Fluticasone Furoate

Fluticasone Furoate ELLIPTA is indicated for the maintenance treatment of asthma in adult and pediatric patients aged 5 years and older. Limitations of Use Fluticasone Furoate ELLIPTA is NOT indicated for the relief of acute bronchospasm. Fluticasone Furoate ELLIPTA is an inhaled corticosteroid indicated for the maintenance treatment of asthma in adult and pediatric patients aged 5 years and older. ( 1 ) Limitations of Use: Not indicated for relief of acute bronchospasm. ( 1 , 5.2 )

Inhalation powder: Plastic inhaler containing a foil blister strip of powder. Each blister contains fluticasone furoate 50 mcg, 100 mcg, or 200 mcg. Inhalation powder: A foil blister strip of powder formulation for oral inhalation. Each blister contains 50 mcg, 100 mcg, or 200 mcg of fluticasone furoate. ( 3 )

Fluticasone Furoate ELLIPTA 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 furoate or any of the excipients [see Warnings and Precautions ( 5.8 ), Description ( 11 )] .
• Primary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures. ( 4 )
• Severe hypersensitivity to milk proteins ( 4 )
• Demonstrated hypersensitivity to any ingredients. ( 4 )

• 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 )
• Do not use for relief of acute symptoms. Patients require immediate re-evaluation during rapidly deteriorating asthma. ( 5.2 )
• Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; 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. Wean patients slowly from systemic corticosteroids if transferring to Fluticasone Furoate ELLIPTA. ( 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 Fluticasone Furoate ELLIPTA slowly. ( 5.5 )
• If paradoxical bronchospasm occurs, discontinue Fluticasone Furoate ELLIPTA and institute alternative therapy. ( 5.7 )
• Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.9 )
• Monitor growth of pediatric patients. ( 5.10 )
• Glaucoma and cataracts may occur with long-term use of inhaled corticosteroids. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use Fluticasone Furoate ELLIPTA long term. ( 5.11 )

5.1 Oropharyngeal Candidiasis Fluticasone Furoate ELLIPTA contains fluticasone furoate, an ICS. Localized infections of the mouth and pharynx with Candida albicans have occurred in subjects treated with orally inhaled drug products containing fluticasone furoate. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with Fluticasone Furoate ELLIPTA continues. In some cases, therapy with Fluticasone Furoate ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following administration of Fluticasone Furoate ELLIPTA to help reduce the risk of oropharyngeal candidiasis.

5.2 Acute Asthma Episodes Fluticasone Furoate ELLIPTA is not indicated for the relief of acute symptoms, i.e., as rescue therapy for treatment of acute episodes of bronchospasm. Fluticasone Furoate ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta 2 -agonist. Instruct patients to contact their healthcare providers immediately if episodes of asthma not responsive to bronchodilators occur during the course of treatment with Fluticasone Furoate ELLIPTA. During such episodes, patients may require therapy with oral corticosteroids.

5.3 Immunosuppression and Risk of Infections Persons who are using drugs that suppress the immune system, such as corticosteroids, including Fluticasone Furoate ELLIPTA, are more susceptible to infections than healthy individuals. Chickenpox and measles 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 safety and effectiveness of Fluticasone Furoate ELLIPTA have not been established in pediatric patients less than 5 years of age and Fluticasone Furoate ELLIPTA is not indicated for use in this population. 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) or pooled intravenous immunoglobulin (IVIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the Prescribing Information for VZIG, IVIG, and IG.) 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 HPA Suppression/Adrenal Insufficiency 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 Fluticasone Furoate ELLIPTA 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 healthcare practitioner 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 Fluticasone Furoate ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with Fluticasone Furoate ELLIPTA. Lung function (forced expiratory volume in 1 second [FEV 1 ] or peak expiratory flow [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. Unmasking of Allergic Conditions Previously Suppressed by Systemic Corticosteroids Transfer of patients from systemic corticosteroid therapy to Fluticasone Furoate ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Corticosteroid Withdrawal Symptoms 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 Furoate ELLIPTA will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. […]

