Fluticasone Propionate HFA

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Oropharyngeal candidiasis infection [see Warnings and Precautions ( 5.1 )] • Immunosuppression and risk of infections [see Warnings and Precautions ( 5.3 )] • Hypercorticism and adrenal suppression [see Warnings and Precautions ( 5.5 )] • Reduction in bone mineral density [see Warnings and Precautions ( 5.7 )] • Growth effects [see Warnings and Precautions ( 5.8 )] • Glaucoma and cataracts [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence >3%) are upper respiratory tract infection or inflammation, throat irritation, sinusitis, dysphonia, candidiasis, cough, bronchitis, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The incidence of common adverse reactions in Table 1 is based upon 2 placebo-controlled U.S. clinical trials in which 812 adult and adolescent subjects (457 females and 355 males) previously treated with as-needed bronchodilators and/or ICS were treated twice daily for up to 12 weeks with 2 inhalations of fluticasone propionate HFA 44 mcg, fluticasone propionate HFA 110 mcg, fluticasone propionate HFA 220 mcg (dosages of 88, 220, or 440 mcg twice daily), or placebo. Table 1. Adverse Reactions with Fluticasone Propionate HFA with >3% Incidence and More Common than Placebo in Subjects Aged 12 Years and Older with Asthma Adverse Event Fluticasone Propionate HFA 88 mcg Twice Daily (n = 203) % Fluticasone Propionate HFA 220 mcg Twice Daily (n = 204) % Fluticasone Propionate HFA 440 mcg Twice Daily (n = 202) % Placebo (n = 203) % Ear, nose, and throat Upper respiratory tract infection 18 16 16 14 Throat irritation 8 8 10 5 Upper respiratory inflammation 2 5 5 1 Sinusitis/sinus infection 6 7 4 3 Hoarseness/dysphonia 2 3 6 <1 Gastrointestinal Candidiasis mouth/throat and non-site specific 4 2 5 <1 Lower respiratory Cough 4 6 4 5 Bronchitis 2 2 6 5 Neurological Headache 11 7 5 6 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 groups treated with fluticasone propionate HFA and were more common than in the placebo group. Less than 2% of subjects discontinued from the trials because of adverse reactions. The average duration of exposure was 73 to 76 days in the active treatment groups compared with 60 days in the placebo group. Additional Adverse Reactions Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with asthma treated with fluticasone propionate HFA compared with subjects treated with placebo include the following: rhinitis, rhinorrhea/post-nasal drip, nasal sinus disorders, laryngitis, diarrhea, viral gastrointestinal infections, dyspeptic symptoms, gastrointestinal discomfort and pain, hyposalivation, musculoskeletal pain, muscle pain, muscle stiffness/tightness/rigidity, dizziness, migraines, fever, viral infections, pain, chest symptoms, viral skin infections, muscle injuries, soft tissue injuries, urinary infections. Fluticasone propionate inhalation aerosol (440 or 880 mcg twice daily) was administered for 16 weeks to 168 subjects with asthma requiring oral corticosteroids (Trial 3). Adverse reactions not included above but reported by more than 3 subjects in either group treated with fluticasone propionate HFA and more commonly than in the placebo group included nausea and vomiting, arthralgia and articular rheumatism, and malaise and fatigue. In 2 long-term trials (26 and 52 weeks), the pattern of adverse reactions in subjects treated with fluticasone propionate HFA at dosages up to 440 mcg twice daily was similar to that observed in the 12-week trials. There were no new and/or unexpected adverse reactions with long-term treatment. Pediatric Subjects Aged 4 to 11 Years Fluticasone propionate HFA has been evaluated for safety in 56 pediatric subjects who received 88 mcg twice daily for 4 weeks. Types of adverse reactions in these pediatric subjects were generally similar to those observed in adults and adolescents. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of fluticasone propionate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone propionate or a combination of these factors. Ear, Nose, and Throat Aphonia, facial and oropharyngeal edema, and throat soreness and irritation. Endocrine and Metabolic Cushingoid features, growth velocity reduction in children/adolescents, hyperglycemia, osteoporosis, and weight gain. Eye Cataracts. Gastrointestinal Disorders Dental caries and tooth discoloration. Immune System Disorders Immediate and delayed hypersensitivity reactions, including urticaria, anaphylaxis, rash, and angioedema and bronchospasm, have been reported. Infections and Infestations Esophageal candidiasis. Psychiatry Agitation, aggression, anxiety, depression, and restlessness. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children. Respiratory Asthma exacerbation, chest tightness, cough, dyspnea, immediate and delayed bronchospasm, paradoxical bronchospasm, pneumonia, and wheeze. Skin Contusions, cutaneous hypersensitivity reactions, ecchymoses, and pruritus.

4 CONTRAINDICATIONS Fluticasone Propionate HFA is contraindicated in the following conditions: • Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required [see Warnings and Precautions ( 5.2 )] . • Hypersensitivity to any of the ingredients [see Warnings and Precautions ( 5.6 ), Adverse Reactions ( 6.2 ), Description ( 11 )] . • Primary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures. ( 4 ) • Hypersensitivity to any ingredient. ( 4 )

11 DESCRIPTION Fluticasone Propionate HFA is a pressurized metered dose inhaler for oral inhalation. The active component of Fluticasone Propionate HFA 44 mcg, Fluticasone Propionate HFA 110 mcg, and Fluticasone Propionate HFA 220 mcg 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: Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C 25 H 31 F 3 O 5 S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. Fluticasone Propionate HFA is a dark orange plastic inhaler with a peach cap containing a pressurized metered-dose aerosol canister fitted with a counter. Each canister contains a microcrystalline suspension of micronized fluticasone propionate 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 will depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. Prime Fluticasone Propionate HFA before using for the first time by releasing 4 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 spray into the air away from the face. Avoid spraying in eyes. Fluticasone propionate chemical structure

