Arnuity Drug Information

Generic name: FLUTICASONE FUROATE

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Uses of Arnuity

is indicated for the maintenance treatment of asthma in adult and pediatric patients aged 5 years and older. Limitations of Use ARNUITY ELLIPTA is NOT indicated for the relief of acute bronchospasm. ARNUITY ELLIPTA is an inhaled corticosteroid indicated for the maintenance treatment of asthma in adult and pediatric patients aged 5 years and older.

Limitations of Use: Not indicated for relief of acute bronchospasm.

Dosage & Administration of Arnuity

  • 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 )] .

Side Effects of Arnuity

  • 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 GlaxoSmithKline at 1-888-825-5249 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 ARNUITY 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. ARNUITY ELLIPTA 100 mcg was studied in 1,663 subjects, and ARNUITY 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 ARNUITY ELLIPTA 100 mcg and ARNUITY 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 ARNUITY 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 ARNUITY 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 ARNUITY ELLIPTA 100 mcg with ≥3% Incidence and More Common than Placebo (Trial 1, Intent-to-Treat Population) Adverse Reaction ARNUITY 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 ARNUITY 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 ARNUITY ELLIPTA 200 mcg with ≥3% Incidence (Trial 3, Safety Population) Adverse Reaction ARNUITY ELLIPTA 200 mcg (n = 119) % ARNUITY 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. ARNUITY 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 ARNUITY 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 ARNUITY 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 ARNUITY ELLIPTA or a combination of these factors. Immune System Disorders Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria.

Warnings & Cautions for Arnuity

  • 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 ARNUITY 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 ARNUITY ELLIPTA slowly. ( 5.5 )
  • If paradoxical bronchospasm occurs, discontinue ARNUITY 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 ARNUITY ELLIPTA long term. ( 5.11 ) 5.1 Oropharyngeal Candidiasis ARNUITY 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 ARNUITY ELLIPTA continues. In some cases, therapy with ARNUITY ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following administration of ARNUITY ELLIPTA to help reduce the risk of oropharyngeal candidiasis. 5.2 Acute Asthma Episodes ARNUITY ELLIPTA is not indicated for the relief of acute symptoms, i.e., as rescue therapy for treatment of acute episodes of bronchospasm. ARNUITY 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 ARNUITY 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 ARNUITY 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 ARNUITY ELLIPTA have not been established in pediatric patients less than 5 years of age and ARNUITY 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 ARNUITY 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 ARNUITY ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with ARNUITY 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 ARNUITY 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 ARNUITY ELLIPTA will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since ARNUITY ELLIPTA is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of ARNUITY ELLIPTA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with ARNUITY ELLIPTA 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, particularly when fluticasone furoate is administered at higher than recommended doses over prolonged periods of time. If such effects occur, reduce the dose of ARNUITY ELLIPTA slowly, consistent with accepted procedures for reducing systemic corticosteroids, and consider other treatments for management of asthma symptoms. 5.6 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of ARNUITY ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors (including, but not limited to, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid adverse effects may occur [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . 5.7 Paradoxical Bronchospasm As with other inhaled therapies, ARNUITY ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with ARNUITY ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; ARNUITY ELLIPTA should be discontinued immediately; and alternative therapy should be instituted. 5.8 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions such as anaphylaxis, angioedema, urticaria, flushing, allergic dermatitis, and bronchospasm may occur after administration of ARNUITY ELLIPTA. Discontinue ARNUITY ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use ARNUITY ELLIPTA [see Contraindications ( 4 )] . 5.9 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. 5.10 Effect on Growth Orally inhaled corticosteroids, including ARNUITY ELLIPTA, may cause a reduction in growth velocity when administered to pediatric patients. The safety and effectiveness of ARNUITY ELLIPTA have not been established in pediatric patients less than 5 years of age. Monitor the growth of pediatric patients receiving ARNUITY ELLIPTA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ARNUITY ELLIPTA, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration ( 2.2 ), Use in Specific Populations ( 8.4 )] . 5.11 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma following the long-term administration of ICS, including fluticasone furoate. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use ARNUITY ELLIPTA long term.

Drug Interactions with Arnuity

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 ARNUITY ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors .

Pregnancy Safety for Arnuity

Pregnancy Risk Summary There are insufficient data on the use of ARNUITY 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.