Systemic and local corticosteroid use may result in the following:

• Oropharyngeal Candidiasis [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 BMD [see Warnings and Precautions ( 5.9 )]
• Growth Effects in Pediatrics [see Warnings and Precautions ( 5.10 )]
• Glaucoma and Cataracts [see Warnings and Precautions ( 5.11 )] Most common adverse reactions reported in ≥5% of adult and pediatric subjects aged 12 years and older are nasopharyngitis, bronchitis, upper respiratory tract infection, and headache. ( 6.1 ) Most common adverse reactions reported in ≥3% of pediatric subjects aged 5 to 11 years are pharyngitis, bronchitis, and viral infection. ( 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. Adult and Pediatric Subjects Aged 12 Years and Older The safety of fluticasone furoate ELLIPTA was evaluated in 10 double-blind, parallel-group, controlled trials (7 with placebo) of 8 to 76 weeks’ duration that enrolled 6,219 subjects with asthma. Doses of fluticasone furoate studied ranged from 25 to 800 mcg. Fluticasone furoate ELLIPTA 100 mcg was studied in 1,663 subjects, and fluticasone furoate ELLIPTA 200 mcg was studied in 608 subjects. Subject ages ranged from 12 to 84 years, 65% were female, and 75% were Caucasian. In these trials, the proportion of subjects who discontinued study treatment early due to adverse reactions was 2% for subjects treated with both fluticasone furoate ELLIPTA 100 mcg and fluticasone furoate ELLIPTA 200 mcg and ≤1% for placebo-treated subjects. Serious adverse events, whether considered drug-related or not by the investigators, that occurred in more than 1 subject and in a greater percentage of subjects treated with fluticasone furoate ELLIPTA than placebo included hypertension, abscess, breast cancer, traumatic limb amputation, subarachnoid hemorrhage, and intervertebral disc protrusion; all events occurred at rates ≤1%. The incidence of adverse reactions associated with fluticasone furoate ELLIPTA 100 mcg is shown in Table 1 and is based on one 24-week trial (Trial 1) in adult and pediatric subjects aged 12 years and older with asthma. Table 1. Adverse Reactions with Fluticasone Furoate ELLIPTA 100 mcg with ≥3% Incidence and More Common than Placebo (Trial 1, Intent-to-Treat Population) Adverse Reaction Fluticasone Furoate ELLIPTA 100 mcg (n = 114) % Placebo (n = 115) % Nasopharyngitis 8 5 Bronchitis 7 6 Upper respiratory tract infection 6 5 Headache 6 4 Pharyngitis 4 3 Sinusitis 4 <1 Toothache 3 <1 Gastroenteritis viral 3 0 Oral candidiasis 3 0 Oropharyngeal candidiasis 3 0 Oropharyngeal pain 3 0 The incidence of adverse reactions associated with fluticasone furoate ELLIPTA 200 mcg is shown in Table 2 and is based on one 24-week trial (Trial 3) in adult and pediatric subjects aged 12 years and older with asthma. This trial did not have a placebo arm. Table 2. Adverse Reactions with Fluticasone Furoate ELLIPTA 200 mcg with ≥3% Incidence (Trial 3, Safety Population) Adverse Reaction Fluticasone Furoate ELLIPTA 200 mcg (n = 119) % Fluticasone Furoate ELLIPTA 100 mcg (n = 119) % Nasopharyngitis 13 12 Headache 13 10 Bronchitis 7 12 Influenza 7 4 Upper respiratory tract infection 6 2 Sinusitis 4 7 Oropharyngeal pain 4 3 Pharyngitis 3 6 Back pain 3 3 Dysphonia 3 2 Oral candidiasis 3 <1 Procedural pain 3 <1 Rhinitis 3 <1 Throat irritation 3 <1 Abdominal pain 3 0 Cough 3 0 Adverse reactions observed in the other trials were consistent with those described in Tables 1 and 2 . Long-term Safety Long-term safety data are based on 2 trials in adult and pediatric subjects aged 12 years and older with asthma. In one 52-week trial, subjects received fluticasone furoate 100 mcg (n = 201) or fluticasone furoate 200 mcg (n = 202) in combination with a LABA. Subjects had a mean age of 39 years (pediatric patients 12 years and older made up 16% of the population), 63% were female, and 67% were Caucasian. In addition to the events shown in Table 1 and Table 2 , adverse events occurring in ≥3% of the subjects treated with fluticasone furoate 100 mcg or fluticasone furoate 200 mcg, in combination with a LABA, included pyrexia, extrasystoles, upper abdominal pain, respiratory tract infection, diarrhea, and allergic rhinitis. In a second 24- to 76-week trial, subjects received fluticasone furoate 100 mcg (n = 1,010). Subjects participating in this trial had a history of 1 or more asthma exacerbations that required treatment with oral/systemic corticosteroids or emergency department visit or in-patient hospitalization for the treatment of asthma within the previous 12 months. Subjects had a mean age of 42 years (pediatric patients 12 years and older made up 14% of the population), 67% were female, and 73% were Caucasian. In addition to the events shown in Table 1 and Table 2 , adverse events occurring in ≥3% of subjects treated with fluticasone furoate 100 mcg for up to 76 weeks included allergic rhinitis, nasal congestion, and arthralgia. Pediatric Subjects Aged 5 to 11 Years The safety data for pediatric subjects is based upon one 12-week clinical trial that enrolled 593 subjects with asthma aged 5 to 11 years. Dosages of fluticasone furoate studied were 25, 50, or 100 mcg administered once daily. Fluticasone furoate ELLIPTA 50 mcg was studied in 120 subjects (46 females and 74 males) [see Clinical Studies ( 14.2 )] . Adverse reactions (≥3% and greater than placebo) seen in pediatric subjects were similar to those reported in adult and pediatric subjects aged 12 years and older. Adverse reactions occurring in ≥3% of subjects treated with fluticasone furoate ELLIPTA 50 mcg and greater than placebo were pharyngitis, bronchitis, and viral infection.