2 DOSAGE AND ADMINISTRATION • For oral inhalation only. ( 2.1 ) • Starting dosage is based on prior asthma therapy and disease severity. ( 2.2 ) • Adult and adolescent patients aged 12 years and older: 88 mcg twice daily up to a maximum dosage of 880 mcg twice daily. ( 2.2 ) • Pediatric patients aged 4 to 11 years: 88 mcg twice daily. ( 2.2 ) 2.1 Administration Information Fluticasone Propionate HFA should be administered by the orally inhaled route only. After inhalation, rinse mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis. A valved holding chamber and mask may be used to deliver Fluticasone Propionate HFA to young patients. Priming Prime Fluticasone Propionate HFA before using for the first time by releasing 4 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 spray into the air away from the face. Avoid spraying in eyes. 2.2 Recommended Dosage Adult and Adolescent Patients Aged 12 Years and Older The recommended starting dosage for patients aged 12 years and older who are not on an inhaled corticosteroid (ICS): 88 mcg (2 inhalations of 44 mcg fluticasone propionate) twice daily by oral inhalation, approximately 12 hours apart. • The maximum recommended dosage for patients aged 12 years and older is 880 mcg twice daily. Pediatric Patients Aged 4 to 11 Years The recommended dosage for patients aged 4 to 11 years: 88 mcg (2 inhalations of 44 mcg fluticasone propionate) twice daily by oral inhalation, approximately 12 hours apart. General Dosing Recommendations The starting dosage is based on previous asthma therapy and asthma severity, including consideration of patients’ current control of asthma symptoms and risk of future exacerbation. If symptoms arise between doses, an inhaled short-acting beta 2 -agonist should be used for immediate relief. 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. For other patients, and for patients who do not respond adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide additional asthma control. If a dosage regimen fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, e.g., replacing the current strength with a higher strength, initiating an ICS and long-acting beta 2 -agonist (LABA) combination product, or initiating oral corticosteroids, should be considered. After asthma stability has been achieved, titrate to the lowest effective dosage to reduce the possibility of side effects.

1 INDICATIONS AND USAGE Fluticasone Propionate HFA is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients aged 4 years and older. Limitations of Use Fluticasone Propionate HFA is not indicated for the relief of acute bronchospasm. Fluticasone Propionate HFA is an inhaled corticosteroid indicated for: • Maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients aged 4 years and older. ( 1 ) Limitations of use: Not indicated for relief of acute bronchospasm. ( 1 )

10 OVERDOSAGE Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions ( 5.5 )] .

7 DRUG INTERACTIONS Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended. May increase risk of systemic corticosteroid effects. ( 7.1 ) 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone propionate is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with Fluticasone Propionate HFA is not recommended because increased systemic corticosteroid adverse effects may occur. Ritonavir A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology ( 12.3 )] . During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Ketoconazole Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of 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 have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. 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. Trials in subjects 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. 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 trial 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 trial in 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 subjects 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 trial. 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 trial (69% of subjects later randomized to placebo and 72% to 78% of subjects later randomized to fluticasone propionate HFA). At week 16, 8 subjects (73%) on placebo compared with 14 (54%) and 13 (68%) subjects receiving fluticasone propionate HFA (440 and 880 mcg twice daily, respectively) had post-stimulation cortisol levels of <18 mcg/dL. 12.3 Pharmacokinetics Absorption Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Trials 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. 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. Elimination Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for <0.02% of the total. 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. Metabolism: The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite had less affinity (approximately 1/2,000) 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. Specific Populations Male and Female Patients: No significant difference in clearance (CL/F) of fluticasone propionate was observed. Pediatric Patients: A population pharmacokinetic analysis was performed for fluticasone propionate 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 subjects (161 males and 108 females) with asthma aged 6 months to 66 years who received treatment with fluticasone propionate HFA. Most of these subjects (n = 215) were treated with fluticasone propionate HFA 44 mcg given as 88 mcg twice daily. Fluticasone propionate HFA was delivered using an AeroChamber Plus VHC with a mask to subjects aged younger than 4 years. Data from adult subjects with asthma following fluticasone propionate HFA 110 mcg given as 220 mcg twice daily (n = 15) and following fluticasone propionate HFA 220 mcg given as 440 mcg twice daily (n = 17) at steady state were also included. Data for 22 subjects came from a single-dose crossover study of 264 mcg (6 doses of fluticasone propionate HFA 44 mcg) with and without AeroChamber Plus VHC in children with asthma aged 4 to 11 years. Stratification of exposure data following fluticasone propionate 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 3 . Table 3. Systemic Exposure to Fluticasone Propionate following Fluticasone Propionate HFA 88 mcg Twice Daily Age Valved Holding Chamber N AUC (0-τ), pg•h/mL (95% CI) C max , 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 trial with fluticasone propionate HFA 44 mcg given as 264 mcg. In this trial, use of a VHC increased systemic exposure to fluticasone propionate ( Table 4 ), possibly correcting for the inability to coordinate actuation and inhalation. Table 4. Systemic Exposure to Fluticasone Propionate following a Single Dose of Fluticasone Propionate HFA 264 mcg Age Valved Holding Chamber N AUC (0-∞) , pg•h/mL (95% CI) C max , 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 subjects 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. Patients with Hepatic and Renal Impairment: Formal pharmacokinetic studies using fluticasone propionate 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. Racial or Ethnic Groups: No significant difference in clearance (CL/F) of fluticasone propionate in Caucasian, African‑American, Asian, or Hispanic populations was observed. Drug Interaction Studies Inhibitors of Cytochrome P450 3A4: 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 trial 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 (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 trial 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 trial, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.

12.1 Mechanism of Action Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of 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 have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. 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. Trials in subjects 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.

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 trial 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 trial in 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 subjects 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 trial. 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 trial (69% of subjects later randomized to placebo and 72% to 78% of subjects later randomized to fluticasone propionate HFA). At week 16, 8 subjects (73%) on placebo compared with 14 (54%) and 13 (68%) subjects receiving fluticasone propionate HFA (440 and 880 mcg twice daily, respectively) had post-stimulation cortisol levels of <18 mcg/dL.

