Symptoms: in the study of the bioavailability of the drug with intranasal administration, doses were used 24 times higher than the recommended dose for adults, for more than 3 days, while no adverse systemic reactions were observed.
Treatment: it is unlikely that an acute overdose will require other measures than medical supervision.
Symptoms of acute and chronic overdose have not been reported. When intranasal administration of 2 mg of fluticasone to volunteers 2 times a day for 7 days, no effect on the hypothalamic-pituitary-adrenal system was found.
Symptoms: acute — a temporary decrease in the function of the adrenal cortex, chronic-suppression of the function of the adrenal cortex.
Treatment: chronic overdose-monitoring of the reserve function of the adrenal cortex (treatment with the drug can be continued in doses sufficient to maintain the therapeutic effect).
Hypersensitivity, acute bronchospasm, asthmatic status (as a primary remedy), non-asthmatic bronchitis, children's age (up to 1 year).
With caution — for cirrhosis of the liver, glaucoma, hypothyroidism, systemic infections (bacterial, fungal, parasitic, viral), osteoporosis, pulmonary tuberculosis, pregnancy and lactation.
Fluticasone furoate is rapidly metabolized in the liver by the cytochrome P450 isoenzyme CYP3A4. In the study of the drug interaction of fluticasone furoate and the inhibitor of CYP3A4-ketoconazole, there were more cases of determining the concentrations of fluticasone furoate above the threshold in the plasma in the ketoconazole group (6 out of 20 patients) compared with placebo (1 out of 20 patients). This small increase does not lead to a statistically significant difference in the plasma cortisol content over 24 hours between the two groups.
Based on theoretical data, there are no assumptions about any drug interactions of fluticasone furoate, used intranasally, and other drugs that are metabolized with the participation of the cytochrome P450 system. Thus, clinical studies to study the interaction of fluticasone furoate and other drugs have not been conducted.
Based on data obtained in a study with another drug containing corticosteroids, which is also metabolized by cytochrome CYP3A4 isoenzymes, co-administration with ritonavir is not recommended due to the potential risk of increased systemic exposure to fluticasone furoate.
Interaction with other drugs is unlikely, since the plasma concentrations of fluticasone are very low in the intranasal route of administration. When used concomitantly with strong inhibitors of the cytochrome P450 isoenzyme CYP3A4 (ritonavir), it is possible to increase the systemic effect of fluticasone and develop side effects (Cushing's syndrome, suppression of the function of the adrenal cortex). When used simultaneously with other inhibitors of the cytochrome P450 system (erythromycin, ketoconazole), there is a slight increase in the concentration of fluticasone in the blood, which practically does not affect the cortisol content.
Concomitant administration with CYP3A4 inhibitors (ketoconazole, ritonavir) may increase the systemic effect of fluticasone propionate (caution should be exercised).
Candidiasis of the oral cavity and pharynx, hoarseness (after inhalation, it is necessary to rinse the mouth and throat with water), paradoxical bronchospasm (requires discontinuation of the drug, and continuation of therapy with other means), rarely-the development of allergic reactions (skin rash, angioedema, dyspnea or bronchospasm, anaphylactic reactions), possibly a decrease in the function of the adrenal cortex, osteoporosis, growth retardation in children, cataracts, increased intraocular pressure.
Eczema (atopic, discoid, in children), nodular pruritus, psoriasis (excluding common plaque), neurodermatosis (including lichen simplex, lichen planus, seborrheic dermatitis), discoid lupus erythematosus, red sweating, generalized erythroderma (as an additional means to systemic therapy), insect bites, allergic contact reactions, itching.
Symptomatic treatment of seasonal and year-round allergic rhinitis in adults and children over 2 years of age.
Prevention and treatment of seasonal and year-round allergic rhinitis.
Eczema (atopic, discoid, in children), nodular pruritus, psoriasis (excluding common plaque), neurodermatosis (including lichen simplex, lichen planus, seborrheic dermatitis), discoid lupus erythematosus, red sweating, generalized erythroderma (as an additional means to systemic therapy), insect bites, allergic contact reactions, itching.
