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Fluticasone furoate

Fluticasone furoate structure

CAS No:
397864-44-7
Formula:
C27H29F3O6S
Chemical Name:
Fluticasone furoate
Synonyms:
Androsta-1,4-diene-17-carbothioic acid,6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-,S-(fluoromethyl) ester,(6α,11β,16α,17α)-;6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester;GW 685698X;Fluticasone furoate;Allermist;GSK 685 698;Avamys;Furamist;Veramyst;Alisade
Categories:
Pharmaceutical Intermediates > Bulk Drug Intermediates

Description

Fluticasone furoate is a trifluorinated corticosteroid that consists of 6alpha,9-difluoro-11beta,17alpha-dihydroxy-17beta-{[(fluoromethyl)sulfanyl]carbonyl}-16-methyl-3-oxoandrosta-1,4-diene bearing a 2-furoyl substituent at position 17. Used in combination with vilanterol trifenate for treatment of bronchospasm associated with chronic obstructive pulmonary disease. It has a role as an anti-allergic agent, a prodrug and an anti-asthmatic drug. It is an 11beta-hydroxy steroid, a corticosteroid, a fluorinated steroid, a steroid ester, a 2-furoate ester, a thioester and a 3-oxo-Delta(1),Delta(4)-steroid. It derives from a fluticasone. It derives from a hydride of an androstane.|Fluticasone furoate is a synthetic glucocorticoid available as an inhaler and nasal spray for various inflammatory indications. Fluticasone furoate was first approved in 2007.

Fluticasone furoate Basic Attributes

Molecular Weight：

538.58

Exact Mass：

538.58

EC Number：

222-789-2

UNII：

JS86977WNV

DSSTox ID：

DTXSID60228586

ATC Code：

R03AL08|R03AK10|R01AD12|R - Respiratory system

Characteristics

PSA：

119.11000

XLogP3：

4.92680

Density：

1.39

Melting Point：

250-252

Boiling Point：

625.2±55.0 °C(Predicted)

Water Solubility：

Insoluble

PKA：

12.52±0.70

Safety Information

GHS Classification：

|Danger|H360 (37.5%): May damage fertility or the unborn child [Danger Reproductive toxicity]|P201, P202, P260, P273, P281, P308+P313, P314, P391, P405, and P501|Aggregated GHS information provided by 8 companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Toxicity

Toxicity Summary：

Fluticasone furoate administered nasally may be associated with adrenal suppression or an increase in QTc interval though the association has not been well demonstrated in studies. Fluticasone furoate requires no dosage adjustment in renal impairment but must be used in caution in hepatic impairment due to the elimination mechanisms. Fluticasone furoate is not associated with carcinogenicity, mutagenicity, or impairment of fertility. There are no well controlled studies in pregnancy or lactation though animal studies have shown teratogenicity and hypoadrenalism in the offspring of treated mothers and other corticosteroids are known to be excreted in breast milk. Generally, there are no reported adverse effects with fluticasone in pregnancy. Pediatric patients should be given the lowest possible dose and monitored for reduction in growth velocity. There is insufficient evidence to determine whether geriatric patients respond differently to other patients. Systemic exposure may be 27-49% higher in Japanese, Korean, and Chinese patients compared to Caucasian patients. Caution should be exercised in these patients and the benefit and risk should be assessed before deciding on a treatment.

Protein Binding：

Fluticasone furoate is >99% protein bound in serum and may be as high as 99.6%.

Drug Information

Drug Indication：

Fluticasone furoate is indicated as an inhaler for the treatment and management of asthma by prophylaxis. The fluticasone furoate nasal spray is indicated for treating season and perennial allergic rhinitis.|FDA Label|Trelegy Ellipta is indicated as a maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting β2-agonist.|Temybric Ellipta is indicated as a maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting β2-agonist or a combination of a long-acting β2-agonist and a long-acting muscarinic antagonist (for effects on symptom control and prevention of exacerbations see section 5.1).|Asthma IndicationRevinty Ellipta is indicated in the regular treatment of asthma in adults and adolescents aged 12 years and older, where use of a combination product (long-acting beta2-agonist and inhaled corticosteroid) is appropriate:patients not adequately controlled with inhaled corticosteroids and “as needed” inhaled short acting beta2-agonists.COPD IndicationRevinty Ellipta is indicated for the symptomatic treatment of adults with COPD with a FEV1|Adults, adolescents (12 years and over) and children (6-11 years). Avamys is indicated for the treatment of the symptoms of allergic rhinitis.|Asthma indication:Relvar Ellipta is indicated in the regular treatment of asthma in adults and adolescents aged 12 years and older, where use of a combination product (long-acting beta2-agonist and inhaled corticosteroid) is appropriate:patients not adequately controlled with inhaled corticosteroids and “as needed” inhaled short acting beta2-agonists.patients already adequately controlled on both inhaled corticosteroid and long-acting beta2-agonist.COPD indication:Relvar Ellipta is indicated for the symptomatic treatment of adults with COPD with a FEV1|Elebrato Ellipta is indicated as a maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting β2-agonist.|Adults, adolescents (12 years and over) and children (6 - 11 years). Alisade is indicated for the treatment of the symptoms of allergic rhinitis.|Treatment of asthma