12.3 Pharmacokinetics Absorption Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Trials 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. 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. Elimination Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for <0.02% of the total. 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. Metabolism: The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite had less affinity (approximately 1/2,000) 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. Specific Populations Male and Female Patients: No significant difference in clearance (CL/F) of fluticasone propionate was observed. Pediatric Patients: A population pharmacokinetic analysis was performed for fluticasone propionate 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 subjects (161 males and 108 females) with asthma aged 6 months to 66 years who received treatment with fluticasone propionate HFA. Most of these subjects (n = 215) were treated with fluticasone propionate HFA 44 mcg given as 88 mcg twice daily. Fluticasone propionate HFA was delivered using an AeroChamber Plus VHC with a mask to subjects aged younger than 4 years. Data from adult subjects with asthma following fluticasone propionate HFA 110 mcg given as 220 mcg twice daily (n = 15) and following fluticasone propionate HFA 220 mcg given as 440 mcg twice daily (n = 17) at steady state were also included. Data for 22 subjects came from a single-dose crossover study of 264 mcg (6 doses of fluticasone propionate HFA 44 mcg) with and without AeroChamber Plus VHC in children with asthma aged 4 to 11 years. Stratification of exposure data following fluticasone propionate 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 3 . Table 3. Systemic Exposure to Fluticasone Propionate following Fluticasone Propionate HFA 88 mcg Twice Daily Age Valved Holding Chamber N AUC (0-τ), pg•h/mL (95% CI) C max , 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 trial with fluticasone propionate HFA 44 mcg given as 264 mcg. In this trial, use of a VHC increased systemic exposure to fluticasone propionate ( Table 4 ), possibly correcting for the inability to coordinate actuation and inhalation. Table 4. Systemic Exposure to Fluticasone Propionate following a Single Dose of Fluticasone Propionate HFA 264 mcg Age Valved Holding Chamber N AUC (0-∞) , pg•h/mL (95% CI) C max , 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 subjects 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. Patients with Hepatic and Renal Impairment: Formal pharmacokinetic studies using fluticasone propionate 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. Racial or Ethnic Groups: No significant difference in clearance (CL/F) of fluticasone propionate in Caucasian, African‑American, Asian, or Hispanic populations was observed. Drug Interaction Studies Inhibitors of Cytochrome P450 3A4: 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 trial 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 (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 trial 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 trial, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.

20230131

2

3 DOSAGE FORMS AND STRENGTHS Inhalation aerosol: dark orange plastic inhaler with a peach cap containing a pressurized metered-dose aerosol canister containing 120 metered inhalations and fitted with a counter. • 44 mcg of fluticasone propionate from the mouthpiece per actuation • 110 mcg of fluticasone propionate from the mouthpiece per actuation • 220 mcg of fluticasone propionate from the mouthpiece per actuation Inhalation aerosol: • 44 mcg fluticasone propionate per actuation. ( 3 ) • 110 mcg fluticasone propionate per actuation. ( 3 ) • 220 mcg fluticasone propionate per actuation. ( 3 )

Fluticasone Propionate HFA fluticasone propionate FLUTICASONE PROPIONATE FLUTICASONE NORFLURANE

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 3 and 10 times the MRHDID for adults and children aged 4 to 11 years, respectively, on a mcg/m 2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 0.3 times and approximately equivalent to the MRHDID for adults and children aged 4 to 11 years, respectively, on a mcg/m 2 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. Fertility and reproductive performance were unaffected in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 0.3 times the MRHDID for adults on a mcg/m 2 basis).

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 3 and 10 times the MRHDID for adults and children aged 4 to 11 years, respectively, on a mcg/m 2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 0.3 times and approximately equivalent to the MRHDID for adults and children aged 4 to 11 years, respectively, on a mcg/m 2 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. Fertility and reproductive performance were unaffected in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 0.3 times the MRHDID for adults on a mcg/m 2 basis).

NDA021433

Fluticasone Propionate HFA

fluticasone propionate

53002-2294

HUMAN PRESCRIPTION DRUG

RESPIRATORY (INHALATION)

FLUTICASONE PROPIONATE HFA (FLUTICASONE PROPIONATE) AEROSOL, METERED Label Image

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Oropharyngeal Candidiasis Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with Fluticasone Propionate HFA, but at times therapy with Fluticasone Propionate HFA may need to be temporarily interrupted under close medical supervision. Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush. [See Warnings and Precautions (5.1).] Status Asthmaticus and Acute Asthma Symptoms Inform patients that Fluticasone Propionate HFA is not a bronchodilator and is not intended for use as rescue medicine for acute asthma exacerbations. Advise patients to treat acute asthma symptoms with an inhaled, short-acting beta 2 -agonist such as albuterol. Instruct patients to contact their physicians immediately if there is deterioration of their asthma. [See Warnings and Precautions (5.2).] Immunosuppression and Risk of Infections Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. [See Warnings and Precautions (5.3).] Hypercorticism and Adrenal Suppression Advise patients that Fluticasone Propionate HFA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, inform patients 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 Fluticasone Propionate HFA. [See Warnings and Precautions (5.5).] Hypersensitivity Reactions, including Anaphylaxis Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of Fluticasone Propionate HFA. Patients should discontinue Fluticasone Propionate HFA if such reactions occur. [See Warnings and Precautions (5.6).] Reduction in Bone Mineral Density Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk. [See Warnings and Precautions (5.7).] Reduced Growth Velocity Inform patients that orally inhaled corticosteroids, including Fluticasone Propionate 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. [See Warnings and Precautions (5.8).] Glaucoma and Cataracts Advise patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations. [See Warnings and Precautions (5.9).] Use Daily for Best Effect Patients should use Fluticasone Propionate 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. Instruct patients not to stop use of Fluticasone Propionate HFA abruptly. Patients should contact their physicians immediately if they discontinue use of Fluticasone Propionate HFA. Trademarks are owned by or licensed to the GSK group of companies. The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the GSK group of companies. The makers of these brands are not affiliated with and do not endorse the GSK group of companies or its products. Manufactured for: Prasco Laboratories Mason, OH 45040 USA Manufactured by: GlaxoSmithKline Research Triangle Park, NC 27709 FLH-PS:3PI