Bronchial asthma (basic anti-inflammatory therapy) in adults and children 1 year and older (including those with a severe course of the disease, with dependence on systemic corticosteroids), chronic obstructive pulmonary disease in adults.
Fluticasone furoate-a synthetic trifluorinated GCS with a high affinity for GCS receptors-has a pronounced anti-inflammatory effect.
GCS for topical use. In the recommended doses, it has a pronounced anti-inflammatory, anti-edematous and anti-allergic effect. The anti-inflammatory effect is realized as a result of the interaction of the drug with the GCS receptors. Inhibits the proliferation of mast cells, eosinophils, lymphocytes, macrophages, neutrophils, reduces the production and release of inflammatory mediators and other biologically active substances (in t.tsch. histamine, PG, LT, cytokines) during the early and late phase of an allergic reaction. The anti-allergic effect is already evident in 2-4 hours after the first application. Reduces itching in the nose, sneezing, runny nose, nasal congestion, unpleasant sensations in the paranasal sinuses and a feeling of pressure around the nose and eyes. Relieves eye symptoms associated with allergic rhinitis. The effect of the drug persists for 24 hours after a single application. When used in therapeutic doses, fluticasone does not show a systemic effect and has virtually no effect on the hypothalamic-pituitary-adrenal system
Reduces the severity of symptoms and reduces the frequency of exacerbations of diseases accompanied by airway obstruction, reduces the need for additional courses of tablet corticosteroids, and is characterized by an increase in the quality of life of the patient. Restores the patient's reaction to bronchodilators, reduces the frequency of their use. The therapeutic effect manifests itself within 24 hours after inhalation, reaches a maximum within 1-2 weeks or more after the start of treatment and persists for several days after discontinuation of the drug.
Suction. Fluticasone furoate is not fully absorbed, undergoing primary metabolism in the liver, resulting in minor systemic effects. Intranasal administration at a dose of 110 mcg once a day usually leads to the determination of immeasurable plasma concentrations (<10 pg/ml). The absolute bioavailability of fluticasone furoate when administered intranasally at a dose of 880 mcg 3 times a day (daily dose of 2640 mcg) is 0.5%.
Distribution. Fluticasone furoate binds to plasma proteins by more than 99%. When reaching Css Vd fluticasone furoate averages 608 l.
Metabolism. Fluticasone furoate is rapidly eliminated from the systemic circulation (total plasma clearance 58.7 L), mainly by liver metabolism to form an inactive 17β-carboxyl metabolite (GW694301X) with the participation of the cytochrome P450 enzyme CYP3A4. The main pathway of metabolism is the hydrolysis of the S-fluoromethylcarbothioate group to form the 17β-carboxylic acid metabolite. Researches in vivo It was shown that the cleavage of fluticasone furoate to fluticasone does not occur.
Output. The excretion of fluticasone furoate and its metabolites during oral and intravenous administration is carried out mainly through the intestine, which reflects their excretion with bile. About 1 and 2% are excreted by the kidneys with oral administration and intravenous administration, respectively.
Special patient groups
Elderly patients: pharmacokinetic data are presented only for a small number of elderly patients (n=23/872, 2.6%). There is no evidence that quantifiable concentrations of fluticasone furoate are higher in elderly patients than in young patients.
Children: fluticasone furoate is usually detected in concentrations that are not quantifiable (<10 pg / ml), when administered intranasally at a dose of 110 mcg once a day. Quantifiable concentrations were reported in less than 16% of children with intranasal administration at a dose of 110 mcg once a day and in less than 7% of children using 55 mcg once a day. There is no evidence that children under 6 years of age are more likely to experience an increase in the concentration of fluticasone furoate.
Patients with impaired renal function: fluticasone furoate was not detected in the urine of healthy volunteers during intranasal administration. Less than 1% of the metabolites are excreted through the kidneys, so impaired renal function theoretically cannot affect the pharmacokinetics of fluticasone furoate.