Pediatric Use of Arnuity

Pediatric Use The safety and effectiveness of ARNUITY ELLIPTA for maintenance treatment of asthma have been established in pediatric patients aged 5 years and older. Use of ARNUITY 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 ARNUITY 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 . The safety and effectiveness of ARNUITY 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 ARNUITY 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 ARNUITY 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 ARNUITY 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 ARNUITY 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) .

Contraindications for Arnuity

  • 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 )

Overdosage Information for Arnuity

No human overdosage data have been reported for ARNUITY ELLIPTA. The potential for acute toxic corticosteroid effects following overdosage with ARNUITY ELLIPTA is low. Because of low systemic bioavailability (13.9%) and an absence of acute drug-related systemic findings in clinical trials, overdosage of fluticasone furoate is unlikely to require any treatment other than observation. If used at excessive doses for prolonged periods, systemic effects such as hypercorticism may occur . Single- and repeat-dose trials of fluticasone furoate at doses of 50 to 4,000 mcg have been studied in human subjects.

Decreases in mean serum cortisol were observed at dosages of 500 mcg or higher given once daily for 14 days.

Clinical Studies of Arnuity

Dose-Ranging Trials Eight doses of fluticasone furoate ranging from 25 to 800

mcg once daily were evaluated in 3 randomized, double-blind, placebo-controlled, 8-week trials in adult and pediatric subjects aged 12 years and older with asthma. Across the 3 trials, subjects were uncontrolled at baseline on treatments of short-acting beta 2 -agonist and/or non-corticosteroid controller medications (Trial 687 NCT00603382), low-dose ICS (Trial 685 NCT00603278), or medium doses of ICS (Trial 684 NCT00603746). The trials in Figure 3 were dose-ranging trials of ARNUITY ELLIPTA not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority/inferiority to fluticasone propionate. A dose-related increase in trough FEV1 at Week 8 was seen for doses from 25 to 200 mcg with no consistent additional benefit for doses above 200 mcg as seen in Figure 3. To evaluate dosing frequency, a separate trial compared fluticasone furoate 200 mcg once daily, fluticasone furoate 100 mcg twice daily, fluticasone propionate 100 mcg twice daily, and fluticasone propionate 200 mcg once daily.

The results supported the selection of the once-daily dosing frequency. Figure 3. Dose-Ranging Trials FF = Fluticasone furoate, FP = Fluticasone propionate, OD = Once daily, BD = Twice daily. Figure 3

Confirmatory Trials Adult and Pediatric Subjects Aged 12 Years and Older

The clinical development program for ARNUITY ELLIPTA included 4 confirmatory trials in adult and pediatric subjects with asthma aged 12 years and older. The trials were designed to evaluate the safety and efficacy of ARNUITY ELLIPTA given once daily in the evening on lung function in subjects who were not controlled on their current treatments of ICS, or combination therapy consisting of an ICS plus a LABA. Study treatments were delivered as inhalation powders. The primary endpoint in all trials was change from baseline in evening trough FEV 1 measured approximately 24 hours after the final dose of study medication.

Trough FEV 1 (assessed at approximately 24 hours after the previous dose) was also assessed at clinic visits throughout the trials. Trials 2 and 4 had a co-primary endpoint of change from baseline in weighted mean serial FEV 1 measured after the final dose of study medication at 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours post-dose. Clinical Trials with ARNUITY ELLIPTA 100 mcg: Trial 1 (NCT01159912) was a 24-week trial that evaluated the efficacy of ARNUITY ELLIPTA 100 mcg compared with placebo on lung function in subjects with asthma.

Inhaled fluticasone propionate 250 mcg twice daily was included as an active control. Of the 343 subjects, 59% were female and 79% were Caucasian. The mean age was 41 years.

The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual low- to mid-dose ICS therapy (i.e., fluticasone propionate 100 to 500 mcg daily or equivalent). Mean baseline percent predicted FEV 1 was approximately 73% overall and was similar across the 3 treatment groups. Thirty-five percent of subjects on placebo and 19% of subjects on ARNUITY ELLIPTA 100 mcg failed to complete the 24-week trial. The change in trough FEV 1 from baseline to Week 24, or the last available on-treatment visit prior to Week 24, was assessed to evaluate the efficacy of ARNUITY ELLIPTA 100 mcg.

The mean change from baseline in trough FEV 1 was greater among subjects receiving ARNUITY ELLIPTA 100 mcg than among those receiving placebo (mean treatment difference from placebo 146 mL; 95% CI: 36, 257) as shown in Table 3. Table 3. Change from Baseline in Trough FEV 1 (mL) at Week 24 – Trial 1 FEV 1 = forced expiratory volume in 1 second, SE = standard error. Trough FEV 1 (Week 24) Placebo (n = 113) ARNUITY ELLIPTA 100 mcg (n = 111) Fluticasone Propionate 250 mcg Twice Daily (n = 107) Least squares mean 2,372 2,519 2,517 Least squares mean change (SE) 15 161 159 Column vs. placebo Difference — 146 145 95% CI — 36, 257 33, 257 P value — 0.009 0.011 Trial 2 (NCT01165138) was a 12-week trial that evaluated the efficacy of ARNUITY ELLIPTA 100 mcg on lung function in subjects with asthma compared with placebo. The combination of fluticasone furoate 100 mcg and vilanterol 25 mcg was also included as a treatment arm.

Of the 609 subjects, 58% were female and 84% were Caucasian. The mean age was 40 years. The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual low- to mid-dose ICS (fluticasone propionate 200 to 500 mcg/day or equivalent). If LABA were used prior to screening, their use was discontinued during the run-in.

Mean baseline percent predicted FEV 1 was approximately 70% in both treatment groups. Twenty-six percent of subjects on placebo and 10% of subjects on ARNUITY ELLIPTA 100 mcg failed to complete the 12-week trial. The co-primary efficacy endpoints in Trial 2 were change from baseline in trough FEV 1 at Week 12 and weighted mean FEV 1 (0-24 hours) at the end of the 12-week treatment period.

Trough FEV 1 was assessed at clinic visits throughout the trial. Weighted mean FEV 1 (0-24 hours) was recorded at baseline and after the final study dose with serial measurements taken at frequent intervals (at 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours post-dose) in a subset of subjects (n = 201). ARNUITY ELLIPTA 100 mcg once daily had greater mean changes from baseline in trough FEV 1 than placebo throughout the trial. At Week 12 or the last available on-treatment visit prior to Week 12, the mean change from baseline in trough FEV 1 was greater among subjects receiving ARNUITY ELLIPTA 100 mcg once daily than among those receiving placebo (mean treatment difference 136 mL; 95% CI: 51, 222). Lung function improvements were sustained over the 24-hour period following the final dose of ARNUITY ELLIPTA 100 mcg ( Figure 4 ). Compared with placebo, at Week 12 the change from baseline in weighted mean FEV 1 was significantly greater for ARNUITY ELLIPTA 100 mcg (mean treatment difference 186 mL; 95% CI: 62, 310). Figure 4. Mean Change from Baseline in Individual Serial FEV 1 (mL) Assessments after 12 Weeks of Treatment – Trial 2 Subjects in both Trials 1 and 2 receiving ARNUITY ELLIPTA 100 mcg once daily had a greater improvement from baseline in percentage of 24-hour periods without need of beta 2 -agonist rescue medication use than subjects receiving placebo.

Clinical Trial with ARNUITY ELLIPTA 200 mcg: Trial 3 (NCT01431950) was a 24-week trial that evaluated the relative efficacy of ARNUITY ELLIPTA 100 mcg and ARNUITY ELLIPTA 200 mcg on lung function in subjects with asthma. Of the 219 subjects, 68% were female and 87% were Caucasian. The mean age was 46 years.

The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual mid- to high-dose ICS therapy (i.e., fluticasone propionate greater than 250 to 1,000 mcg/day or equivalent). If LABA were used prior to screening, their use was discontinued during the run-in. Mean baseline percent predicted FEV 1 was approximately 68% overall and similar in the 2 treatment groups. Sixteen percent of subjects on ARNUITY ELLIPTA 100 mcg and 13% of subjects on ARNUITY ELLIPTA 200 mcg failed to complete the 24-week trial.

The primary efficacy endpoint was mean change from baseline in trough FEV 1 at Week 24. There were trends toward greater mean changes from baseline in the group receiving ARNUITY ELLIPTA 200 mcg than the group receiving ARNUITY ELLIPTA 100 mcg throughout the trial ( Figure 5 ). At Week 24 or the last available on-treatment visit prior to Week 24, the mean change from baseline in trough FEV1 was 208 mL for ARNUITY ELLIPTA 100 mcg, as compared with 284 mL for ARNUITY ELLIPTA 200 mcg (difference of 77 mL; 95% CI: -39, 192) as seen in Figure 5. Figure 5. Mean Change from Baseline in Trough FEV 1 (mL) over Time – Trial 3 Trial 4 (NCT01134042) was a 24-week trial that evaluated the efficacy of ARNUITY ELLIPTA 200 mcg once daily and fluticasone propionate 500 mcg twice daily on lung function in subjects with asthma. The combination of fluticasone furoate 200 mcg and vilanterol 25 mcg was also included as a treatment arm (data not shown). Of the 586 subjects, 59% were female and 84% were Caucasian. The mean age was 46 years.