INSTRUCTIONS FOR USE Fluticasone Propionate HFA inhalation aerosol for oral inhalation use Your Fluticasone Propionate HFA inhaler Figure A • The metal canister holds the medicine. See Figure A. • The metal 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 dark orange plastic actuator. See Figure A. • 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 . • Do not 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 metal canister. • The dark orange plastic actuator sprays the medicine from the metal canister. The plastic actuator has a peach protective cap that covers the mouthpiece. See Figure A. Keep the protective cap on the mouthpiece when the metal canister is not in use. • Do not use the plastic actuator with a canister of medicine from any other inhaler. • Do not use a Fluticasone Propionate HFA metal canister with an actuator from any other inhaler. Before using your Fluticasone Propionate HFA inhaler • The inhaler should be at room temperature before you use it. • 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. Priming your Fluticasone Propionate HFA inhaler Figure B Figure C Figure D Before you use Fluticasone Propionate HFA for the first time, you must prime the inhaler so that you will get the right amount of medicine when you use it. 1. To take the cap off the mouthpiece, squeeze the sides of the cap and pull it straight out. See Figure B. 2. Shake the inhaler well for 5 seconds. 3. Spray the inhaler 1 time into the air away from your face. Avoid spraying in eyes. See Figure C. 4. Shake and spray the inhaler like this 3 more times to finish priming it. The counter should now read 120 . See Figure D. 5. You must prime your inhaler again if you have not used it in more than 7 days or if you have dropped it. To take the cap off the mouthpiece, squeeze the sides of the cap and pull it straight out. Shake the inhaler well for 5 seconds. Then spray it 1 time into the air away from your face. How to use your Fluticasone Propionate HFA inhaler Follow these steps every time you use Fluticasone Propionate HFA. Figure E Figure F Figure G Figure H Step 1. Make sure the metal canister fits firmly in the plastic actuator. The counter should show through the window in the plastic actuator. To take the cap off the mouthpiece, squeeze the sides of the cap and pull out it straight out. Look inside the mouthpiece for foreign objects and take out any you see. Step 2. Hold the inhaler with the mouthpiece down and shake it well for 5 seconds . See Figure E. Step 3. Breathe out through your mouth and push as much air from your lungs as you can. See Figure F. Step 4. Put the mouthpiece in your mouth and close your lips around it. Push the top of the metal canister firmly all the way down while you breathe in deeply and slowly through your mouth. See Figure G. Step 5. After the spray comes out, take your finger off the metal canister. After you have breathed in all the way, take the inhaler out of your mouth and close your mouth. Step 6. Hold your breath for about 10 seconds, or for as long as is comfortable. Breathe out slowly as long as you can. Wait about 30 seconds and shake the inhaler well for 5 seconds. Repeat Step 2 through Step 6. Step 7. Rinse your mouth with water after breathing in the medicine. Spit out the water. Do not swallow it. See Figure H. Step 8. Put the cap back on the mouthpiece after you finish using the inhaler. Make sure it snaps firmly into place. Cleaning your Fluticasone Propionate HFA inhaler Figure I Figure J Clean your inhaler at least 1 time each week after your evening dose. You may not see any medicine build-up on the inhaler, but it is important to keep it clean so medicine build-up will not block the spray. See Figure I. Step 9. Take the cap off the mouthpiece by squeezing the sides of the cap and pulling it straight out. Do not take the metal canister out of the plastic actuator. Step 10. Use a clean cotton swab dampened with water to clean the small circular opening where the medicine sprays out of the metal canister. Gently twist the swab in a circular motion to take off any medicine. See Figure J. Repeat with a new swab dampened with water to take off any medicine still at the opening. Step 11. Wipe the inside of the mouthpiece with a clean tissue dampened with water. Let the plastic actuator air-dry overnight. Step 12. Put the cap back on the mouthpiece after the plastic actuator has dried. Replacing your Fluticasone Propionate HFA inhaler • When the counter reads 020 , you should refill your prescription or ask your healthcare provider if you need another prescription for Fluticasone Propionate HFA. • When the counter reads 000, throw the inhaler away. You should not keep using the inhaler when the counter reads 000 because you may not receive the right amount of medicine. • Do not use the inhaler after the expiration date, which is on the packaging it comes in. For correct use of your Fluticasone Propionate HFA inhaler, remember: • The metal canister should always fit firmly in the plastic actuator. • Shake the inhaler well for 5 seconds before each spray. • Breathe in deeply and slowly to make sure you get all the medicine. • Hold your breath for about 10 seconds after breathing in the medicine. Then breathe out fully. • After each dose, rinse your mouth with water and spit it out. Do not swallow the water. • Do not take the inhaler apart. • Always keep the protective cap on the mouthpiece when your inhaler is not in use. • Always store your inhaler with the mouthpiece pointing down. • Clean your inhaler at least 1 time each week. For more information about Fluticasone Propionate HFA, call 1-866-525-0688. Trademarks are owned by or licensed to the GSK group of companies. Manufactured for: Prasco Laboratories Mason, OH 45040 USA Manufactured by: GlaxoSmithKline Research Triangle Park, NC 27709 FLH-PS:4IFU This Instructions for Use has been approved by the U.S. Food and Drug Administration Revised: November 2021 Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J

