Arnuity Ellipta (Fluticasone Furoate)

ARNUITY ELLIPTA is indicated for the maintenance treatment of asthma in adult and pediatric patients aged 5 years and older.

ARNUITY ELLIPTA is NOT indicated for the relief of acute bronchospasm.

• •For oral inhalation only. (
  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 ]

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• •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 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 beta₂-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 beta₂-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 ]

  .
  )
• •Maintenance treatment of asthma in pediatric patients aged 5 to 11 years: 1 actuation of ARNUITY ELLIPTA 50 mcg once daily. (
  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 beta₂-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 beta₂-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 ]

  .
  )

Inhalation powder: Plastic inhaler containing a foil blister strip of powder. Each blister contains fluticasone furoate 50 mcg, 100 mcg, or 200 mcg.

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

12.3 Pharmacokinetics

The pharmacokinetics of fluticasone furoate was characterized in trials of fluticasone furoate given as a single component and in trials of fluticasone furoate given in combination with vilanterol. Linear pharmacokinetics was observed for fluticasone furoate (200 to 800 mcg). On repeated once-daily inhalation administration, steady state of fluticasone furoate plasma concentration was achieved after 6 days, and the accumulation was up to 2.6-fold as compared with single dose.

Absorption

Fluticasone furoate plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 0.5 to 1 hour. Absolute bioavailability of fluticasone furoate when administrated by inhalation was 13.9%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose is low (approximately 1.3%) due to extensive first-pass metabolism. Systemic exposure (AUC) in subjects with asthma was 26% lower than observed in healthy subjects.

Distribution

Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 661 L. Binding of fluticasone furoate to human plasma proteins was high (99.6%).

Elimination

Metabolism:

Fluticasone furoate is cleared from systemic circulation principally by hepatic metabolism via CYP3A4 to metabolites with significantly reduced corticosteroid activity. There was no in vivo evidence for cleavage of the furoate moiety resulting in the formation of fluticasone.

Excretion:

Fluticasone furoate and its metabolites are eliminated primarily in the feces, accounting for approximately 101% and 90% of the orally and intravenously administered doses, respectively. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered doses, respectively. Following repeat-dose inhaled administration, the plasma elimination phase half-life averaged 24 hours.

Specific Populations

The effects of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of fluticasone furoate are shown in Figure 1.

Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF)

• ^aAge, gender, and ethnicity comparison for ARNUITY ELLIPTA in adult and pediatric subjects aged 12 years and older with asthma.
• ^bRenal groups (fluticasone furoate/vilanterol 200 mcg/25 mcg) and hepatic groups (fluticasone furoate/vilanterol 200 mcg/25 mcg or fluticasone furoate/vilanterol 100 mcg/12.5 mcg) compared with healthy control group.

Pediatric Patients:

A population pharmacokinetics analysis to assess impact of age on fluticasone furoate systemic exposure was conducted using combined data from clinical trials in pediatric subjects aged 5 to 11 years (n = 306). There was no relevant effect of age on the apparent clearance of fluticasone furoate. The rate and extent of fluticasone furoate systemic exposure at steady state in children aged 5 to 11 years were comparable to that observed in adult and pediatric subjects aged 12 years and older following dosing with fluticasone furoate 100 mcg monotherapy.

Racial or Ethnic Groups:

Systemic exposure [AUC_(0-24)] to inhaled fluticasone furoate 200 mcg was 27% to 49% higher in healthy subjects of Japanese, Korean, and Chinese heritage compared with White subjects. Similar differences were observed for subjects with asthma . However, there is no evidence that this higher exposure to fluticasone furoate results in clinically relevant effects on urinary cortisol excretion or on efficacy in these racial groups.

Patients with Hepatic Impairment:

Following repeat dosing of fluticasone furoate/vilanterol 200/25 mcg (100/12.5 mcg in the severe impairment group) for 7 days, there was an increase of 34%, 83%, and 75% in fluticasone furoate systemic exposure (AUC) in subjects with mild, moderate, and severe hepatic impairment, respectively, compared with healthy subjects .

In subjects with moderate hepatic impairment receiving fluticasone furoate/vilanterol 200/25 mcg, mean serum cortisol (0 to 24 hours) was reduced by 34% (90% CI: 11%, 51%) compared with healthy subjects. In subjects with severe hepatic impairment receiving fluticasone furoate/vilanterol 100/12.5 mcg, mean serum cortisol (0 to 24 hours) was increased by 14% (90% CI: -16%, 55%) compared with healthy subjects. Patients with moderate to severe hepatic disease should be closely monitored.

Patients with Renal Impairment:

Fluticasone furoate systemic exposure was not increased in subjects with severe renal impairment compared with healthy subjects . There was no evidence of greater corticosteroid class-related systemic effects (assessed by serum cortisol) in subjects with severe renal impairment compared with healthy subjects.

Drug Interaction Studies

The potential for fluticasone furoate to inhibit or induce metabolic enzymes and transporter systems is negligible at low inhalation doses.

Inhibitors of Cytochrome P450 3A4:

The exposure (AUC) of fluticasone furoate was 36% higher after single and repeated doses when coadministered with ketoconazole 400 mg compared with placebo . The increase in fluticasone furoate exposure was associated with a 27% reduction in weighted mean serum cortisol (0 to 24 hours).

Figure 2. Impact of Coadministered Ketoconazole^aon the Pharmacokinetics (PK) of Fluticasone Furoate

• ^aCompared with placebo group.

• •
  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 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.
  )
• •Do not use for relief of acute symptoms. Patients require immediate re-evaluation during rapidly deteriorating asthma. (
  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 beta₂-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.
  )
• •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 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.
  )
• •Risk of impaired adrenal function when transferring from systemic corticosteroids. Wean patients slowly from systemic corticosteroids if transferring to ARNUITY ELLIPTA. (
  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 [FEV₁] 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.
  )
• •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 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.
  )
• •If paradoxical bronchospasm occurs, discontinue ARNUITY ELLIPTA and institute alternative therapy. (
  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.
  )
• •Assess for decrease in bone mineral density initially and periodically thereafter. (
  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.
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• •Monitor growth of pediatric patients. (
  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 , Use in Specific Populations ]

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• •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 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.
  )