. Figure 1. A 12-Week Clinical Trial in Patients ≥12 Years of Age Inadequately Controlled on Bronchodilators Alone: Mean Percent Change From Baseline in FEV1 Prior to AM Dose (Study 1) 238 239 240 241 242 243