Pharmacology：

Systemically, in vitro experiments show fluticasone furoate activates glucocorticoid receptors, inhibits nuclear factor kappa b, and inhibits lung eosinophilia in rats.

Absorption：

Intranasal exposure of fluticasone furoate results in patients swallowing a larger portion of the dose. However, absorption is poor and metabolism is high, therefore there is negligible systemic exposure with a nasal bioavailability of 0.50% and oral bioavialability of 1.26%. Inhaled bioavailability is 13.9%. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 6.3-18.4%.|Fluticasone furoate is eliminated ≥90% in the feces and 1-2% in the urine.|608L at steady state for intravenous administration of fluticasone furoate. Other reports suggest the mean volume of distribution at steady state is 661L. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 704L following intravenous administration.|57.8L/h for fluticasone furoate. A study of 24 healthy Caucasian males showed a clearance of 71.8L/h following intravenous administration.

Metabolism/Metabolites：

Fluticasone furoate is cleared from hepatic metabolism by cytochrome P450 3A4. Fluticasone furoate is hydrolysed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite.

Biological Half-Life：

15.1 hours for intranasal fluticasone furoate and 24 hours for the inhaled formulation. A study of 24 healthy Caucasian males showed a half life of 13.6 hours following intravenous administration and 17.3-23.9 hours followed inhalation.

Mechanism of Action：

Fluticasone furoate works through an unknown mechanism to affect the action of various cell types and mediators of inflammation. In vitro experiments show fluticasone furoate activating glucocorticoid receptors, inhibiting nuclear factor kappa b, and inhibiting lung eosinophilia in rats.

MeSH Entry Terms：

fluticasone furoate

Fluticasone furoate Use and Manufacturing

Uses

A synthetic corticosteroid

Use Classification：

Human drugs -> Trelegy Ellipta -> EMA Drug Category|Drugs for obstructive airway diseases -> Human pharmacotherapeutic group|Human drugs -> Temybric Ellipta -> EMA Drug Category|Human drugs -> Revinty Ellipta -> EMA Drug Category|Adrenergics and other drugs for obstructive airway diseases -> Human pharmacotherapeutic group|Human drugs -> Avamys -> EMA Drug Category|Nasal preparations, Corticosteroids -> Human pharmacotherapeutic group|Human drugs -> Relvar Ellipta -> EMA Drug Category|Human drugs -> Elebrato Ellipta -> EMA Drug Category|Human drugs -> Alisade -> EMA Drug Category|Nasal preparations -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

Computed Properties

Molecular Weight:538.6
XLogP3:4.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:10
Rotatable Bond Count:6
Exact Mass:538.16369430
Monoisotopic Mass:538.16369430
Topological Polar Surface Area:119
Heavy Atom Count:37
Complexity:1080
Defined Atom Stereocenter Count:9
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes

Drug Function and Efficacy

It is a synthetic trichlorinated glucocorticoid with anti-inflammatory activity. It works by activating glucocorticoid response components, inhibiting pro-inflammatory transcription factors such as NFKB, and inhibiting antigen-induced pulmonary eosinophilia in sensitized rats.

This ingredient has been used in drugs with the following functions (note: it does not mean that the ingredient itself has the following health functions)

