Arnuity Drug Information

ARNUITY ELLIPTA 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.

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.

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 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.

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. Doses of fluticasone furoate studied ranged from 25 to 800 mcg. 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.

This trial did not have a placebo arm. Table 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 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.

Dosages of fluticasone furoate studied were 25, 50, or 100 mcg administered once daily. 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.

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.

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 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 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 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. 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).

• ARNUITY ELLIPTA is contraindicated in the following conditions:
• Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.
• Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone furoate or any of the excipients.
• Primary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures.
• Severe hypersensitivity to milk proteins
• Demonstrated hypersensitivity to any ingredients.

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.