fluticasone propionate

1 INDICATIONS AND USAGE Fluticasone Propionate DISKUS is indicated for the maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older. Important Limitation of Use Fluticasone Propionate DISKUS is NOT indicated for the relief of acute bronchospasm. Fluticasone Propionate DISKUS is an inhaled corticosteroid (ICS) indicated for: • Maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older. ( 1 ) Important limitation: • Not indicated for relief of acute bronchospasm. ( 1 )

2 DOSAGE AND ADMINISTRATION • For oral inhalation only. ( 2.1 ) • Starting dosage is based on prior asthma therapy and disease severity. ( 2.2 ) • Treatment of asthma in patients aged 12 years and older: 100 mcg twice daily up to a maximum recommended dosage of 1,000 mcg twice daily. ( 2.2 ) • Treatment of asthma in patients aged 4 to 11 years: 50 mcg twice daily up to a maximum recommended dosage of 100 mcg twice daily. ( 2.2 ) 2.1 Administration Information Fluticasone Propionate DISKUS should be administered by the orally inhaled route in patients aged 4 years and older. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis. 2.2 Recommended Dosage Adult and Adolescent Patients Aged 12 Years and Older 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. The recommended starting dosage for patients aged 12 years and older who are not on an inhaled corticosteroid (ICS) is 100 mcg twice daily, approximately 12 hours apart. 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. The maximum recommended dosage for patients aged 12 years and older is 1,000 mcg twice daily. Pediatric Patients Aged 4 to 11 Years 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. For patients aged 4 to 11 years not on an ICS, the recommended starting dosage is 50 mcg twice daily, approximately 12 hours apart. For other patients, and for patients who do not respond adequately to the starting dosage after 2 weeks of therapy, increasing the dosage to 100 mcg twice daily may provide additional asthma control. The maximum recommended dosage for patients aged 4 to 11 years is 100 mcg twice daily. General Dosing Recommendations 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. 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.

3 DOSAGE FORMS AND STRENGTHS Inhalation powder: Inhaler containing a foil blister strip of powder formulation for oral inhalation. The strip contains fluticasone propionate 50, 100, or 250 mcg per blister. Inhalation powder: Inhaler containing fluticasone propionate (50, 100, or 250 mcg) as a powder formulation for oral inhalation. ( 3 )

4 CONTRAINDICATIONS The use of Fluticasone Propionate DISKUS 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 )] • Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate [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 ) • Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate. ( 4 )

6 ADVERSE REACTIONS Systemic and local corticosteroid use may result in the following: • Candida albicans infection [see Warnings and Precautions ( 5.1 )] • Immunosuppression [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%) include upper respiratory tract infection or inflammation, throat irritation, sinusitis, rhinitis, oral candidiasis, nausea and vomiting, gastrointestinal discomfort, fever, 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 7 placebo-controlled U.S. clinical trials in which 1,176 pediatric, adolescent, and adult subjects (466 females and 710 males) previously treated with as-needed bronchodilators and/or ICS were treated twice daily for up to 12 weeks with fluticasone propionate DISKUS (doses of 50 to 500 mcg) or placebo. Table 1. Adverse Reactions with Fluticasone Propionate DISKUS with >3% Incidence and More Common than Placebo in Subjects with Asthma Adverse Event Fluticasone Propionate DISKUS 50 mcg Twice Daily (n = 178) % Fluticasone Propionate DISKUS 100 mcg Twice Daily (n = 305) % Fluticasone Propionate DISKUS 250 mcg Twice Daily (n = 86) % Fluticasone Propionate DISKUS 500 mcg Twice Daily (n = 64) % Placebo (n = 543) % Ear, nose, and throat Upper respiratory tract infection 20 18 21 14 16 Throat irritation 13 13 3 22 8 Sinusitis/sinus infection 9 10 6 6 6 Upper respiratory inflammation 5 5 0 5 3 Rhinitis 4 3 1 2 2 Oral candidiasis <1 9 6 5 7 Gastrointestinal Nausea and vomiting 8 4 1 2 4 Gastrointestinal discomfort and pain 4 3 2 2 3 Viral gastrointestinal infection 4 3 3 5 1 Non-site specific Fever 7 7 1 2 4 Viral infection 2 2 0 5 2 Lower respiratory Viral respiratory infection 4 5 1 2 4 Cough 3 5 1 5 4 Bronchitis 2 3 0 8 1 Neurological Headache 12 12 2 14 7 Musculoskeletal and trauma Muscle injury 2 0 1 5 1 Musculoskeletal pain 4 3 2 5 2 Injury 2 <1 0 5 <1 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 DISKUS 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 79 days in the active treatment groups compared with 56 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 DISKUS compared with subjects treated with placebo include the following: palpitations; soft tissue injuries; contusions and hematomas; wounds and lacerations; burns; poisoning and toxicity; pressure-induced disorders; hoarseness/dysphonia; epistaxis; ear, nose, throat, and tonsil signs and symptoms; ear, nose, and throat polyps; allergic ear, nose, and throat disorders; throat constriction; fluid disturbances; weight gain; appetite disturbances; keratitis and conjunctivitis; blepharoconjunctivitis; gastrointestinal signs and symptoms; oral ulcerations; dental discomfort and pain; oral erythema and rashes; mouth and tongue disorders; oral discomfort and pain; tooth decay; cholecyst …

