Fluticasone

Crystals. MW 500.57. MP 272-273 °C (decomposes). Specific optical rotation: +30 deg at 25 °C/D (c = 0.35). Practically insolluble in water. Freely soluble in dimethylsulfoxide, dimethyl formate; slightly soluble in methanol, 95% ethanol. /Fluticasone propionate/

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]；H312 (100%): Harmful in contact with skin [Warning Acute toxicity, dermal]；H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]；H319 (100%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]；H332 (100%): Harmful if inhaled [Warning Acute toxicity, inhalation]

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P317, P321, P330, P332+P317, P337+P317, P362+P364, and P501 (click each P-code to see the statement)

The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

Androsta-1,4-diene-17-carbothioic acid, 6,9-difluoro-11,17-dihydroxy-16-methyl-3-oxo-, S-(fluoromethyl) ester, (6.alpha.,11.beta.,16.alpha.,17.alpha.)-: Does not have an individual approval but may be used under an appropriate group standard

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fluticasone propionate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Fluticasone propionate/

Fluticasone propionate HFA contents /are/ under pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120 °F may cause bursting. Never throw into fire or incinerator. Store at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F). Store the inhaler with the mouthpiece down. For best results, the inhaler should be at room temperature before use.

Store /fluticasone propionate inhalation powder/ at controlled room temperature, 20 to 25 °C (68 to 77 °F) in a dry place away from direct heat or sunlight. Keep out of reach of children. The Diskus inhalation device is not reusable. The device should be discarded 6 weeks after removal from the moisture-protective foil pouch or after all blisters have been used (when the dose indicator reads "0"), whichever comes first. Do not attempt to take the device apart.

Fluticasone propionate cream /and ointment should be/ stored between 2 and 30 °C (36 and 86 °F).

Fluticasone propionate nasal pump spray should be stored at 4-30 °C.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations.

In a placebo-controlled crossover study in 8 healthy volunteers, coadministration of a single dose of orally inhaled fluticasone propionate with multiple doses of ketoconazole to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should be exercised when fluticasone propionate is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 290(SRC), determined from a structure estimation method(2), indicates that fluticasone is expected to have moderate mobility in soil(SRC). Volatilization of fluticasone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.3X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Fluticasone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.4X10-13 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2009).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 290(SRC), determined from a structure estimation method(2), indicates that fluticasone is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.3X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from an estimated log Kow of 1.4(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2009).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), fluticasone, which has an estimated vapor pressure of 7.4X10-13 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase fluticasone may be removed from the air by wet or dry deposition(SRC). Fluticasone does not contain chromophores that absorb at wavelengths >290 nm(3) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

The adverse events from fluticasone include:；Local；* Dysphonia；* Oropharyngeal candidiasis；* Cough；* Pneumonia；Between 10% and 20% of inhaled corticosteroids make it to the lungs, meaning 80% to 90% go through to the gastrointestinal tract. The liver inactivates much of the medication during its first pass. The amount of drug not inactivated by the liver and the medication absorbed in the lungs are responsible for the systemic effects.；Systemic；* Adrenal suppression；* Growth suppression；* Bruising；* Osteoporosis；* Cataracts；* Glaucoma；* Metabolic abnormalities；* Psychiatric disturbances；In patients with asthma, there is a 21% higher risk of severe asthma exacerbation when treated with fluticasone alone compared to those treated with a combination of fluticasone and salmeterol.；Drug-Drug Interactions；Fluticasone, a substrate of CYP3A4, interacts with strong inhibitors of this enzyme, such as ritonavir, ketoconazole, and others. Co-administration with these inhibitors is not recommended due to the potential for increased adverse effects. Ritonavir specifically has been shown to significantly elevate plasma fluticasone levels and the risk of systemic adverse effects.

In lactating rats, subcutaneous administration of tritiated fluticasone propionate (10 ug/kg, approximately one-third the maximum recommended daily intranasal dosage in adults on a ug/sq m basis) resulted in measurable radioactivity in both plasma and milk.

