Arnuity Ellipta: Indications, Dosage, Precautions, Adverse Effects
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Arnuity Ellipta - Product Information

Manufacture: GlaxoSmithKline
Country: Canada
Condition: Asthma, Maintenance
Class: Inhaled corticosteroids
Form: Inhaler
Ingredients: Fluticasone Furoate, Lactose Monohydrate

fluticasone furoate dry powder for oral inhalation

Summary Product Information

Route of Administration Dosage Form / Strength Clinically Relevant Nonmedicinal Ingredients
Oral Inhalation Dry powder for oral inhalation/ 100 mcg fluticasone furoate 200 mcg fluticasone furoate Lactose monohydrate (which contains milk protein)

Indications and Clinical use

ARNUITY ELLIPTA (fluticasone furoate) is indicated for the once-daily maintenance treatment of steroid-responsive bronchial asthma in patients aged 12 years and older.

ARNUITY ELLIPTA is not indicated for the relief of acute bronchospasm (see WARNINGS AND PRECAUTIONS, General).

Geriatrics (≥ 65 years of age)

No dosage adjustment is required in patients over 65 years of age.

Pediatrics (< 12 years of age)

The safety and efficacy of ARNUITY ELLIPTA have not been established in children less than 12 years of age.

Contraindications

  • Patients who are hypersensitive to fluticasone furoate or to any ingredient in the formulation or component of the container (see DOSAGE FORMS, COMPOSITION ANDACKAGING PACKAGING).
  • Patients with severe hypersensitivity to milk proteins (see WARNINGS AND PRECAUTIONS, Hypersensitivity).
  • In the primary treatment of status asthmaticus or other acute episodes of asthma.

Warnings and Precautions

General

Acute Asthma Episodes

ARNUITY ELLIPTA is not a bronchodilator and is not indicated for rapid relief of bronchospasm. An inhaled, short-acting beta2-agonist, not ARNUITY ELLIPTA, should be used to relieve acute symptoms such as shortness of breath. When prescribing ARNUITY ELLIPTA, the physician must provide the patient with an inhaled, short-acting beta2-agonist for treatment of acute symptoms, despite regular once-daily use of ARNUITY ELLIPTA. Patients should be instructed to contact their physician immediately if episodes of asthma not responsive to their usual doses of bronchodilators occur during the course of treatment with ARNUITY ELLIPTA. During such episodes, patients may require therapy with oral corticosteroids.

Carcinogenesis and Mutagenesis

Animal data only (see TOXICOLOGY).

Ear/Nose/Throat

Oropharyngeal Candidiasis

Localized infections of the mouth and pharynx with Candida albicans, which are associated with the use of inhaled glucocoticosteroids, have occurred in patients treated with ARNUITY ELLIPTA during clinical studies. Patients should therefore be advised to rinse their mouth with water (without swallowing) after inhalation of ARNUITY ELLIPTA to reduce the risk of oropharyngeal candidiasis

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. However, at times, therapy with ARNUITY ELLIPTA may need to be interrupted for the treatment of severe infections (see DRUG INTERACTIONS, Drug-Drug Interactions).

Endocrine and Metabolism

Systemic Effects

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur with inhaled corticosteroids than with oral corticosteroids. Possible systemic effects of ARNUITY ELLIPTA include: Cushing’s syndrome, Cushingoid features, hypothalamic-pituitary-adrenal (HPA) axis suppression, decrease in bone mineral density (BMD), growth retardation in children and adolescents, cataracts and glaucoma.

Hypercorticism and Adrenal Suppression

Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics). Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic dose of ARNUITY ELLIPTA. However, exceeding the recommended dosage or co-administration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction (see DRUG INTERACTIONS, Drug-Drug Interactions).

It is possible that systemic corticosteroid effects, such as hypercorticism and adrenal suppression (including adrenal crisis), may appear in a small number of patients who are sensitive to these effects. In light of the possibility of systemic absorption of inhaled corticosteroids, 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. If such effects occur, ARNUITY ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and other treatments for management of asthma symptoms should be considered.