Patients with impaired liver function: a study in patients with moderate hepatic impairment who used 400 mcg of fluticasone furoate once inhaled showed an increase in Cmax by 42% and increase in AUC0–∞ by 172% compared to healthy volunteers. Based on the results of the study, on average, the expected exposure to fluticasone furoate at a dose of 110 mcg when administered intranasally in this group of patients will not lead to cortisol suppression. Therefore, moderate hepatic impairment is not likely to result in clinically significant effects when given a standard adult dose.
Other pharmacokinetic parameters: fluticasone furoate concentrations are usually not determined (<10 pg / ml) when administered intranasally at a dose of 110 mcg once a day. Detectable concentrations were observed only in less than 31% of patients aged 12 years and older and in less than 16% of patients younger than 12 years when administered 110 mcg once a day intranasally.
No dependence on gender, age (including child age), or race was observed in cases where concentrations were above or below the detection threshold.
Absorption
After intranasal administration of fluticasone (200 mcg/day) Cmax blood plasma levels in most patients are below the detection level (<0.01 ng / ml). Direct absorption from the nasal mucosa is extremely low due to the low solubility of the drug in water, as a result, most of the dose is swallowed. From the gastrointestinal tract, less than 1% of the dose enters the blood due to low absorption and presystemic metabolism. These reasons are due to the extremely low total absorption of the drug from the nasal mucosa and gastrointestinal tract.
Distribution
Fluticasone in a stable state has a significant Vd - about 318 l. The binding to plasma proteins is 91%.
Metabolism
It has the effect of first passing through the liver. It is metabolized in the liver with the participation of the cytochrome P450 isoenzyme CYP3A4 with the formation of an inactive carboxyl metabolite.
Output
T1/2 It is 3 hours. It is mainly excreted through the intestine. The renal clearance of fluticasone is less than 0.2%, and the renal clearance of the metabolite containing the carboxyl group is less than 5%.
After inhaled administration, the absolute bioavailability is 10-30% (depending on the drug delivery system). Absorbed mainly in the lungs. If part of the inhaled dose is swallowed, the systemic effect is minimal due to the weak solubility of the drug in water and intensive metabolism during the" first pass " through the liver. The bioavailability of fluticasone propionate when absorbed from the gastrointestinal tract is less than 1%. There is a direct relationship between the value of the inhaled dose and the systemic effect of fluticasone propionate. The binding to plasma proteins is 91%. It has a large distribution volume (about 300 l). It is metabolized in the liver with the participation of the enzyme CYP3A4 of the cytochrome P450 system with the formation of an inactive metabolite. Renal clearance is insignificant (less than 0.2%). It has a high plasma Cl — 1150 ml / min. T1/2 it is 8 hours. It is excreted in the urine as a metabolite (less than 5%).
Arnuity Ellipta
Pregnant women and women during lactation should be prescribed the drug only if the expected benefit to the mother exceeds any possible risk to the fetus or child. There is insufficient data on the use of salmeterol and fluticasone propionate during pregnancy and lactation.
Excessive systemic concentration of active beta2- adrenomimetics and corticosteroids have an effect on the fetus. Extensive clinical experience with the use of drugs of this class indicates that when using therapeutic doses, the described effects are not clinically significant. Salmeterol and fluticasone propionate do not have genotoxicity.
The concentration of salmeterol and fluticasone propionate in the blood plasma after inhaling the drug in therapeutic doses is extremely low, so their concentration in breast milk should be as low. There are no data on the concentration of salmeterol and fluticasone propionate in breast milk of women during lactation.
Fluticasone Propionate
Included as part of the PRECAUTIONS section.
PRECAUTIONS Local Effects Of Inhaled CorticosteroidsIn 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 EpisodesARNUITY ELLIPTA is not indicated for the relief of acute symptoms, i.e., as rescue therapy for treatment of acute episodes 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 (e.g., albuterol) for treatment of acute symptoms, despite regular once-daily use of ARNUITY ELLIPTA. 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.
ImmunosuppressionPersons 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 patients who have not had these diseases or who have not 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 and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.
Inhaled corticosteroids 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 TherapyParticular care is needed for patients who are 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 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 improve control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid 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 medical identification warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.