There is documentation of substantial lactic acidosis after an overdose of inhaled salmeterol and fluticasone. The patient inhaled 60 puffs of the combination medication in a suicide attempt and presented with sympathomimetic syndrome, metabolic acidosis, and hyperlactatemia. She received supportive therapy and was within normal health limits the following day. This clinical presentation was likely due to the salmeterol being more than the fluticasone, which lent support to the idea that fluticasone is a relatively safe medication.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of fluticasone can be estimated to be 290(SRC). According to a classification scheme(2), this estimated Koc value suggests that fluticasone is expected to moderate mobility in soil.

/HUMAN EXPOSURE STUDIES/ Repeat oral doses up to 80 mg daily for 10 days in volunteers and repeat oral doses up to 10 mg daily for 14 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.

/HUMAN EXPOSURE STUDIES/ Intranasal administration of 2 mg of fluticasone propionate twice daily for 7 days to healthy human volunteers was well tolerated. Single oral doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported.

/SIGNS AND SYMPTOMS/ Particular care is needed for patients who are transferred from systemically active corticosteroids to fluticasone propionate inhalation powder 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.

/SIGNS AND SYMPTOMS/ Chronic overdosage may result in signs/symptoms of hypercorticism.

An estimated BCF of 3 was calculated in fish for fluticasone(SRC), using an estimated log Kow of 1.4(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for fluticasone is estimated as 2.3X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that fluticasone is expected to be essentially nonvolatile from water surfaces(2). Fluticasone's Henry's Law constant indicates that volatilization from moist soil surfaces may not occur(SRC). Fluticasone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.4X10-13 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ No evidence of carcinogenicity was seen in mice receiving oral fluticasone propionate dosages up to 1 mg/kg (approximately 20 times the maximum recommended daily intranasal dosage in adults and approximately 10 times the maximum recommended daily intranasal dosage in children on a ug/sq m basis) for 78 weeks or in rats receiving inhaled fluticasone propionate dosages up to 57 ug/kg (approximately 2 times the maximum recommended daily intranasal dosage in adults and approximately equivalent to the maximum recommended daily intranasal dosage in children on a ug/sq m basis) for 104 weeks.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Two 18-month studies were performed in mice to evaluate the carcinogenic potential of fluticasone propionate when given topically (as an 0.05% ointment) and orally. No evidence of carcinogenicity was found in either study.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Fluticasone propionate has been shown to be teratogenic and embryotoxic in mice or rats when administered subcutaneously at daily dosages of 45 or 100 ug/kg, respectively (approximately equivalent to 4 times the maximum recommended daily intranasal dosage in adults based on surface area). Observed fetal toxicity was characteristic of potent glucocorticoid compounds and included embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. ... Following oral administration of up to 300 ug/kg (approximately 25 times the maximum recommended daily intranasal dosage in adults on a ug/sq m basis) daily of fluticasone propionate in rabbits, the drug was not detected in plasma, and no maternal effects nor increased incidence of external, visceral, or skeletal fetal defects was detected. The low bioavailability and small distribution of fluticasone propionate across the placenta may account for the lack of teratogenicity; in rats and rabbits receiving oral fluticasone propionate dosages of 100 ug/kg (590 ug/sq m) or 300 ug/kg (3.6 mg/sq m), respectively, less than 0.008% of the dose crossed the placenta.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Fetal weight reduction and cleft palate were observed in offspring of rabbits given fluticasone propionate 4 ug/kg subcutaneously (less than the maximum recommended daily intranasal dosage in adults).

For more Non-Human Toxicity Excerpts (Complete) data for Fluticasone (6 total), please visit the HSDB record page.

Pediatric patients may be more susceptible to systemic toxicity from equivalent doses /of topical fluticasone propionate/ due to their larger skin surface to body mass ratios.

Parents of pediatric patients should be advised not to use this medication in the treatment of diaper dermatitis. Fluticasone propionate cream should not be applied in the diaper areas as diapers or plastic pants may constitute occlusive dressing.