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 Furoate ELLIPTA. 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 Furoate ELLIPTA or a combination of these factors. Immune System Disorders Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria.

Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. May cause systemic corticosteroid effects. ( 7.1 )

7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone furoate is a substrate of CYP3A4. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate. Caution should be exercised when considering the coadministration of Fluticasone Furoate ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors [see Warnings and Precautions ( 5.6 ), Clinical Pharmacology ( 12.3 )] .

Hepatic impairment: Fluticasone furoate systemic exposure may increase in patients with moderate or severe impairment. Monitor for systemic corticosteroid effects. ( 8.6 , 12.3 )

8.1 Pregnancy Risk Summary There are insufficient data on the use of Fluticasone Furoate ELLIPTA in pregnant women to inform a drug‑associated risk (see Clinical Considerations ). In animal reproduction studies, fluticasone furoate administered by inhalation to rats and rabbits during the period of organogenesis produced no fetal structural abnormalities. The highest fluticasone furoate doses in the rat and rabbit studies were 4 times and 1 time, respectively, the maximum recommended human daily inhalation dose (MRHDID) (see Data .) . The estimated risk of major birth defects and miscarriage for the indicated populations 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 should be closely monitored and medication adjusted as necessary to maintain optimal control of asthma. Data Animal Data: Fluticasone Furoate : In 2 separate embryofetal developmental studies, pregnant rats and rabbits received fluticasone furoate during the period of organogenesis at doses up to approximately 4 and 1 times, respectively, the MRHDID (on a mcg/m 2 basis at maternal inhalation doses up to 91 and 8 mcg/kg/day, respectively). No evidence of structural abnormalities in fetuses was observed in either species. In a perinatal and postnatal developmental study in rats, dams received fluticasone furoate during late gestation and lactation periods at doses up to approximately 1 time the MRHDID (on a mcg/m 2 basis at maternal inhalation doses up to 27 mcg/kg/day). No evidence of effects on offspring development was observed.