Systemic Steroid Replacement by Inhaled Steroid

Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of 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 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 (mean forced expiratory volume in 1 second [FEV1] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

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.

Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. 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.

Effect on Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric and adolescent patients (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Pediatrics). Monitor the growth of adolescent patients receiving ARNUITY ELLIPTA (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ARNUITY ELLIPTA, titrate to the lowest dose that effectively controls symptoms.

Hypersensitivity

Immediate hypersensitivity reactions may occur after administration of ARNUITY ELLIPTA. If signs suggesting allergic reactions (in particular, difficulties in breathing or swallowing, swelling of tongue, lips and face, urticaria, skin rash) occur, ARNUITY ELLIPTA should be discontinued immediately and alternative therapy instituted. The patient should NOT be re-challenged with ARNUITY ELLIPTA if this is identified as the cause of the hypersensitivity reaction (see CONTRAINDICATIONS).

There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not use ARNUITY ELLIPTA (see CONTRAINDICATIONS).

Immune

Patients 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 patients using corticosteroids. In such patients 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) 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 and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

As with all medications containing a corticosteroid, ARNUITY ELLIPTA should be administered with caution, and only if necessary, in patients with active or quiescent tuberculosis infections of the respiratory tract; chronic or untreated infections , such as systemic fungal, bacterial, viral, or parasitic; or ocular herpes simplex.

Ophthalmologic

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Respiratory

Paradoxical bronchospasm

As with other inhalation therapies, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a rapid onset, short-acting inhaled bronchodilator such as salbutamol. ARNUITY ELLIPTA should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Pneumonia

In studies in patients with asthma, no difference was observed in the incidence of pneumonia with ARNUITY ELLIPTA 100 mcg compared to placebo. An increased incidence of pneumonia in asthmatic patients with higher doses of inhaled corticosteroids cannot be excluded.

An increase in the incidence of pneumonia has been observed in patients with Chronic Obstructive Pulmonary Disease (COPD) receiving inhaled corticosteroids.

Special Populations

Pregnant Women

There are no adequate and well-controlled studies with ARNUITY ELLIPTA in pregnant women. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal studies are not always predictive of human response, ARNUITY ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking ARNUITY ELLIPTA.

Labour and Delivery

There are no adequate and well-controlled human studies that have investigated the effects of ARNUITY ELLIPTA during labour and delivery.

Nursing Women

It is not known whether fluticasone furoate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. A risk to breastfed newborns/infants cannot be excluded. Since there are no data from controlled trials on the use of ARNUITY ELLIPTA by nursing mothers, caution should be exercised when it is administered to a nursing woman, the use of ARNUITY ELLIPTA by breast-feeding women should only be considered if the expected benefit to the woman is greater than any possible risk to the infant.

Pediatrics

The safety and efficacy of ARNUITY ELLIPTA have not been established in children less than 12 years of age.

Geriatrics

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.

Hepatic Impairment

Fluticasone furoate systemic exposure increased by up to 3-fold in subjects with mild, moderate and severe hepatic impairment compared with healthy subjects. Use ARNUITY ELLIPTA with caution in patients with hepatic impairment. For patients with moderate or severe hepatic impairment, the maximum dose is ARNUITY ELLIPTA 100 mcg (see DOSAGE AND ADMINISTRATION). Patients should be monitored for corticosteroid-related side effects.

Renal Impairment

There were no significant increases in fluticasone furoate exposure in subjects with severe renal impairment (CrCl<30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment (see DOSAGE AND ADMINISTRATION).

Monitoring and Laboratory Tests

Patients with hepatic impairment should be monitored for corticosteroid effects due to potentially increased systemic exposure of fluticasone furoate.

Physicians should monitor the growth of children and adolescents taking corticosteroids by any route.

For patients at risk, monitoring of bone and ocular effects (cataract and glaucoma) should also be considered in patients receiving maintenance therapy with ARNUITY ELLIPTA.

