Fluticasone Furoate Nitto

Composition and Product Description: See Table 1.

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Physicochemical Properties: Nonproprietary name: Fluticasone furoate.
Chemical name: 6α,9-Difluoro-17β-[(fluoromethylsulfanyl)carbonyl]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17α-yl furan-2-carboxylate.
Molecular formula: C₂₇H₂₉F₃O₆S.
Molecular weight: 538.58.

Pharmacology: Mechanism of Action: Fluticasone furoate is a synthetic corticosteroid which exerts suppressive effects on allergic rhinitis and eosinophilic infiltration and has anti-inflammatory effects by stimulating the glucocorticoid receptor.
Suppressive effect on allergic rhinitis: In rat models of allergic rhinitis, nasal symptoms (sneezing and nose scratching) were suppressed with intranasal administration of fluticasone furoate, and the potency was similar to that of fluticasone propionate. Moreover, the duration of the effect against nose scratching was similar to that of fluticasone propionate, and the duration of the effect against sneezing was longer than that of fluticasone propionate.
Suppressive effect on eosinophilic infiltration: In actively sensitized rats, antigen-induced eosinophilic infiltration of the trachea was suppressed with intratracheal administration of fluticasone furoate, and the potency was similar to that of fluticasone propionate.
Anti-inflammatory effect: In rat and mouse models of delayed hypersensitivity, antigen-induced auricular edema was suppressed with topical application of fluticasone furoate to the auricle, and the potency was similar to that of fluticasone propionate.
Pharmacokinetics: Blood Level: Healthy adults: Regarding blood levels of fluticasone furoate when administered intranasally at 110, 220, and 440 µg^Note) as a single dose and once daily (440 µg/day^Note)) repeatedly for 7 days, the levels were below the lower limit of quantification (10 pg/mL) with single doses up to 220 µg. At 440 µg, the levels were slightly above the lower limit of quantification in 1 of 8 subjects who had received a single dose and in 3 of 8 subjects who had received repeated doses. In subjects whose blood levels exceeding the lower limit of quantification, the maximum plasma concentration in the subject who had received a single dose and the 3 subjects who had received repeated doses was 10.7-14.6 pg/mL.
Pediatric patients with perennial allergic rhinitis: The blood levels at 0.5-2.0 h after the dose on the last day of 12-week intranasal administration of fluticasone furoate at 55 µg once daily were below the lower limit of quantification (10 pg/mL) in most of the subjects. In subjects whose blood levels exceeding the lower limit of quantification, the plasma concentrations of 2 subjects in the 2 to <6 years group were 10.9 and 13.1 pg/mL, and those of 3 subjects in the 6 to <15 years group were 14.9-23.7 pg/mL.
Comparative study of systemic exposure: Either Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray (56 Sprays) or Allermist 27.5 μg metered nasal spray 56 sprays (reference product) was administered at a dose of 2 sprays (110 µg as fluticasone furoate) into each nostril in 36 healthy adult males in a crossover study, and plasma fluticasone furoate concentrations were then measured. As a result, the mean and maximum values for the maximum plasma concentrations (C_max) of unchanged drug at all measurement time points in all the subjects were confirmed to be below the prescribed acceptable limit (25 pg/mL).
Distribution: The human plasma protein binding rate was ≥99% in vitro.
Metabolism: Fluticasone furoate was mainly metabolized by CYP3A4 in the liver, and 17β-carboxylate was the main circulating metabolite with oral administration in healthy adult volunteers (data obtained from non-Japanese participants). (See Interactions).
Excretion: The main route of excretion was via the feces, and urinary excretion rates with oral administration and intravenous administration were approximately 1% and 2%, respectively (data obtained from non-Japanese participants).
Patients with Specific Backgrounds: Patients with hepatic impairment: Intranasal administration of fluticasone furoate in patients with hepatic impairment has not been evaluated.
Increases in C_max and area under the concentration-time curve (AUC) have been reported in patients with moderate hepatic impairment who inhaled a single dose of fluticasone furoate at 400 µg^Note) (data obtained from non-Japanese participants).
Drug-Drug Interaction: CYP3A4 inhibitors: In subjects receiving repeated intranasal administration of fluticasone furoate at 110 µg/day for 7 days, coadministration with the potent CYP3A4 inhibitor ketoconazole (orally administered at 200 mg once daily, not marketed in Japan) resulted in more subjects (6 of 20 subjects) with quantifiable fluticasone furoate blood concentrations compared to placebo (1 of 20 subjects). Following 7-day coadministration, the ratio (90% confidence interval in parentheses) of the weighted average for 24-h serum cortisol levels in ketoconazole group compared to that in placebo group was 0.95 (0.86-1.04) (data obtained from non-Japanese participants). (See Precautions for Co-administration under Interactions.)
^Note):The approved dosage of Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray is 2 sprays (27.5 µg×2) per dose into each nostril once daily (110 µg/day) for adults and 1 spray (27.5 µg×1) per dose into each nostril once daily (55 µg/day) for children.

Allergic rhinitis.

Adults and Adolescents (12 years and over): Usual dose is 2 sprays (1 spray containing 27.5 mcg of fluticasone furoate) in each nostril once daily.
Children (2 to 11 years of age): Usual dose is 1 spray (1 spray containing 27.5 mcg of fluticasone furoate) in each nostril once daily.