Patients requiring systemic corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to ARNUITY ELLIPTA. Lung function (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 systemic 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.
Hypercorticism And Adrenal SuppressionARNUITY 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 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.
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 symptoms.
Drug Interactions With Strong Cytochrome P450 3A4 InhibitorsCaution should be exercised when considering the coadministration 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) because increased systemic corticosteroid adverse effects may occur.
Paradoxical Bronchospasm And Upper Airway SymptomsAs with other inhaled medicines, bronchospasm may occur with an immediate increase in wheezing after dosing. If 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 AnaphylaxisHypersensitivity 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 products containing lactose; therefore, patients with severe milk protein allergy should not use ARNUITY ELLIPTA.
Reduction In Bone Mineral DensityDecreases 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 outcomes, such as fracture, is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, 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 GrowthOrally 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.
Glaucoma And CataractsGlaucoma, 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.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).
Not for Acute SymptomsInform patients that ARNUITY ELLIPTA is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose. ARNUITY ELLIPTA is not a bronchodilator and should not be used to treat status asthmaticus or to relieve acute asthma symptoms. 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:
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 or reduce therapy with ARNUITY ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation.
Local EffectsInform 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.
ImmunosuppressionWarn 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 SuppressionAdvise patients that ARNUITY ELLIPTA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, instruct 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 DensityAdvise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk.
Reduced Growth VelocityInform 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.
Ocular EffectsAdvise patients that long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.
Hypersensitivity Reactions Including AnaphylaxisAdvise 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 EffectAdvise 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.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityFluticasone 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 in adults 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 equal to and 4 times, respectively, the MRHDID in adults on a mcg/m² basis).
Use In Specific Populations Pregnancy Teratogenic EffectsPregnancy Category C.
There are no adequate and well-controlled trials 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 reproduction 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.
There were no teratogenic effects in rats and rabbits at approximately 4 times and equal to, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mcg/m² basis at maternal inhaled doses up to 91 and 8 mcg/kg/day in rats and rabbits, respectively). There were no effects on perinatal and postnatal development in rats at approximately equal to the MRHDID in adults (on a mcg/m² basis at maternal doses up to 27 mcg/kg/day).
Nonteratogenic EffectsHypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.
Labor And DeliveryThere are no adequate and well-controlled human trials that have investigated the effects of ARNUITY ELLIPTA during labor and delivery.
Nursing MothersIt is not known whether fluticasone furoate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. 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.
Pediatric UseThe safety and efficacy in pediatric patients younger than 12 years have not been established.
Effects on GrowthOrally 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 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 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 his/her 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 systemic exposure of fluticasone furoate in this trial is lower than that of ARNUITY ELLIPTA. 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).
Geriatric UseFor the 4 confirmatory trials, 71 subjects were aged 65 and older (56 of which were treated with ARNUITY ELLIPTA) and 5 were aged 75 and older (1 of which was treated with ARNUITY ELLIPTA). 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 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 patients. 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.
Hepatic ImpairmentFluticasone furoate systemic exposure increased by up to 3-fold in 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.
Renal ImpairmentThere were no significant increases in fluticasone furoate exposure in subjects with severe renal impairment (CrCl less than 30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment.
Locally.
Treatment of acute and chronic dermatoses. The ointment or cream is applied in a thin layer to the affected areas of the skin 1-2 times a day. The course of treatment is 2 weeks.
Reducing the risk of relapses of the disease. After achieving a therapeutic effect in the acute phase of the disease, the frequency of application of the ointment or cream is reduced: it is recommended to apply the drug once 2 times a week without applying an occlusive dressing. Cutivate is applied to all previously affected areas of the skin or to areas where a relapse of the disease can be expected.
Intranasally.
To achieve the maximum therapeutic effect, it is necessary to adhere to a regular application scheme. The onset of action can be observed within 8 hours after the first administration. It may take several days to achieve the maximum effect. The absence of an immediate effect should be carefully explained to the patient.