Adverse Reactions

Adverse Drug Reaction Overview

Systemic and local corticosteroid use may result in the following:

  • Candida albicans infection
  • Immunosuppression
  • Hypercorticism and adrenal suppression
  • Reduction in BMD
  • Growth effects in pediatrics
  • Glaucoma and cataracts

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The clinical program for fluticasone furoate in the ELLIPTA inhaler included 10 double-blind, parallel-group, controlled studies (7 with placebo) in 6,219 patients with asthma who ranged in age from 12 to 84 years. The studies ranged in duration from 8 to 76 weeks. Doses of fluticasone furoate studied ranged from 25 to 800 mcg. ARNUITY ELLIPTA 100 mcg was studied in 1,663 patients and ARNUITY ELLIPTA 200 mcg was studied in 608 patients. The majority of the patients who received ARNUITY ELLIPTA were female (66% of the group receiving the 100 mcg strength and 62% of the group receiving the 200 mcg strength).

The safety profile of fluticasone furoate was generally consistent with the known class effects of an ICS.

12-week and 24-week Studies

The incidence of adverse events associated with ARNUITY ELLIPTA in Table 1 is based on one 12-week (HZA106827) and three 24-week studies (FFA112059, FFA114496 and HZA106829) of ARNUITY ELLIPTA 100 mcg and ARNUITY ELLIPTA 200 mcg in 1,378 adolescent and adult patients with asthma. Two of the studies had a placebo arm (HZA106827 and FFA112059). Patients received one inhalation once-daily of ARNUITY ELLIPTA 100 mcg or 200 mcg. Other treatments included fluticasone propionate 250 mcg and 500 mcg twice daily. Subject withdrawals due to adverse events was low across all treatment groups (<1% to 2%). Adverse events observed in the other studies were consistent with those described below.

Adverse events in subjects receiving ARNUITY ELLIPTA reported with a frequency of equal to or greater than 1%, and exceeding the rate in subjects receiving placebo are listed in Table 1.

Table 1 - Adverse Events With ≥1% Incidence and More Common than Placebo with ARNUITY ELLIPTA in Subjects with Asthma
Adverse Event ARNUITY ELLIPTA
3200 mcg
(n=313)
%
ARNUITY ELLIPTA
100 mcg
(n=438)
%
Placebo
(n= 318)
%
Infections and Infestations
Nasopharyngitis
Bronchitis
Upper respiratory tract infection
Sinusitis
Pharyngitis
Influenza
Respiratory tract infection viral
Oral candidiasis
Rhinitis
Oropharyngeal candidiasis
Gastroenteritis
Cystitis

13
4
3
4
2
5
3
2
2
<1
<1
1

8
5
3
3
3
1
<1
1
<1
1
1
<1

7
3
2
<1
2
0
0
0
0
0
<1
<1
Respiratory, Thoracic and
Mediastinal Disorders

Oropharyngeal pain
Cough
Dysphonia
Rhinitis allergic
Nasal congestion
Respiratory disorder


4
3
2
<1
<1
1


2
<1
1
1
1
0


<1
1
0
<1
<1
0
Nervous System Disorders
Headache

9

6

4
Gastrointestinal Disorders
Toothache
Abdominal pain
Abdominal pain upper
Diarrhea

1
2
<1
1

2
0
1
<1

<1
<1
<1
<1
Injury, Poisoning and Procedural
Complications

Procedural pain


1


<1


<1
Musculoskeletal and Connective
Tissue Disorders

Back pain


3


3


<1
Vascular Disorders
Hypertension

1

<1

0

Studies FFA112059, FFA114496, HZA106827 and HZA106829

Less Common Clinical Trial Adverse Drug Reactions (<1%)

The following adverse events were seen at a frequency of <1%.

Infections and Infestations: oral herpes, respiratory tract infection, vaginal infection, viral infection, abscess, herpes zoster, otitis externa, tooth abscess, tooth infection, viral pharyngitis, vulvovaginal mycotic infection, bacterial rhinitis, Escherichia bacteraemia, folliculitis, gastrointestinal viral infection, gingivitis, haemophilus infection, infection, laryngitis viral, localised infection, lower respiratory tract infection, nail infection, otitis media, pharyngotonsilitis, pulpitis dental, skin infection, tonsillitis bacterial, viral rhinitis, viral tracheitis, viral upper respiratory tract infection.

