fluticasone propionate 0.5 MG/ML Topical Lotion [Cutivate]

INDICATIONS AND USAGE Fluticasone propionate inhalation aerosol 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 inhalation aerosol is not indicated for the relief of acute bronchospasm. Fluticasone propionate inhalation aerosol 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 )

DOSAGE AND ADMINISTRATION • For oral inhalation only. ( 2.1 ) • Maintenance treatment of asthma in adult and pediatric patients aged 12 years and older: The starting dosage, 1 actuation of ARNUITY ELLIPTA 100 mcg or ARNUITY ELLIPTA 200 mcg once daily, is based on prior asthma therapy and disease severity. ( 2.2 ) • Maintenance treatment of asthma in pediatric patients aged 5 to 11 years: 1 actuation of ARNUITY ELLIPTA 50 mcg once daily. ( 2.2 ) 2.1 Administration • Administer 1 actuation of ARNUITY ELLIPTA once daily by oral inhalation. • After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis. • ARNUITY ELLIPTA should be used at the same time every day. Do not use ARNUITY ELLIPTA more than 1 time every 24 hours. • The maximum benefit may not be achieved for up to 2 weeks or longer after starting treatment. Individual patients may experience a variable time to onset and degree of symptom relief. No dosage adjustment is required for geriatric patients, patients with renal impairment, or patients with mild hepatic impairment [see Clinical Pharmacology ( 12.3 )] . 2.2 Recommended Dosage Adult and Pediatric Patients Aged 12 Years and Older The recommended starting dosage for adult and pediatric patients aged 12 years and older not on an inhaled corticosteroid (ICS) is fluticasone furoate 100 mcg (1 actuation of ARNUITY ELLIPTA 100 mcg) once daily by oral inhalation. • For other adult and pediatric patients aged 12 years and older, the recommended starting dosage should be based on previous asthma drug therapy and disease severity. • For adult and pediatric patients aged 12 years and older who do not respond to ARNUITY ELLIPTA 100 mcg after 2 weeks of therapy, replacement with ARNUITY ELLIPTA 200 mcg may provide additional asthma control. • The maximum recommended dosage in adult and pediatric patients aged 12 years and older is ARNUITY ELLIPTA 200 mcg once daily. • If asthma symptoms arise in the period between doses, an inhaled, short-acting beta 2 -agonist (rescue medicine, e.g., albuterol) should be used for immediate relief. • If a previously effective dosage regimen of ARNUITY ELLIPTA fails to provide adequate improvement in asthma control, the therapeutic regimen should be re-evaluated and additional therapeutic options (e.g., replacing the current strength of ARNUITY ELLIPTA with a higher strength, initiating an ICS and long-acting beta 2 -agonist [LABA] combination product, initiating oral corticosteroids) should be considered. • After asthma stability has been achieved, it is desirable to titrate to the lowest effective dosage to help reduce the possibility of adverse reactions. Pediatric Patients Aged 5 to 11 Years The recommended dosage for pediatric patients aged 5 to 11 years is fluticasone furoate 50 mcg (1 actuation of ARNUITY ELLIPTA 50 mcg) once daily by oral inhalation [see Warnings and Precautions ( 5.10 )] .

WARNINGS AND PRECAUTIONS • Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.1 ) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. ( 5.3 ) • Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to FLOVENT DISKUS. ( 5.4 ) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue FLOVENT DISKUS slowly. ( 5.5 ) • Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.7 ) • Monitor growth of pediatric patients. ( 5.8 ) • Glaucoma and cataracts may occur with long-term use of ICS. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use FLOVENT DISKUS long term. ( 5.9 ) 5.1 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with FLOVENT DISKUS. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with FLOVENT DISKUS continues, but at times therapy with FLOVENT DISKUS may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. 5.2 Acute Asthma Episodes FLOVENT DISKUS is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm. Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with FLOVENT DISKUS. During such episodes, patients may require therapy with oral corticosteroids. 5.3 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.4 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available ICS. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although FLOVENT DISKUS may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to FLOVENT DISKUS. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with FLOVENT DISKUS. Lung function (mean forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to FLOVENT DISKUS may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function. 5.5 Hypercorticism and Adrenal Suppression Fluticasone propionate will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of FLOVENT DISKUS in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing FLOVENT DISKUS. Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with FLOVENT DISKUS should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, FLOVENT DISKUS should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of asthma symptoms should be considered. 5.6 Immediate Hyp

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 )

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. The precise mechanism through which fluticasone propionate affects rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. In 7 trials in adults, fluticasone propionate nasal spray has decreased nasal mucosal eosinophils in 66% of patients (35% for placebo) and basophils in 39% of patients (28% for placebo). The direct relationship of these findings to long-term symptom relief is not known. 12.2 Pharmacodynamics HPA Axis Effect The potential systemic effects of fluticasone propionate nasal spray on the HPA axis were evaluated. Fluticasone propionate nasal spray given as 200 mcg once daily or 400 mcg twice daily was compared with placebo or oral prednisone 7.5 or 15 mg given in the morning. Fluticasone propionate nasal spray at either dosage for 4 weeks did not affect the adrenal response to 6-hour cosyntropin stimulation, while both dosages of oral prednisone significantly reduced the response to cosyntropin. Cardiac Electrophysiology A study specifically designed to evaluate the effect of fluticasone propionate nasal spray on the QT interval has not been conducted. 12.3 Pharmacokinetics The activity of fluticasone propionate nasal spray is due to the parent drug, fluticasone propionate. Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration. Absorption Indirect calculations indicate that fluticasone propionate delivered by the intranasal route has an absolute bioavailability averaging less than 2%. 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. After intranasal treatment of patients with rhinitis for 3 weeks, fluticasone propionate plasma concentrations were above the level of detection (50 pg/mL) only when recommended doses were exceeded and then only in occasional samples at low plasma levels. 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 averaged 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 blood clearance of fluticasone propionate is high (average: 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. 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. Excretion: Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites. Special Populations Fluticasone propionate nasal spray was not studied in any special populations, and no gender-specific pharmacokinetic data have been obtained. Drug Interactions 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: 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 AUC, but had no effect on urinary excretion of cortisol. Erythromycin: In a multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.