For the symptomatic treatment of seasonal and year-round allergic rhinitis
Adults and adolescents (12 years and older): the recommended initial dose is 2 sprays (27.5 mcg of fluticasone furoate in 1 spray) in each nostril 1 time per day (110 mcg/day). When adequate control of symptoms is achieved, reducing the dose to 1 injection in each nostril once a day (55 mcg/day) may be effective for maintenance treatment.
Children from 2 to 11 years old: the recommended initial dose is 1 injection (27.5 mcg of fluticasone furoate in 1 injection) into each nostril once a day (55 mcg/day). In the absence of the desired effect with 1 spray in each nostril 1 time per day, it is possible to increase the dose to 2 sprays in each nostril 1 time per day (110 mcg/day). When adequate control of symptoms is achieved, it is recommended to reduce the dose to 1 spray in each nostril once a day (55 mcg/day).
Children under 2 years of age: There is insufficient data to recommend the use of fluticasone furoate intranasally as a treatment for seasonal and year-round allergic rhinitis in children under 2 years of age.
Elderly patients: no dose adjustment is required.
Patients with impaired renal function: no dose adjustment is required.
Patients with impaired liver function: dose adjustment is not required in patients with mild to moderate hepatic impairment. There are no data on the use in patients with severe hepatic impairment.
Instructions for use of nasal spray
Description of nasal spray: the drug is available in orange glass bottles of 30, 60 and 120 doses (Figure 1), which are in plastic cases.
The indicator window in the plastic packaging allows you to monitor the level of the drug in the bottle. In 30-or 60-dose vials, the level of the drug will be visible immediately, and in 120-dose vials, the initial level of the drug is above the upper limit of the viewing window.
To perform the injection, press the spray button with force. The removable cap protects the sprayer from dust and clogging.
Six important facts about the drug
1. Nasal spray is available in orange glass bottles. In order to check the level of the drug in the bottle, you need to look through it to the light. The level will be visible through the viewing window.
2. If the nasal spray is used for the first time, shake the bottle well for 10 seconds without removing the cap. The drug is a fairly thick suspension and becomes more liquid when shaken (Figure 2). Injection is only possible after shaking.
3. To perform the injection, press the button with force (Figure 3).
4. If you cannot press the button with one thumb, you must use the fingers of both hands (Figure 4).
5. Always keep the nasal spray bottle closed. The cap protects the sprayer from dust and clogging and seals the bottle. In addition, the cap prevents accidental pressing of the button.
6. Do not attempt to clean the tip hole with a pin or other sharp objects. They can damage the spray bottle.
Preparation for use should be carried out if:
- the spray is used for the first time,
"or the bottle was left open."
Proper preparation for the use of the spray will ensure the injection of the required dose of the drug.
Before use:
- without removing the cap, shake the bottle well for 10 seconds.,
- remove the cap by gently pulling it with your thumb and forefinger (Figure 5),
- it is necessary to hold the bottle vertically and point the tip away from you,
- press the button hard, make several taps (at least 6), until a small cloud appears from the tip (Figure 6).
Use of nasal spray
1. Shake the bottle thoroughly.
2. Remove the cap.
3. Clear your nose and tilt your head slightly forward.
4. Insert the tip into one nostril while still holding the bottle vertically (Figure 7).
5. Point the tip of the spray gun at the outer wall of the nose, not at the nasal septum. This will ensure the correct injection of the drug.
6. Start inhaling through your nose and press your finger once to inject the drug (Figure 8).
7. Avoid getting the spray in your eyes! If the drug gets into your eyes, you should thoroughly rinse them with water.
8. Remove the nebulizer from the nostril and exhale through the mouth.
9. If, according to the doctor's recommendation, it is necessary to make 2 injections in each nostril, it is necessary to repeat steps 4-6.
10. Repeat the procedure for the other nostril.
11. Close the bottle with a cap.
Care of the sprayer
After each application:
- blot the tip and the inner surface of the cap with a dry, clean cloth (Figure 9 and 10), avoid water ingress.,
- never attempt to clean the tip hole with a pin or other sharp objects.,
- it is always necessary to close the bottle, the cap protects the sprayer from dust and clogging and seals the bottle.