14 CLINICAL STUDIES 14.1 Adult and Adolescent Subjects Aged 12 Years and Older Three randomized, double-blind, parallel-group, placebo-controlled, U.S. clinical trials were conducted in 980 adult and adolescent subjects (aged 12 years and older) with asthma to assess the efficacy and safety of fluticasone propionate 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. Subjects in these trials included those inadequately controlled with bronchodilators alone (Trial 1), those already receiving ICS (Trial 2), and those requiring oral corticosteroid therapy (Trial 3). In all 3 trials, subjects were allowed to use VENTOLIN (albuterol, USP) Inhalation Aerosol as needed for relief of acute asthma symptoms. In Trials 1 and 2, other maintenance asthma therapies were discontinued. Trial 1 enrolled 397 subjects with asthma inadequately controlled on bronchodilators alone. Fluticasone propionate HFA was evaluated at dosages of 88, 220, and 440 mcg twice daily for 12 weeks. Baseline FEV 1 values were similar across groups (mean 67% of predicted normal). All 3 dosages of fluticasone propionate HFA demonstrated a statistically significant improvement in lung function as measured by improvement in AM pre-dose FEV 1 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 FEV 1 was greater in all 3 groups treated with fluticasone propionate HFA (9.0% to 11.2%) compared with the placebo group (3.4%). The mean differences between the groups treated with fluticasone propionate 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 FEV 1 prior to AM dose) for the recommended starting dosage of fluticasone propionate HFA (88 mcg twice daily) and placebo from Trial 1. This trial used predetermined criteria for lack of efficacy (indicators of worsening asthma), resulting in withdrawal of more subjects in the placebo group. Therefore, pulmonary function results at Endpoint (the last evaluable FEV 1 result, including most subjects’ lung function data) are also displayed. Figure 1. A 12-Week Clinical Trial in Subjects Aged 12 Years and Older Inadequately Controlled on Bronchodilators Alone: Mean Percent Change from Baseline in FEV 1 Prior to AM Dose (Trial 1) In Trial 2, fluticasone propionate HFA at dosages of 88, 220, and 440 mcg twice daily was evaluated over 12 weeks of treatment in 415 subjects with asthma who were already receiving an ICS at a daily dose within its recommended dose range in addition to as-needed albuterol. Baseline FEV 1 values were similar across groups (mean 65% to 66% of predicted normal). All 3 dosages of fluticasone propionate HFA demonstrated a statistically significant improvement in lung function, as measured by improvement in FEV 1 , 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 trial for lack of efficacy (defined by a pre-specified decrease in FEV 1 or PEF, or an increase in use of VENTOLIN or nighttime awakenings requiring treatment with VENTOLIN) were lower in the groups treated with fluticasone propionate HFA (6% to 11%) compared with placebo (50%). At Endpoint (last observation), mean change from baseline in AM pre-dose percent predicted FEV 1 was greater in all 3 groups treated with fluticasone propionate HFA (2.2% to 4.6%) compared with the placebo group (-8.3%). The mean differences between the groups treated with fluticasone propionate 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 FEV 1 from Week 1 through Week 12. This trial also used predetermined criteria for lack of efficacy, resulting in withdrawal of more subjects in the placebo group; therefore, pulmonary function results at Endpoint are also displayed. Figure 2. A 12-Week Clinical Trial in Subjects Aged 12 Years and Older Already Receiving Daily Inhaled Corticosteroids: Mean Percent Change from Baseline in FEV 1 Prior to AM Dose (Trial 2) In both trials, use of VENTOLIN, AM and PM PEF, and asthma symptom scores showed numerical improvement with fluticasone propionate HFA compared with placebo. Trial 3 enrolled 168 subjects with asthma requiring oral prednisone therapy (average baseline daily prednisone dose ranged from 13 to 14 mg). Fluticasone propionate HFA at dosages of 440 and 880 mcg twice daily was evaluated over a 16-week treatment period. Baseline FEV 1 values were similar across groups (mean 59% to 62% of predicted normal). Over the course of the trial, subjects treated with either dosage of fluticasone propionate HFA required a statistically significantly lower mean daily oral prednisone dose (6 mg) compared with placebo-treated subjects (15 mg). Both dosages of fluticasone propionate HFA enabled a larger percentage of subjects (59% and 56% in the groups treated with fluticasone propionate 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 fluticasone propionate HFA 880 mcg twice daily compared with 440 mcg twice daily. Accompanying the reduction in oral corticosteroid use, subjects treated with either dosage of fluticasone propionate HFA had statistically significantly improved lung function, fewer asthma symptoms, and less use of VENTOLIN Inhalation Aerosol compared with the placebo-treated subjects. Figure 3. A 16-Week Clinical Trial in Subjects Aged 12 Years and Older Requiring Chronic Oral Prednisone Therapy: Change in Maintenance Prednisone Dose Two long-term safety trials (Trial 4 and Trial 5) of ≥6 months’ duration were conducted in 507 adult and adolescent subjects with asthma. Trial 4 was designed to monitor the safety of 2 doses of fluticasone propionate HFA, while Trial 5 compared fluticasone propionate HFA with fluticasone propionate CFC. Trial 4 enrolled 182 subjects who were treated daily with low to high doses of ICS, 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. Fluticasone propionate HFA at dosages of 220 and 440 mcg twice daily was evaluated over a 26-week treatment period in 89 and 93 subjects, respectively. Trial 5 enrolled 325 subjects who were treated daily with moderate to high doses of ICS, 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 subjects, respectively. Baseline FEV 1 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 trials, none of the subjects were withdrawn due to lack of efficacy. Figure 1. A 12-Week Clinical Trial in Subjects Aged 12 Years and Older Inadequately Controlled on Bronchodilators Alone: Mean Percent Change from Baseline in FEV1 Prior to AM Dose (Trial 1) Figure 2. A 12-Week Clinical Trial in Subjects Aged 12 Years and Older Already Receiving Daily Inhaled Corticosteroids: Mean Percent Change from Baseline in FEV1 Prior to AM Dose (Trial 2) Figure 3. A 16-Week Clinical Trial in Subjects Aged 12 Years and Older Requiring Chronic Oral Prednisone Therapy: Change in Maintenance Prednisone Dose 14.2 Pediatric Subjects Aged 4 to 11 Years A 12-week clinical trial conducted in 241 pediatric subjects with asthma was supportive of efficacy but inconclusive due to measurable levels of fluticasone propionate in 6/48 (13%) of the plasma samples from subjects randomized to placebo. Efficacy in subjects aged 4 to 11 years is extrapolated from adult data with fluticasone propionate HFA and other supporting data [see Use in Specific Populations ( 8.4 )] .

8.5 Geriatric Use Of the total number of subjects treated with fluticasone propionate HFA in U.S. and non-U.S. clinical trials, 173 were aged 65 years or older, 19 of which were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

8.4 Pediatric Use The safety and effectiveness of fluticasone propionate HFA in pediatric patients aged 4 years and older have been established [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.2 )] . Use of fluticasone propionate HFA in patients aged 4 to 11 years is supported by evidence from adequate and well-controlled trials in adults and adolescents aged 12 years and older, pharmacokinetic trials in patients aged 4 to 11 years, established efficacy of fluticasone propionate formulated as FLOVENT DISKUS (fluticasone propionate inhalation powder) and FLOVENT ROTADISK (fluticasone propionate inhalation powder) in patients aged 4 to 11 years, and supportive findings with fluticasone propionate HFA in a trial conducted in subjects aged 4 to 11 years. The safety and effectiveness of fluticasone propionate HFA in pediatric patients younger than 4 years have not been established. Effects on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids including ICS. The effects of long-term treatment of children and adolescents with ICS, including fluticasone propionate, on final adult height are not known. Controlled clinical trials have shown that ICS may cause a reduction in growth in pediatric patients. In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appeared to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown. The growth of children and adolescents receiving orally inhaled corticosteroids, including Fluticasone Propionate HFA, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including Fluticasone Propionate HFA, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. Since a cross trial comparison in adult and adolescent subjects (aged 12 years and older) indicated that systemic exposure of inhaled fluticasone propionate from fluticasone propionate HFA would be higher than exposure from FLOVENT ROTADISK, results from a trial to assess the potential growth effects of FLOVENT ROTADISK in pediatric subjects (aged 4 to 11 years) are provided. A 52-week placebo-controlled trial to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT ROTADISK) at 50 and 100 mcg twice daily was conducted in the U.S. in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years. 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-mcg group (n = 98), and 5.66 cm/year in the 100-mcg 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 trial revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg group (n = 79). In children aged 8.5 years, the mean age of children in this trial, 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 clinical relevance of these growth data is not certain. Pediatric Patients Younger than 4 Years Pharmacokinetics: [see Clinical Pharmacology ( 12.3 )] . Pharmacodynamics: A 12-week, double-blind, placebo-controlled, parallel-group trial was conducted in children with asthma aged 1 to younger than 4 years. Twelve-hour overnight urinary cortisol excretion after a 12-week treatment period with 88 mcg of fluticasone propionate HFA twice daily (n = 73) and with placebo (n = 42) were calculated. The mean and median change from baseline in urine cortisol over 12 hours were -0.7 and 0.0 mcg for fluticasone propionate HFA and 0.3 and -0.2 mcg for placebo, respectively. In a 1-way crossover trial in children aged 6 to younger than 12 months with reactive airways disease (N = 21), serum cortisol was measured over a 12-hour dosing period. Subjects received placebo treatment for a 2-week period followed by a 4-week treatment period with 88 mcg of fluticasone propionate HFA twice daily with an AeroChamber Plus Valved Holding Chamber (VHC) with mask. The geometric mean ratio of serum cortisol over 12 hours [AUC (0-12 h) ] following fluticasone propionate HFA (n = 16) versus placebo (n = 18) was 0.95 (95% CI: 0.72, 1.27). Safety: Fluticasone propionate HFA administered as 88 mcg twice daily was evaluated for safety in 239 pediatric subjects aged 1 to younger than 4 years in a 12-week, double-blind, placebo-controlled trial. Treatments were administered with an AeroChamber Plus VHC with mask. The following events occurred with a frequency >3% and more frequently in subjects receiving fluticasone propionate HFA than in subjects receiving placebo, regardless of causality assessment: pyrexia, nasopharyngitis, upper respiratory tract infection, vomiting, otitis media, diarrhea, bronchitis, pharyngitis, and viral infection. Fluticasone propionate HFA administered as 88 mcg twice daily was evaluated for safety in 23 pediatric subjects aged 6 to 12 months in an open-label placebo-controlled trial. Treatments were administered with an AeroChamber Plus VHC with mask for 2 weeks with placebo followed by 4 weeks with active drug. There was no discernable difference in the types of adverse events reported between subjects receiving placebo compared with the active drug. In Vitro Testing of Dose Delivery with Holding Chambers: In vitro dose characterization studies were performed to evaluate the delivery of fluticasone propionate HFA via holding chambers with attached masks. The studies were conducted with 2 different holding chambers (AeroChamber Plus VHC and AeroChamber Z-STAT Plus VHC) with masks (small and medium size) at inspiratory flow rates of 4.9, 8.0, and 12.0 L/min in combination with holding times of 0, 2, 5, and 10 seconds. The flow rates were selected to be representative of inspiratory flow rates of children aged 6 to 12 months, 2 to 5 years, and over 5 years, respectively. The mean delivered dose of fluticasone propionate through the holding chambers with masks was lower than the 44 mcg of fluticasone propionate delivered directly from the actuator mouthpiece. The results were similar through both holding chambers (see Table 2 for data for the AeroChamber Plus VHC). The fine particle fraction (approximately 1 to 5 μm) across the flow rates used in these studies was 70% to 84% of the delivered dose, consistent with the removal of the coarser fraction by the holding chamber. In contrast, the fine particle fraction for fluticasone propionate HFA delivered without a holding chamber typically represents 42% to 55% of the delivered dose measured at the standard flow rate of 28.3 L/min. These data suggest that, on a per kilogram basis, young children receive a comparable dose of fluticasone propionate when delivered via a holding chamber and mask as adults do without their use. Table 2. In Vitro Medication Delivery through AeroChamber Plus Valved Holding Chamber with a Mask a Centers for Disease Control growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). Ranges correspond to the average of the 50 th percentile weight for boys and girls at the ages indicated. b A single inhalation of fluticasone propionate HFA in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 44 mcg, or 0.6 mcg/kg. Age Mask Flow Rate (L/min) Holding Time (seconds) Mean Medication Delivery through AeroChamber Plus VHC (mcg/actuation) Body Weight 50 th Percentile (kg) a Medication Delivered per Actuation (mcg/kg) b 6 to 12 Months Small 4.9 0 2 5 10 8.3 6.7 7.5 7.5 7.5-9.9 0.8-1.1 0.7-0.9 0.8-1.0 0.8-1.0 2 to 5 Years Small 8.0 0 2 5 10 7.3 6.8 6.7 7.7 12.3-18.0 0.4-0.6 0.4-0.6 0.4-0.5 0.4-0.6 2 to 5 Years Medium 8.0 0 2 5 10 7.8 7.7 8.1 9.0 12.3-18.0 0.4-0.6 0.4-0.6 0.5-0.7 0.5-0.7 >5 Years Medium 12.0 0 2 5 10 12.3 11.8 12.0 10.1 18.0 0.7 0.7 0.7 0.6