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 DISKUS 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.

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 DISKUS in pregnant women. There are clinical considerations with the use of fluticasone propionate DISKUS 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 were 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 0.15 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 0.13 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 wit …

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.

11 DESCRIPTION Fluticasone Propionate DISKUS inhalation powder is a dry powder inhaler for oral inhalation. The active component of Fluticasone Propionate DISKUS 50 mcg, Fluticasone Propionate DISKUS 100 mcg, and Fluticasone Propionate DISKUS 250 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 DISKUS is an orange plastic inhaler containing a foil blister strip. Each blister on the strip contains a white powder mix of micronized fluticasone propionate (50, 100, or 250 mcg) in 12.5 mg of formulation containing lactose monohydrate (which contains milk proteins). After the inhaler is activated, the powder is dispersed into the airstream created by the patient inhaling through the mouthpiece. Under standardized in vitro test conditions, Fluticasone Propionate DISKUS delivers 46, 94, and 229 mcg of fluticasone propionate from Fluticasone Propionate DISKUS 50 mcg, Fluticasone Propionate DISKUS 100 mcg, and Fluticasone Propionate DISKUS 250 mcg, respectively, when tested at a flow rate of 60 L/min for 2 seconds. In adult subjects with obstructive lung disease and severely compromised lung function (mean FEV 1 20% to 30% of predicted), mean peak inspiratory flow (PIF) through the DISKUS inhaler was 82.4 L/min (range: 46.1 to 115.3 L/min). In children with asthma aged 4 and 8 years, mean PIF through Fluticasone Propionate DISKUS was 70 and 104 L/min, respectively (range: 48 to 123 L/min). The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile. Fluticasone propionate chemical structure

10 OVERDOSAGE Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions ( 5.5 )] . Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated. Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in subjects were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.

16 HOW SUPPLIED/STORAGE AND HANDLING Fluticasone Propionate DISKUS 50 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters. The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 85766-235-60 relabeled from NDC 66993-790-97). Fluticasone Propionate DISKUS 100 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters. The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 85766-236-60 relabeled from NDC 66993-791-97). Fluticasone Propionate DISKUS 250 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters. The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 85766-237-60 relabeled from NDC 66993-792-97). Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature]. Store in a dry place away from direct heat or sunlight. Keep out of reach of children. Fluticasone Propionate DISKUS should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use. Discard Fluticasone Propionate DISKUS 6 weeks (50-mcg strength) or 2 months (100- and 250-mcg strengths) after opening the foil pouch or when the counter reads “0” (after all blisters have been used), whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart.