Included as part of the "PRECAUTIONS" Section
Local Effects Of Inhaled Corticosteroids
In clinical trials, the development of localized infections of the mouth and pharynx with Candida
albicans has occurred in subjects treated with ARNUITY ELLIPTA. 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, but at times therapy with ARNUITY
ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water
without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.
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
physicians 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.
Persons who are using drugs that suppress the immune system are more susceptible to infections
than healthy individuals. Chickenpox and measles, for example, can have a more serious or even
fatal course in susceptible children or adults using corticosteroids. In such children or adults who
have not had these diseases or been properly immunized, particular care should be taken to avoid
exposure. How the dose, route, and duration of corticosteroid administration affect the risk of
developing a disseminated infection is not known. The contribution of the underlying disease
and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to
chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) 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 respective package inserts
for complete VZIG, IVIG, and IG prescribing information.) If chickenpox develops, treatment
with antiviral agents may be considered.
ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis
infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic
infections; or ocular herpes simplex.
Transferring Patients From Systemic Corticosteroid Therapy
Particular care is needed for patients who have been transferred from systemically active
corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients with
asthma during and after transfer from systemic corticosteroids to less systemically available ICS.
After withdrawal from systemic corticosteroids, a number of months are required for recovery of
hypothalamic-pituitary-adrenal (HPA) function.
Patients who have been previously maintained on 20 mg or more of prednisone (or its
equivalent) may be most susceptible, particularly when their systemic corticosteroids have been
almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs
and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection
(particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although
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 physicians for further instruction. These patients should also be
instructed to carry a warning card indicating that they may need supplementary systemic
corticosteroids during periods of stress or a severe asthma attack.
Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use
after transferring to 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
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).
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
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
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, the dosage of ARNUITY ELLIPTA should be reduced slowly, consistent
with accepted procedures for reducing systemic corticosteroids and for management of asthma
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 (e.g., ritonavir, clarithromycin,
conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin,
troleandomycin, voriconazole) because increased systemic corticosteroid adverse effects may
occur [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].
As with other inhaled medicines, 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.
Hypersensitivity Reactions, Including Anaphylaxis
Hypersensitivity reactions such as 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].
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 longterm
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.
Effect On Growth
Orally inhaled corticosteroids, including ARNUITY ELLIPTA, may cause a reduction in growth
velocity when administered to children and adolescents. Monitor the growth of children and
adolescents 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].
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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and
Instructions for Use).
Not For Acute Symptoms
Inform patients that ARNUITY ELLIPTA is not meant to relieve acute symptoms of asthma and
extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an
inhaled, short-acting beta2-agonist such as albuterol. Provide patients with such medication and
instruct them in how it should be used.
Instruct patients to seek medical attention immediately if they experience any of the following:
- Decreasing effectiveness of inhaled, short-acting beta2-agonists
- Need for more inhalations than usual of inhaled, short-acting beta2-agonists
- Significant decrease in lung function as outlined by the physician
Advise patients not to increase the dose or frequency of ARNUITY ELLIPTA. The daily dosage
of ARNUITY ELLIPTA should not exceed 1 inhalation. If they miss a dose, instruct patients to
take their next dose at the same time they normally do.
Tell patients they should not stop therapy with ARNUITY ELLIPTA without physician/provider
guidance since symptoms may recur after discontinuation.
Inform patients that localized infections with Candida albicans occurred in the mouth and
pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or
systemic (i.e., oral) antifungal therapy while still continuing therapy with ARNUITY ELLIPTA,
but at times therapy with ARNUITY ELLIPTA may need to be temporarily interrupted under
close medical supervision. Advise patients to rinse the mouth with water without swallowing
after inhalation to help reduce the risk of thrush.
Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to
chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients
of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections or
ocular herpes simplex.
Hypercorticism And Adrenal Suppression
Advise patients that ARNUITY ELLIPTA may cause systemic corticosteroid effects of
hypercorticism and adrenal suppression. Additionally, inform patients that deaths due to adrenal
insufficiency have occurred during and after transfer from systemic corticosteroids. Patients
should taper slowly from systemic corticosteroids if transferring to ARNUITY ELLIPTA.
Reduction In Bone Mineral Density
Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids
may pose an additional risk.
Reduced Growth Velocity
Inform patients that orally inhaled corticosteroids, including ARNUITY ELLIPTA, may cause a
reduction in growth velocity when administered to pediatric patients. Physicians should closely
follow the growth of children and adolescents taking corticosteroids by any route.
Glaucoma And Cataracts
Advise patients that long-term use of ICS may increase the risk of some eye problems (cataracts
or glaucoma); consider regular eye examinations.
Hypersensitivity Reactions, Including Anaphylaxis
Advise patients that hypersensitivity reactions (e.g., urticaria, flushing, allergic dermatitis,
bronchospasm), including anaphylaxis, may occur after administration of ARNUITY ELLIPTA.
Instruct patients to 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.
Use Daily For Best Effect
Advise patients to use ARNUITY ELLIPTA at regular intervals, since its effectiveness depends
on regular use. Maximum benefit may not be achieved for 1 week or longer after starting
treatment. If symptoms do not improve after 2 weeks of therapy or if the condition worsens,
instruct patients to contact their physicians.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year
inhalation studies in rats and mice at inhaled doses up to 9 and 19 mcg/kg/day, respectively (less
than the MRHDID on a mcg/m2 basis).
Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a
mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro. There was also no
evidence of genotoxicity in the in vivo micronucleus test in rats.
No evidence of impairment of fertility was observed in male and female rats at inhaled
fluticasone furoate doses up to 29 and 91 mcg/kg/day, respectively (approximately 1 and 4 times,
respectively, the MRHDID in adults on a mcg/m2 basis).
Use In Specific Populations
There are insufficient data on the use of ARNUITY ELLIPTA in pregnant women. There are
clinical considerations with 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 times the maximum recommended human daily inhalation dose
(MRHDID), respectively. (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.
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.
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 the MRHDID, respectively (on a mcg/m2 basis at maternal
inhalation doses up to 91 and 8 mcg/kg/day). 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/m2 basis at maternal inhalation doses up to
27 mcg/kg/day). No evidence of effects on offspring development was observed.
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 ARNUITY ELLIPTA and any
potential adverse effects on the breastfed child from fluticasone furoate or from the underlying
The safety and efficacy of ARNUITY ELLIPTA in pediatric patients with asthma aged 5 to 11
years have been established in 3 clinical trials. In those trials, 234 subjects were administered
ARNUITY ELLIPTA 50 mcg once daily. Subjects aged 5 to 11 years demonstrated safety and
efficacy results similar to those observed in subjects aged 12 years and older. The safety and
efficacy of ARNUITY ELLIPTA have not been established in pediatric patients aged younger
than 5 years. [see DOSAGE AND ADMINISTRATION , ADVERSE REACTIONS , CLINICAL PHARMACOLOGY , Clinical Studies]
Effects On Growth
Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to
children and adolescents. A reduction of growth velocity in children and adolescents may occur
as a result of poorly controlled asthma or from use of corticosteroids, including ICS. The effects
of long-term treatment of children and adolescents 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 children and
adolescents 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
A randomized, double-blind, parallel-group, multicenter, 1-year, placebo-controlled trial
evaluated the effect of once-daily treatment with 110 mcg of fluticasone furoate in the nasal
spray formulation on growth velocity assessed by stadiometry. The systemic exposure of
fluticasone furoate in this trial is lower than that of ARNUITY ELLIPTA 50 mcg. The subjects
were 474 prepubescent children (girls aged 5 to 7.5 years and boys aged 5 to 8.5 years). Mean
growth velocity over the 52-week treatment period was lower in the subjects receiving
fluticasone furoate nasal spray (5.19 cm/year) compared with placebo (5.46 cm/year). The mean
reduction in growth velocity was 0.27 cm/year (95% CI: 0.06, 0.48) [see WARNINGS AND PRECAUTIONS].
For the 4 confirmatory trials, 71 subjects were aged 65 years and older (56 of which were treated
with ARNUITY ELLIPTA) and 5 were aged 75 years and older (1 of which was treated with
ARNUITY ELLIPTA) [see Clinical Studies]. Based on available data, no adjustment of
the dosage of ARNUITY ELLIPTA in geriatric patients is necessary, but greater sensitivity in
some older individuals cannot be ruled out. Clinical trials of ARNUITY 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.
Fluticasone furoate systemic exposure increased by up to 3-fold in adult subjects with hepatic
impairment compared with healthy subjects. Use ARNUITY 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].
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].