8.1 Pregnancy Risk Summary There are insufficient data on the use of fluticasone propionate HFA in pregnant women. There are clinical considerations with the use of fluticasone propionate HFA in pregnant women. (See Clinical Considerations.) In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight, and/or skeletal variations in rats, mice, and rabbits, was observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m 2 basis. (See Data.) However, fluticasone propionate administered via inhalation to rats decreased fetal body weight but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m 2 basis. (See Data.) Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. The estimated risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Data Human Data: Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery. Animal Data: In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species. Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 0.5 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). The rat no observed adverse effect level (NOAEL) was observed at approximately 0.17 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 30 mcg/kg/day). Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.1 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). The mouse NOAEL was observed with a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 15 mcg/kg/day). In an embryofetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.14 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity. The NOAEL was observed with a dose approximately 0.03 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 5.5 mcg/kg/day). In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.006 times the MRHDID and higher (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day). Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). The NOAEL was observed in rabbit fetuses with a dose approximately 0.001 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day). Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits. In a pre- and post-natal development study in pregnant rats dosed from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 0.3 times the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).

8 USE IN SPECIFIC POPULATIONS Hepatic impairment: Monitor patients for signs of increased drug exposure. ( 8.6 ) 8.1 Pregnancy Risk Summary There are insufficient data on the use of fluticasone propionate HFA in pregnant women. There are clinical considerations with the use of fluticasone propionate HFA in pregnant women. (See Clinical Considerations.) In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight, and/or skeletal variations in rats, mice, and rabbits, was observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m 2 basis. (See Data.) However, fluticasone propionate administered via inhalation to rats decreased fetal body weight but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m 2 basis. (See Data.) Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. The estimated risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Data Human Data: Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery. Animal Data: In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species. Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 0.5 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). The rat no observed adverse effect level (NOAEL) was observed at approximately 0.17 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 30 mcg/kg/day). Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.1 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). The mouse NOAEL was observed with a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 15 mcg/kg/day). In an embryofetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.14 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity. The NOAEL was observed with a dose approximately 0.03 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 5.5 mcg/kg/day). In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.006 times the MRHDID and higher (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day). Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). The NOAEL was observed in rabbit fetuses with a dose approximately 0.001 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day). Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits. In a pre- and post-natal development study in pregnant rats dosed from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 0.3 times the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses up to 50 mcg/kg/day). 8.2 Lactation Risk Summary There are no available data on the presence of fluticasone propionate in human milk, the effects on the breastfed child, or the effects on milk production. Other corticosteroids have been detected in human milk. However, fluticasone propionate concentrations in plasma after inhaled therapeutic doses are low and therefore concentrations in human breast milk are likely to be correspondingly low [see Clinical Pharmacology ( 12.3 )] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fluticasone propionate HFA and any potential adverse effects on the breastfed child from fluticasone propionate HFA or from the underlying maternal condition. Data Animal Data: Subcutaneous administration of tritiated fluticasone propionate at a dose of 10 mcg/kg/day to lactating rats resulted in measurable levels in milk. 8.4 Pediatric Use The safety and effectiveness of fluticasone propionate HFA in pediatric patients aged 4 years and older have been established [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.2 )] . Use of fluticasone propionate HFA in patients aged 4 to 11 years is supported by evidence from adequate and well-controlled trials in adults and adolescents aged 12 years and older, pharmacokinetic trials in patients aged 4 to 11 years, established efficacy of fluticasone propionate formulated as FLOVENT DISKUS (fluticasone propionate inhalation powder) and FLOVENT ROTADISK (fluticasone propionate inhalation powder) in patients aged 4 to 11 years, and supportive findings with fluticasone propionate HFA in a trial conducted in subjects aged 4 to 11 years. The safety and effectiveness of fluticasone propionate HFA in pediatric patients younger than 4 years have not been established. Effects on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids including ICS. The effects of long-term treatment of children and adolescents with ICS, including fluticasone propionate, on final adult height are not known. Controlled clinical trials have shown that ICS may cause a reduction in growth in pediatric patients. In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appeared to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown. The growth of children and adolescents receiving orally inhaled corticosteroids, including Fluticasone Propionate HFA, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including Fluticasone Propionate HFA, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. Since a cross trial comparison in adult and adolescent subjects (aged 12 years and older) indicated that systemic exposure of inhaled fluticasone propionate from fluticasone propionate HFA would be higher than exposure from FLOVENT ROTADISK, results from a trial to assess the potential growth effects of FLOVENT ROTADISK in pediatric subjects (aged 4 to 11 years) are provided. A 52-week placebo-controlled trial to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT ROTADISK) at 50 and 100 mcg twice daily was conducted in the U.S. in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years. 