The trial included a 4-week run-in period during which the subjects were symptomatic while taking their usual mid- to high-dose ICS (fluticasone propionate 500 to 1,000 mcg/day or equivalent). If LABA were used prior to screening, their use was discontinued during the run-in. Mean baseline percent predicted FEV 1 was approximately 67% in both treatment groups. Both ARNUITY ELLIPTA 200 mcg once daily and fluticasone propionate 500 mcg twice daily produced improvement from baseline in lung function.

At Week 24 the mean change from baseline in trough FEV 1 was 201 mL for ARNUITY ELLIPTA 200 mcg once daily and 183 mL for fluticasone propionate 500 mcg twice daily (treatment difference of 18 mL, 95% CI: -66, 102). Lung function improvements were sustained over the 24-hour period following the final dose of ARNUITY ELLIPTA 200 mcg ( Figure 6 ). At Week 24, the change from baseline in weighted mean FEV 1 was 328 mL for ARNUITY ELLIPTA 200 mcg once daily and 258 mL for fluticasone propionate 500 twice daily (difference of 70 mL; 95% CI: -67, 208). Figure 6. Mean Change from Baseline in Individual Serial FEV 1 (mL) Assessments after 24 Weeks of Treatment – Trial 4 Pediatric Subjects Aged 5 to 11 Years A 12-week trial (NCT01563029) evaluated the efficacy of fluticasone furoate (25, 50, or 100 mcg) administered once daily in the evening compared with placebo in 593 pediatric subjects with asthma aged 5 to 11 years. Inhaled fluticasone propionate 100 mcg twice daily was included as an active control. At trial entry subjects were symptomatic, had at least a 6-month history of asthma, and had been receiving stable asthma therapy for at least 4 weeks prior to screening.

Subjects had to have a pre-bronchodilator PEF of ≥60% to ≤90% of their best post-bronchodilator value and, in subjects able to perform the maneuver, demonstrate a ≥12% reversibility of FEV 1 within approximately 10 to 40 minutes following 2 to 4 inhalations of albuterol inhalation aerosol. The primary endpoint of this trial was the mean change from baseline in daily pre-dose AM PEF from the patient electronic daily diary averaged over the 12-week treatment period. A secondary endpoint was the change from baseline in the percentage of rescue-free 24-hour periods during the 12-week treatment period.

Of the 593 subjects, the mean age was 8 years, 62% were male, and 42% were Caucasian. Lung function improvements based on the primary endpoint of mean change from baseline in AM PEF are presented in Table 4. Table 4. Least Squares Mean Change from Baseline in Pre-Dose AM PEF over the 12-Week Treatment Period (Intent-to-Treat Population) AM PEF = Morning Peak Expiratory Flow, LS = Least squares, SE = standard error. a Average over Weeks 1 to 12. Primary Endpoint Placebo (n = 119) Fluticasone Furoate 25 mcg (n = 118) Fluticasone Furoate 50 mcg (n = 120) Fluticasone Furoate 100 mcg (n = 118) Fluticasone Propionate 100 mcg (n = 118) AM PEF (L/min) a n = 119 n = 117 n = 118 n = 118 n = 117 LS mean change (SE) 3.3 21.9 22.8 15.8

Difference vs placebo 18.6 19.5 12.5 14.0 (95% CI) Pediatric subjects receiving

ARNUITY ELLIPTA 50 mcg had a greater improvement from baseline in percentage of 24-hour periods without need of beta 2 -agonist rescue medication use than subjects receiving placebo. Given the demonstration of efficacy of ARNUITY ELLIPTA 100 mcg and ARNUITY ELLIPTA 200 mcg in the adult and pediatric population aged 12 years and older, the results support the efficacy of ARNUITY ELLIPTA 50 mcg once daily in pediatric subjects with asthma aged 5 to 11 years. Figure 4 Figure 5 Figure 6

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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