8.2 Lactation Risk Summary There is no information available on the presence of fluticasone furoate in human milk, the effects on the breastfed child, or the effects on milk production. Low concentrations of other ICS have been detected in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fluticasone Furoate ELLIPTA and any potential adverse effects on the breastfed child from fluticasone furoate or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of Fluticasone Furoate ELLIPTA for maintenance treatment of asthma have been established in pediatric patients aged 5 years and older. Use of Fluticasone Furoate ELLIPTA for this indication in patients 12 years of age and older is supported by evidence from 4 adequate and well-controlled trials in adult and pediatric patients 12 years of age and older. Use of Fluticasone Furoate ELLIPTA for this indication in patients 5 to 11 years of age is supported by evidence from an adequate and well-controlled trial in patients 5 to 11 years of age [see Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 ), and Clinical Studies ( 14.2 )] . The safety and effectiveness of Fluticasone Furoate ELLIPTA have not been established in pediatric patients less than 5 years of age. Effects on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in these patients may occur as a result of poorly controlled asthma or from use of corticosteroids, including ICS. The effects of long-term treatment of pediatric patients with ICS, including fluticasone furoate, on final adult height are not known. Controlled clinical trials have shown that ICS may cause a reduction in growth in children. In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appears to be related to dose and duration of exposure. This effect has been 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 children 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 growth of pediatric patients receiving orally inhaled corticosteroids, including Fluticasone Furoate ELLIPTA, 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 Furoate ELLIPTA, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. A randomized, double-blind, parallel-group, multicenter, 1-year, placebo-controlled trial evaluated the effect of once-daily treatment with fluticasone furoate ELLIPTA 50 mcg on growth velocity assessed by stadiometry. The subjects were 457 prepubertal children (girls aged 5 to younger than 8 years and boys aged 5 to younger than 9 years). Mean growth velocity over the 52-week treatment period was lower in the subjects receiving fluticasone furoate ELLIPTA (5.90 cm/year) compared with placebo (6.06 cm/year). The mean difference in growth velocity was -0.16 cm/year (95% CI: -0.46, 0.14) [see Warnings and Precautions ( 5.10 )] .

8.5 Geriatric Use For the 4 confirmatory trials, 71 subjects were aged 65 years and older (56 of which were treated with fluticasone furoate ELLIPTA) and 5 were aged 75 years and older (1 of which was treated with fluticasone furoate ELLIPTA) [see Clinical Studies ( 14.2 )] . Based on available data, no adjustment of the dosage of fluticasone furoate ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of fluticasone furoate ELLIPTA did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment Fluticasone furoate systemic exposure increased by up to 3-fold in adult subjects with hepatic impairment compared with healthy subjects. Use Fluticasone Furoate ELLIPTA with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects. The effect of hepatic impairment on fluticasone furoate systemic exposure in subjects aged younger than 18 years has not been evaluated [see Clinical Pharmacology ( 12.3 )] .

8.7 Renal Impairment There were no significant increases in fluticasone furoate exposure in subjects with severe renal impairment (CrCl <30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology ( 12.3 )] .

Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown. The precise mechanism through which fluticasone furoate affects asthma symptoms is not known. 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. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti‑inflammatory actions of corticosteroids may contribute to their efficacy. Though effective for the treatment of asthma, corticosteroids may not affect 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 furoate. This is explained by a combination of a relatively high local anti‑inflammatory effect, negligible oral systemic bioavailability (approximately 1.3%), and the minimal pharmacological activity of the metabolites detected in man.