Respiratory, Thoracic and Mediastinal Disorders: rhinitis seasonal, respiratory tract congestion, epistaxis, interstitial lung disease, snoring, vocal cord inflammation, asthma exercise induced.

Nervous System Disorders: intercostal neuralgia, syncope, migraine, tremor, presyncope, sciatica, somnolence.

Gastrointestinal Disorders: gastritis, dry mouth, cheilitis, constipation, Crohn’s disease, diverticulum, irritable bowel syndrome, odynophagia, oral mucosa erosion, pancreatitis.

Musculoskeletal and Connective Tissue Disorders: arthralgia, chest pain, osteoarthritis, chondromalacia, chondropathy, fibromyalgia, intervertebral disc degeneration, intervertebral disc protrusion, osteitis, osteochondrosis, osteoporosis, spondylolisthesis.

Injury, Poisoning and Procedural Complications: ligament sprain, hand fracture, rib fracture, animal bite, forearm fracture, joint dislocation, laceration, meniscus lesion, nail injury, post-traumatic neck syndrome.

Skin and Subcutaneous Tissue Disorders: acne, blister, rash generalised.

General Disorders and Administration Site Conditions: influenza like illness, asthenia, chills, facial pain, edema peripheral.

Skin and Subcutaneous Tissue Disorders: dermatitis allergic, dermatitis atopic, dermatitis.

Vascular Disorders: thrombophlebitis, hypertensive crisis, venous thrombosis.

Cardiac Disorders: palpitations, angina pectoris, congestive cardiomyopathy, ventricular extrasystoles.

Investigations: body temperature increased, blood glucose increased, blood pressure increased, hepatic enzyme increased.

Psychiatric Disorders: insomnia, sleep disorder, anxiety disorder, depression.

Reproductive System and Breast Disorders: breast pain, epididymal cyst, metrorrhagia.

Immune System Disorders: seasonal allergy, food allergy, iodine allergy.

Eye Disorders: eyelid edema, cataract, conjunctivitis, conjunctivitis allergic, eye pruritus.

Metabolism and Nutrition Disorders: diabetes mellitus, hypercholesterolemia.

Neoplasms Benign, Malignant and Unspecified (including cysts and polyps): oral papilloma, prostate cancer, thymoma.

Hepatobiliary disorders: cholecystitis acute.

Renal and Urinary Disorders: cystitis haemorrhagic, renal colic.

Endocrine Disorders: hypothyroidism.

Ear and Labyrinth Disorders: eustachian tube obstruction.

Social Circumstances: stress at work.

Post-Market Adverse Drug Reactions

There are currently no post-marketing data available for ARNUITY ELLIPTA 100 mcg or 200 mcg.

The following relevant adverse reactions have been identified from post-approval use of fluticasone furoate intranasal spray for allergic rhinitis:

  • Reports of headache have been common. Rare reports of hypersensitivity reactions, including anaphylaxis, angioedema, dyspnoea, rash and urticaria.

Because these reactions are reported voluntarily from intranasal use of fluticasone furoate in an allergic rhinitis population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure relative to use of an inhaled formulation of fluticasone furoate in an asthma population.

Drug Interactions

Drug-Drug Interactions

Inhibitors of Cytochrome P450 3A4

Fluticasone furoate is rapidly cleared by extensive first pass metabolism mediated by the liver enzyme CYP3A4.

Inhibitors of P-glycoprotein (P-gp)

Fluticasone furoate is a substrate for P-gp, however, concomitant administration of fluticasone furoate with P-gp inhibitors is considered unlikely to alter fluticasone furoate systemic exposure. Clinical pharmacology studies with selective P-gp inhibitors and fluticasone furoate have not been conducted.

Table 2 - Established or Potential Drug-Drug Interactions
Drug Class Ref Effect Clinical comment
Inhibitors of Cytochrome P450 3A4 CT May increase the systemic exposure to fluticasone furoate, which could lead to an increase in potential for adverse reactions. Caution should be exercised when considering the co-administration of ARNUITY ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole).
Inhibitors of P-glycoprotein (P-gp) T Unlikely to alter fluticasone furoate systemic exposure Clinical pharmacology studies with selective P- gp inhibitors and fluticasone furoate have not been conducted.