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-mcg group (n = 98), and 5.66 cm/year in the 100-mcg 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 trial revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg group (n = 79). In children aged 8.5 years, the mean age of children in this trial, 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 clinical relevance of these growth data is not certain. Pediatric Patients Younger than 4 Years Pharmacokinetics: [see Clinical Pharmacology ( 12.3 )] . Pharmacodynamics: A 12-week, double-blind, placebo-controlled, parallel-group trial was conducted in children with asthma aged 1 to younger than 4 years. Twelve-hour overnight urinary cortisol excretion after a 12-week treatment period with 88 mcg of fluticasone propionate HFA twice daily (n = 73) and with placebo (n = 42) were calculated. The mean and median change from baseline in urine cortisol over 12 hours were -0.7 and 0.0 mcg for fluticasone propionate HFA and 0.3 and -0.2 mcg for placebo, respectively. In a 1-way crossover trial in children aged 6 to younger than 12 months with reactive airways disease (N = 21), serum cortisol was measured over a 12-hour dosing period. Subjects received placebo treatment for a 2-week period followed by a 4-week treatment period with 88 mcg of fluticasone propionate HFA twice daily with an AeroChamber Plus Valved Holding Chamber (VHC) with mask. The geometric mean ratio of serum cortisol over 12 hours [AUC (0-12 h) ] following fluticasone propionate HFA (n = 16) versus placebo (n = 18) was 0.95 (95% CI: 0.72, 1.27). Safety: Fluticasone propionate HFA administered as 88 mcg twice daily was evaluated for safety in 239 pediatric subjects aged 1 to younger than 4 years in a 12-week, double-blind, placebo-controlled trial. Treatments were administered with an AeroChamber Plus VHC with mask. The following events occurred with a frequency >3% and more frequently in subjects receiving fluticasone propionate HFA than in subjects receiving placebo, regardless of causality assessment: pyrexia, nasopharyngitis, upper respiratory tract infection, vomiting, otitis media, diarrhea, bronchitis, pharyngitis, and viral infection. Fluticasone propionate HFA administered as 88 mcg twice daily was evaluated for safety in 23 pediatric subjects aged 6 to 12 months in an open-label placebo-controlled trial. Treatments were administered with an AeroChamber Plus VHC with mask for 2 weeks with placebo followed by 4 weeks with active drug. There was no discernable difference in the types of adverse events reported between subjects receiving placebo compared with the active drug. In Vitro Testing of Dose Delivery with Holding Chambers: In vitro dose characterization studies were performed to evaluate the delivery of fluticasone propionate HFA via holding chambers with attached masks. The studies were conducted with 2 different holding chambers (AeroChamber Plus VHC and AeroChamber Z-STAT Plus VHC) with masks (small and medium size) at inspiratory flow rates of 4.9, 8.0, and 12.0 L/min in combination with holding times of 0, 2, 5, and 10 seconds. The flow rates were selected to be representative of inspiratory flow rates of children aged 6 to 12 months, 2 to 5 years, and over 5 years, respectively. The mean delivered dose of fluticasone propionate through the holding chambers with masks was lower than the 44 mcg of fluticasone propionate delivered directly from the actuator mouthpiece. The results were similar through both holding chambers (see Table 2 for data for the AeroChamber Plus VHC). The fine particle fraction (approximately 1 to 5 μm) across the flow rates used in these studies was 70% to 84% of the delivered dose, consistent with the removal of the coarser fraction by the holding chamber. In contrast, the fine particle fraction for fluticasone propionate HFA delivered without a holding chamber typically represents 42% to 55% of the delivered dose measured at the standard flow rate of 28.3 L/min. These data suggest that, on a per kilogram basis, young children receive a comparable dose of fluticasone propionate when delivered via a holding chamber and mask as adults do without their use. Table 2. In Vitro Medication Delivery through AeroChamber Plus Valved Holding Chamber with a Mask a Centers for Disease Control growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). Ranges correspond to the average of the 50 th percentile weight for boys and girls at the ages indicated. b A single inhalation of fluticasone propionate HFA in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 44 mcg, or 0.6 mcg/kg. Age Mask Flow Rate (L/min) Holding Time (seconds) Mean Medication Delivery through AeroChamber Plus VHC (mcg/actuation) Body Weight 50 th Percentile (kg) a Medication Delivered per Actuation (mcg/kg) b 6 to 12 Months Small 4.9 0 2 5 10 8.3 6.7 7.5 7.5 7.5-9.9 0.8-1.1 0.7-0.9 0.8-1.0 0.8-1.0 2 to 5 Years Small 8.0 0 2 5 10 7.3 6.8 6.7 7.7 12.3-18.0 0.4-0.6 0.4-0.6 0.4-0.5 0.4-0.6 2 to 5 Years Medium 8.0 0 2 5 10 7.8 7.7 8.1 9.0 12.3-18.0 0.4-0.6 0.4-0.6 0.5-0.7 0.5-0.7 >5 Years Medium 12.0 0 2 5 10 12.3 11.8 12.0 10.1 18.0 0.7 0.7 0.7 0.6 8.5 Geriatric Use Of the total number of subjects treated with fluticasone propionate HFA in U.S. and non-U.S. clinical trials, 173 were aged 65 years or older, 19 of which were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment Formal pharmacokinetic studies using fluticasone propionate HFA have not been conducted in patients with 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. 8.7 Renal Impairment Formal pharmacokinetic studies using fluticasone propionate HFA have not been conducted in patients with renal impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING Product: 53002-2294 NDC: 53002-2294-1 120 AEROSOL, METERED in a INHALER / 1 in a CARTON