This drug is contraindicated to the following patients: Patients with infections for which no effective antibacterial drugs exist, or deep mycoses [Symptoms may be aggravated]; Patients with a history of hypersensitivity to the ingredients of this product.

Precautions Concerning Dosage and Administration: To achieve an adequate clinical effect with Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray, use the drug continuously.
Important Precautions: In cases where nasal symptoms worsen during treatment with Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray, co-administer an antihistamine or systemic steroid over the short term, and gradually reduce the dose of the co-administered drug in line with improving symptoms.
The dose of the systemic steroid is to be reduced gradually after confirmation that symptoms have stabilized following the start of administration of Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray. The dose reduction is to be performed in accordance with the general dose reduction methods for steroids.
Bronchial asthma and occasionally symptoms such as eczema, urticaria, dizziness, palpitations, malaise, hot flushes of the face, and conjunctivitis may occur or worsen with reduction and withdrawal of systemic steroids. If such symptoms develop, perform appropriate treatment.
In cases where Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray is used over the long term in patients with perennial allergic rhinitis, make efforts towards reducing the dose of the drug when symptomatic improvement is maintained.
Systemic effects (including Cushing's syndrome, Cushingoid features, adrenocortical suppression, growth retardation in children, decreased bone density, cataract, glaucoma, and central serous chorioretinopathy) may develop with administration of nasal steroids, although less probable than with systemic steroids. Particularly in the event of long-term or high-dose administration, perform tests on a regular basis and perform appropriate treatment in cases where the systemic effects are observed.
Precautions Concerning Patients with Specific Backgrounds: Patients with Complication or History of Diseases, etc.: Patients with nose and throat infections (excluding infections for which no effective antibacterial drugs exist, or deep mycoses): Symptoms may be aggravated.
Patients with recurrent epistaxis: Bleeding may be aggravated.
Patients with severe hypertrophic rhinitis or nasal polyps: To ensure the effect of Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray in the nasal cavities, other therapies should be used concomitantly so that the symptoms of these diseases are improved to a certain extent.
Patients on long-term or high-dose systemic steroid therapy: Perform adrenocortical function tests both during reduction and post-withdrawal of systemic steroids, and pay adequate attention to invasion by traumas, surgeries, severe infections, etc. Moreover, temporarily increase the dose of systemic steroids if necessary. Adrenocortical insufficiency may have been occurred in these patients.
Precautions Concerning Use: Precautions concerning the dispensing of the drug: Use solely for the purpose of spraying intranasally.
Shake the container well vertically before using Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray.
When a new spray device is used, prime the device by releasing approximately 10 sprays into the air and confirm that the solution has completely turned into a mist before use.
Other Precautions: Information Based on Clinical Use: It has been reported that nasal congestion occurs as an adverse reaction of antihypertensives such as reserpine and α-methyldopa. In allergic rhinitis patients who are taking such antihypertensives, since the effect of Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray against nasal congestion may be masked, administer the drug while the patients are carefully monitored.
Use in Pregnancy & Lactation: See USE IN PREGNANCY & LACTATION section for further information.
Use in Children: Growth retardation may develop as a result of administration of nasal steroids, particularly in the event of long-term or high-dose administration, although it is less probable comparing to that of a result of administration of systemic steroids. In cases where Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray is administered over the long term in children, monitor the course such as by measuring height, etc., on a regular basis. Moreover, provide proper instructions regarding the methods of use when Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray is used.
No clinical studies have been conducted in low-birth-weight babies, newborns, babies, or infants <2 years old.
Use in the Elderly: Carefully administer Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray while the patient's condition is monitored. The physiological functions of geriatric patients are generally decreased.

Pregnant Women: In pregnant women and women who may be pregnant, administer Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray only when the therapeutic benefits outweigh the risks. Glucocorticoids have been shown to be teratogenic in experimental animals, but no teratogenic effects have been observed with inhalation of fluticasone furoate in rats (up to 91 µg/kg/day) or rabbits (up to 8 µg/kg/day), and no effects on development before and after birth have been observed in rats. Low fetal weight, increased incidence of incomplete ossification (in rats), and miscarriages (in rabbits) related to maternal toxicity due to exposure by inhalation at high doses have been reported.
Breast-feeding Women: Consider whether to continue or discontinue breastfeeding with the benefits of treatment and benefits of breastfeeding in mind.

Since the adverse reactions as follows may occur, perform adequate monitoring and take appropriate measures, including discontinuation of administration, in the event of abnormalities.
Clinically Significant Adverse Reactions: Anaphylactic reaction (incidence unknown).
Other Adverse Reactions: See Table 2.

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This product is mainly metabolized by cytochrome P450 3A4 (CYP3A4). (See Pharmacology: Pharmacokinetics: Metabolism under Actions.)
Precautions for Co-administration: This drug should be administered with caution when co-administered with the following: See Table 3.

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Store at or below 25°C.
Shelf Life: 3 years.

Nasal Decongestants & Other Nasal Preparations

R01AD12 - fluticasone furoate ; Belongs to the class of topical corticosteroids used for prophylaxis and treatment of allergic rhinitis.

P₁S₁S₃