Abbreviations:CT = Clinical Trial, T = Theoretical

Drug-Food Interactions

Interactions with food have not been established. No clinically relevant effect of food would be expected and therefore a food interaction study was not conducted.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Dosage and Administration

Dosing Considerations

  • Patients should be made aware that for optimum benefit, ARNUITY ELLIPTA must be used regularly, even when asymptomatic.
  • Patients should be regularly reassessed by a healthcare professional so that the dose of ARNUITY ELLIPTA they are receiving remains optimal and is only changed on medical advice.
  • After asthma stability has been achieved, it is desirable to titrate to the lowest effective dosage to help reduce the possibility of side effects.
  • 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.

Recommended Dose and Dosage Adjustment

The recommended dose is one inhalation of ARNUITY ELLIPTA 100 mcg or 200 mcg once-daily.

The starting dose is based on the patient’s asthma severity. The usual recommended starting dose for patients not on an inhaled corticosteroid is 100 mcg. For other patients, the starting dose should be based on previous asthma drug therapy and disease severity. For patients who do not respond adequately to one inhalation of ARNUITY ELLIPTA 100 mcg once-daily, switching to one inhalation of ARNUITY ELLIPTA 200 mcg once-daily may provide additional asthma control.

The highest recommended dose is one inhalation of ARNUITY ELLIPTA 200 mcg once-daily. The safety and efficacy of ARNUITY ELLIPTA when administered in excess of the recommended dose have not been established.

For break-through symptoms, an inhaled, short -acting beta2-agonist (rescue medicine, e.g., salbutamol) should be taken as prescribed by a physician for immediate relief.

Dosing in Special Populations

Geriatrics (≥ 65 years of age)

No dosage adjustment is required in patients over 65 years of age (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

Pediatrics (< 12 years of age)

The safety and efficacy of ARNUITY ELLIPTA have not been established in children less than 12 years of age. ARNUITY ELLIPTA is not recommended in children less than 12 years of age.

Hepatic Impairment

A clinical pharmacology study in subjects with mild, moderate and severe hepatic impairment showed up to 3-fold increase in systemic exposure to fluticasone furoate (both Cmax and AUC) (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Impairment). Caution should be exercised when dosing patients with hepatic impairment as patients with hepatic impairment may be more at risk of systemic adverse reactions associated with corticosteroids.

For patients with moderate or severe hepatic impairment, the maximum dose is ARNUITY ELLIPTA 100 mcg.

Renal Impairment

No dose adjustment is required for patients with renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Impairment).

Missed Dose

If a dose is missed, the patient should be instructed to take the next dose when it is due. The patient should be instructed not to take an extra dose.

Administration

ARNUITY ELLIPTA is for oral inhalation only.

ARNUITY ELLIPTA should be administered once-daily at the same time every day. Do not use ARNUITY ELLIPTA more than once every 24 hours. After inhalation, the patient should rinse their mouth with water (without swallowing) to help reduce the risk of oropharyngeal candidiasis.

Overdosage

An overdose of ARNUITY ELLIPTA may produce signs and symptoms consistent with the known inhaled corticosteroid class effects (see WARNINGS and PRECAUTIONS). Chronic overdosage (use at excessive doses for prolonged periods) may result in signs/symptoms of hypercorticism (see WARNINGS and PRECAUTIONS, Endocrine and Metabolism).

There is no specific treatment for an overdose with ARNUITY ELLIPTA. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Further management should be as clinically indicated or as recommended by the regional Poison Control Centre, where available.

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.

Single- and repeat-dose trials of fluticasone furoate at doses of 50 mcg to 4,000 mcg have shown fluticasone furoate to be well tolerated. Decreases in mean serum cortisol were observed at dosages of 500 mcg or higher given once-daily for 14 days.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

Mechanism of Action

Fluticasone furoate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. Inflammation is an important component in the pathogenesis of asthma. The precise mechanism through which fluticasone furoate affects asthma symptoms is not known.

Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, basophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors, such as NFkB resulting in inhibition of pro-inflammatory cytokines, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.

Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. In vitro studies have shown that translocation of the glucocorticoid receptor into the cell nucleus (essential for anti-inflammatory activity) is both more rapid and more prolonged with fluticasone furoate compared with fluticasone propionate. Nuclear localization of the glucocorticoid receptor was observed at 30 hours post-exposure with fluticasone furoate but not with fluticasone propionate. The clinical relevance of these findings is unknown.

Though effective for the treatment of asthma, corticosteroids may not affect symptoms immediately. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer.

Pharmacodynamics

The pharmacodynamics of fluticasone furoate were characterized in studies of fluticasone furoate given as a single component and also in studies of fluticasone furoate given in combination with vilanterol.

HPA Axis Effects

Effects on HPA-axis function are known to occur with systemic administration of corticosteroids and this systemic side effect has also been reported with inhaled and intranasal corticosteroid use. Based on both clinical pharmacology and clinical data, inhaled fluticasone furoate at repeat doses up to 400 mcg was not consistently associated with statistically significant decreases in serum or urinary cortisol in healthy subjects. At higher doses, above the therapeutic range, corticosteroid class-related decreases in serum and urine cortisol levels were observed. In line with the increased fluticasone furoate systemic exposure, serum cortisol was reduced by approximately a third in subjects with moderate hepatic impairment after fluticasone furoate/vilanterol 200/25 mcg administration and a similar effect would be anticipated in subjects with severe hepatic impairment at this dose.

Cardiac Effects

A QT/QTc trial did not demonstrate an effect of fluticasone furoate administration on the QTc interval. The effect of a single dose of 4,000 mcg of orally inhaled fluticasone furoate on the QTc interval was evaluated over 24 hours in 40 healthy male and female subjects in a placebo-and positive-controlled (a single dose of 400 mg oral moxifloxacin) cross-over trial. The QTcF maximal mean change from baseline following fluticasone furoate was similar to that observed with placebo with a treatment difference of 0.788 msec (90% CI: 1.802, 3.378). In contrast, moxifloxacin given as a 400-mg tablet resulted in prolongation of the QTcF maximal mean change from baseline compared with placebo with a treatment difference of 9.929 msec (90% CI: 7.339, 12.520).

Pharmacokinetics

Table 3 - Summary of Fluticasone Furoate Pharmacokinetic Parameters in Healthy Subjects
ARNUITY ELLIPTA Cmax (pg/mL)
Geometric Mean (CV%)
AUC(0-24) (pg.h/mL)
Geometric Mean (CV%)
Tmax (h)
Median (range)
Fluticasone Furoate 100 mcg 28.8 (42.3) 373 (39.4) 0.50 (0.25, 3.00)
Fluticasone Furoate 200 mcg 49.0 (37.6) 643(30.4) 0.75 (0.25, 3.00)
Table 4 - Summary of Fluticasone Furoate (Cmax and AUC(0-24)) in Subjects with Asthma (Geometric Mean [95% CI])
ARNUITY ELLIPTA Cmax (pg/mL) AUC(0-24) (pg.h/mL)
Fluticasone Furoate 100 mcg 27.0 [15.4, 50.3] 180.7 [117.4, 292.0]
Fluticasone Furoate 200 mcg 55.1 [32.6, 98.2] 394.5 [194.4, 917.8]

Absorption

Fluticasone furoate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. The absolute bioavailability for fluticasone furoate when administered by inhalation was, on average, 14%. The oral bioavailability of fluticasone furoate was low, on average, 1.3%. Given this low oral bioavailability, systemic exposure for fluticasone furoate following inhaled administration is primarily due to absorption of the inhaled portion of the dose delivered to the lung.

Distribution

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

Metabolism

Following intravenous administration to healthy subjects, fluticasone furoate was cleared from systemic circulation principally by hepatic metabolism via CYP3A4 (total plasma clearance of 65.4 L/hr). Fluticasone furoate undergoes fast first pass metabolism and is primarily metabolized through hydrolysis of the S-fluoromethyl carbothioate group 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.