In case the sprayer does not work:
- it is necessary to check the level of the remaining drug in the bottle through the viewing window, if there is a very small amount of liquid left, it may not be enough for the sprayer to work,
- check the bottle for damage,
- check if the tip hole is clogged, do not try to clean the tip hole with a pin or other sharp objects . ,
- try to activate the device by repeating the procedure for preparing the nasal spray for use.
Intranasally.
Adults and children 12 years and older: 2 doses (100 mcg) in each nasal passage 1 time a day, preferably in the morning. In some cases, it is necessary to inject 2 doses into each nasal passage 2 times a day (the maximum daily dose is 400 mcg). After achieving the therapeutic effect, a maintenance dose of 50 mcg/day can be administered in each nasal passage (100 mcg). The maximum daily dose should not exceed 400 mcg (4 doses per nasal passage).
Elderly patients no dose adjustment is required.
Children aged 4 to 12 years: one dose (50 mcg) 1 time a day in each nasal passage, preferably in the morning. The maximum daily dose should not exceed 200 mcg in each nasal passage. It is necessary to apply a minimum dosage that ensures effective elimination of symptoms. To achieve the full therapeutic effect, the drug should be used regularly.
Instructions for use
The nasal spray bottle is equipped with a protective cap that protects the tip from dust and dirt.
At the first application, it is necessary to prepare the bottle: press the dispenser 6 times. The spray mechanism is unlocked. If the drug has not been used for more than 1 week, you should prepare the bottle again and unlock the spray mechanism.
Next, you need to:
- clear your nose,
- close one nasal passage and insert the tip into the other nasal passage,
- tilt your head slightly forward while still holding the aerosol bottle vertically,
- start inhaling through the nose and continue to inhale, make a single press with your fingers to spray,
- exhale through the mouth.
Then, in the same way, inject the drug into another nasal passage.
After use, blot the tip with a clean cloth or handkerchief and close it with a cap. The sprayer should be washed at least once a week. To do this, remove the tip, rinse it in warm water, dry it, and then carefully place it in the top of the bottle. Put on the protective cap. If the tip hole is clogged, remove the tip and leave it in warm water for a while. Then rinse under the jet, dry and put it back on the bottle. Do not clean the hole with a pin or other sharp objects.
After opening the package, the drug can be used until the expiration date.
Locally.
Treatment of acute and chronic dermatoses. The ointment or cream is applied in a thin layer to the affected areas of the skin 1-2 times a day. The course of treatment is 2 weeks.
Reducing the risk of relapses of the disease. After achieving a therapeutic effect in the acute phase of the disease, the frequency of application of the ointment or cream is reduced: it is recommended to apply the drug once 2 times a week without applying an occlusive dressing. Arnuity Ellipta is applied to all previously affected areas of the skin or to areas where a relapse of the disease can be expected.
Inhaled, after inhalation, rinse your mouth with water.
Bronchial asthma. Adults and adolescents over 16 years of age: 100-1000 mcg 2 times a day, depending on the severity of the disease: mild asthma — 100-250 mcg, medium form — 250-500 mcg, severe form — 500-1000 mcg. Depending on the individual response of the patient, the initial dose is either increased until the clinical effect appears or reduced to the minimum effective dose.
Children over 4 years of age (only in the form of an aerosol for inhalation, dosed with 50 mcg of fluticasone in one dose): the recommended dose is 50-100 mcg 2 times a day.
Children from 1 to 4 years: (only in the form of an aerosol for inhalation dosed with 50 mcg of fluticasone in one dose): 100 mcg 2 times a day. Younger children require higher doses compared to older children due to the reduced intake of the drug during inhalation (use of spacer, smaller lumen of the bronchi, intense nasal breathing). The drug is administered using an inhaler through a spacer with a face mask ("Babyhaler").
Chronic obstructive pulmonary disease. Adults, 500 mcg 2 times a day.
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 (see Figure 2). 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 Ketoconazolea on
the Pharmacokinetics (PK) of Fluticasone Furoate
a Compared with placebo group.