Related Drugs

Flutimevir inhalation powder
Ingredients	This product is a compound preparation, and its active ingredients are fluticasone furoate, umeclidinium bromide and vilanterol triphenylacetate. Active ingredient: Fluticasone furoate Chemical name: (6,11,16,17)-6,9-difluoro-17-{[(fluoromethyl)thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diethylenetriamine-17-furoic acid methyl ester Chemical structure: Molecular formula: C27H29F3O6S Molecular weight: 538.58 Active ingredient: umeclidinium bromide Chemical name: 1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-nitrogen cation bicyclo[2.2.2]bromooctane Chemical structure: Molecular formula: C29H34NO2·Br Molecular weight: 508.5 Active ingredient: Vilanterol triphenylacetate Chemical name: Triphenylacetic acid-4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol Chemical structure: Molecular formula: C24H33Cl2NO5·C20H16O2 Molecular weight: 774.8 Excipients: lactose (C12H22O11·H2O), magnesium stearate.
Indication	Due to the low plasma concentrations achieved after inhaled administration, clinically significant drug interactions mediated by FF/UMEC/VI are not expected to occur at clinical doses. Interactions with Beta-Blockers Beta-2 adrenergic blockers may attenuate or antagonize the effects of beta-2 adrenergic agonists (e.g., VI). If a beta-blocker is necessary, a cardioselective beta-blocker should be considered, but concomitant use of non-selective and selective beta-blockers should be used with caution. Interactions with CYP3A4 Inhibitors Both FF and VI are rapidly cleared by extensive first-pass metabolism mediated by the CYP3A4 enzyme. Caution should be exercised when coadministering with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, cobicistat-containing products) as systemic exposure of FF and VI may be increased, leading to an increased potential for adverse reactions. Coadministration should be avoided unless the benefit outweighs the increased risk of adverse reactions from systemic corticosteroids, in which case patients should be monitored for systemic corticosteroid adverse reactions. A repeat-dose study was conducted in healthy subjects with FF/VI (200 μg/25 μg) and ketoconazole (400 mg; a strong CYP3A4 inhibitor). Coadministration increased the mean 0-24 hour area under the plasma concentration-time curve (AUC(0-24)) and peak plasma concentration (Cmax) of FF by 36% and 33%, respectively. Increased FF exposure decreased 0-24 hour weighted mean serum cortisol by 27%. Coadministration increased the mean AUC(0-t) and Cmax of VI by 65% and 22%, respectively. Increased VI exposure did not result in β2-agonist-related systemic effects on heart rate or potassium. Interactions with CYP2D6 Inhibitors/CYP2D6 PolymorphismsUMEC is a substrate of cytochrome P4502D6 (CYP2D6). The steady-state pharmacokinetics of UMEC were evaluated in healthy volunteers lacking CYP2D6 (poor metabolizers). At doses 8 times the therapeutic dose, no effects on UMECAUC or Cmax were observed. At dose increases up to 16-fold, an approximately 1.3-fold increase in UMECAUC was observed with no effect on UMECCmax. Based on the magnitude of these changes, no clinically relevant drug interactions are expected to occur when FF/UMEC/VI is co-administered with CYF2D6 inhibitors in patients with genetic defects in CYP2D6 activity (poor metabolizers) (see [Pharmacokinetics]). Interactions with P-glycoprotein inhibitors FF, UMEC, and VI are substrates of the P-glycoprotein transporter (P-gp). The effects of the moderate P-gp inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of UMEC and VI were evaluated in healthy volunteers. No effects of verapamil on UMEC and VICmax were observed. An approximately 1.4-fold increase in UMECAUC was observed with no effect on VIAUC. Based on the magnitude of these changes, no clinically relevant drug interactions are expected to occur when FF/UMEC/VI is co-administered with P-gp inhibitors. Clinical pharmacology studies of specific P-gp inhibitor interactions with FF have not been conducted. Other Long-Acting Antimuscarinics and Long-Acting β2-Adrenergic Agonists Coadministration of vilanterol with other long-acting muscarinic antagonists (LAMAs) or long-acting β2-adrenergic agonists (LABAs) has not been studied and is not recommended because of the potential for enhanced adverse reactions (see Adverse Reactions and Overdosage). Similar to interactions with monoamine oxidase inhibitors and tricyclic antidepressants and other β2-agonists, vilanterol should be used with extreme caution in patients receiving monoamine oxidase inhibitors, tricyclic antidepressants, or medications known to prolong the QTc interval and within 2 weeks of discontinuation of such medications because such medications may enhance the cardiovascular effects of adrenergic agonists. Medications known to prolong the QTc interval increase the risk of ventricular arrhythmias. Additive effects may occur when anticholinergics are coadministered with anticholinergics. Therefore, the concomitant use of this product with other drugs containing anticholinergic agents should be avoided to avoid increased anticholinergic adverse reactions (see [Precautions]). Hypokalemia: Concomitant hypokalemia treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may enhance the hypokalemic effect of β2-adrenergic agonists, so caution should be exercised (see [Precautions]).
Specifications	Fluticasone furoate 100 micrograms, umeclidinium bromide (calculated as umeclidinium) 62.5 micrograms and vilanterol triphenylacetate (calculated as vilanterol) 25 micrograms

Fluticasone furoate nasal spray
Specifications	Each spray contains 27.5 micrograms of fluticasone furoate

Fluticasone furoate nasal spray
Specifications	Each spray contains 27.5 micrograms of fluticasone furoate

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Registered Holders

AURISCO PHARMACEUTICAL CO LTD

United States
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AARTI PHARMALABS LTD

United States
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STERLING SPA

United States
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