Elimination

Fluticasone furoate and its metabolites are eliminated primarily in the feces, accounting for approximately 101% and 90% of the orally and intravenously administered dose, 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.

Special Populations and Conditions

Pediatrics

In adolescents (12 to 17 years of age), there are no recommended dose modifications. The safety and efficacy of ARNUITY ELLIPTA have not been established in children less than 12 years of age.

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids, including inhaled corticosteroids. The effects of long-term treatment of children and adolescents with inhaled corticosteroids, including fluticasone furoate, on final adult height are not known.

Controlled clinical trials have shown that inhaled corticosteroids may cause a reduction in growth in pediatric subjects. 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 pediatric subjects 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 (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 symptoms.

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 subjects were 474 pre-pubescent 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 patients 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 to 0.48) (see WARNINGS and PRECAUTIONS, Endocrine and Metabolism).

Geriatrics

There was no evidence for age (up to 84 years) to affect the pharmacokinetics of ARNUITY ELLIPTA in subjects with asthma.

Clinical trials of ARNUITY ELLIPTA for asthma included 285 subjects aged 65 and older (216 were treated with ARNUITY ELLIPTA 100 mcg or 200 mcg) and 32 subjects aged 75 and older (22 were treated with ARNUITY ELLIPTA 100 mcg or 200 mcg). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

Gender

A population pharmacokinetic analysis showed that no dose adjustment is required for fluticasone furoate based on the effect of gender.

Race

In subjects with asthma, estimates of fluticasone furoate AUC(0-24) for East Asian, Japanese and South East Asian subjects were up to 43% higher, on average, compared with Caucasian subjects. However, there was no evidence for the higher systemic exposure in these populations to be associated with a greater effect on adverse events such as HPA-axis suppression.

Hepatic Impairment

Following repeat dosing of fluticasone furoate/vilanterol 200 mcg/25 mcg (100 mcg/12.5 mcg in the severe impairment group) for 7 days, there was an increase in fluticasone furoate systemic exposure (up to three-fold as measured by AUC (0–24) in subjects with hepatic impairment compared with healthy subjects (Child-Pugh A, B or C). The increase in fluticasone furoate systemic exposure in subjects with moderate hepatic impairment (fluticasone furoate/vilanterol 200/25 mcg) was associated with an average 34% reduction in serum cortisol compared with healthy subjects (Child-Pugh B). Dose-normalized fluticasone furoate systemic exposure was similar in subjects with moderate and severe hepatic impairment (Child-Pugh B or C). For patients with moderate or severe hepatic impairment the maximum dose is 100 mcg.

Renal Impairment

A clinical pharmacology study of fluticasone furoate/vilanterol showed that severe renal impairment (creatinine clearance <30 mL/min) did not result in significantly greater exposure to fluticasone furoate or more marked corticosteroid systemic effects compared with healthy subjects. No dose adjustment is required for patients with renal impairment. The effects of hemodialysis have not been studied.

Storage and Stability

Do not store above 25°C. Store in a dry place away from direct heat or sunlight. If stored in a refrigerator, the inhaler should be allowed to return to room temperature for at least one hour before use.

ARNUITY ELLIPTA should be safely discarded when the dose counter reads “0” or 6 weeks after it was removed from the foil tray, whichever comes first.

Keep out of sight and reach of children.

Special Handling Instructions

ARNUITY ELLIPTA is provided in a foil laminate tray containing a desiccant packet and the tray is sealed with a peelable foil lid, which together, with the desiccant provides moisture protection. The lid should only be opened when the inhaler is ready to be used for the first time. Once the tray is opened, the desiccant package should be discarded.

Dosage Forms, Composition and Packaging

ARNUITY ELLIPTA consists of an inhaler with a plastic light grey body, dose counter and orange mouthpiece cover. The inhaler encompasses a foil strip with 14 or 30 blisters. Each blister contains a white powder mixture of micronized fluticasone furoate (100 mcg or 200 mcg) and lactose monohydrate (to 12.5 mg) for inhalation administration. The lactose monohydrate contains milk proteins.

The actual amount of drug delivered to the lungs will depend on patient factors, such as inspiratory flow rate and inspiratory time.