Androsta-1,4-diene-17-carbothioic acid, 6,9-difluoro-11,17-dihydroxy-16-methyl-3-oxo-, S-(fluoromethyl) ester, (6.alpha.,11.beta.,16.alpha.,17.alpha.)-: Does not have an individual approval but may be used under an appropriate group standard

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fluticasone propionate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Fluticasone propionate/

D07AC17

D - Dermatologicals；D07 - Corticosteroids, dermatological preparations；D07A - Corticosteroids, plain；D07AC - Corticosteroids, potent (group iii)；D07AC17 - Fluticasone

R - Respiratory system；R01 - Nasal preparations；R01A - Decongestants and other nasal preparations for topical use；R01AD - Corticosteroids；R01AD08 - Fluticasone

R - Respiratory system；R03 - Drugs for obstructive airway diseases；R03B - Other drugs for obstructive airway diseases, inhalants；R03BA - Glucocorticoids；R03BA05 - Fluticasone

QR - Respiratory system；QR03 - Drugs for obstructive airway diseases；QR03B - Other drugs for obstructive airway diseases, inhalants；QR03BA - Glucocorticoids；QR03BA05 - Fluticasone

QR - Respiratory system；QR01 - Nasal preparations；QR01A - Decongestants and other nasal preparations for topical use；QR01AD - Corticosteroids；QR01AD08 - Fluticasone

Systemically, in vitro experiments show [DB08906] activates glucocorticoid receptors, inhibits nuclear factor kappa b, and inhibits lung eosinophilia in rats. [DB00588] performs similar activity but is not stated to affect nuclear factor kappa b. [DB00588] as a topical formulation is also associated with vasoconstriction in the skin.

[DB08906] and [DB00588] work through an unknown mechanism to affect the action of various cell types and mediators of inflammation. In vitro experiments show [DB08906] activating glucocorticoid receptors, inhibiting nuclear factor kappa b, and inhibiting lung eosinophilia in rats. [DB00588] performs similar activity but is not stated to affect nuclear factor kappa b.

Fluticasone propionate is a highly selective agonist at the human glucocorticoid receptor with negligible activity at androgen, estrogen, or mineralocorticoid receptors. In preclinical studies, fluticasone propionate reportedly exhibited weak progesterone-like activity. However, as plasma concentrations of fluticasone propionate are very low following intranasal administration of the drug in recommended doses, the clinical importance of this finding is not known. The therapeutic effects of fluticasone propionate are thought to result from local actions of the deposited inhaled dose on the nasal mucosa rather than from the systemic actions of the swallowed portion of the dose.

The exact mechanism(s) of anti-inflammatory action of corticosteroids in allergic rhinitis remains unknown, but may involve reductions in the following: number of mediator cells (basophils, eosinophils, helper-inducer [CD4+, T4] T-cells, mast cells, and neutrophils) in the nasal mucosa, nasal reactivity to allergens, and release of inflammatory mediators and proteolytic enzymes. Following exposure of patients with a history of allergic rhinitis to allergen, eosinophils, basophils, mast cells, T cells, and neutrophils appear to infiltrate nasal secretions and mucosa, releasing inflammatory mediators that generate allergic responses such as pruritus, sneezing, rhinorrhea, and nasal edema. /Corticosteroids/

Other mechanisms by which corticosteroids may improve symptoms of allergic rhinitis may involve inhibition of postcapillary venule dilation and permeability and facilitation of nasomucociliary clearance of nasal secretions. Patients receiving short- and long-term treatment with intranasal fluticasone propionate have demonstrated decreases in nasal turbinate swelling and mucosal inflammation. As inflammatory changes occur during periods of increased nasal hyperresponsiveness, the degree of response to nasal secretory stimuli has been used as an indirect measure of inflammation. In patients with asymptomatic seasonal allergic rhinitis, pretreatment with intranasal fluticasone propionate for 2-6 weeks prior to challenge with allergens or inflammatory mediatorsgenerally reduced the release of tryptase, histamine, eosinophilic cationic protein, and prostaglandin D2 in nasal biopsies or nasal lavage fluid; concentrations of eosinophils or activated eosinophils, CD4+ T-cells, and basophils also were reduced. /Corticosteroids/

Like other topical corticosteroids, fluticasone propionate has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.

15.1 hours for intranasal [DB08906] 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. 7.8 hours for intravenous [DB00588]. A study of 24 healthy Caucasian males shows a half life of 14.0 hours following intravenous administration and 10.8 hours following inhalation.

Following intravenous dose of 1 mg in healthy volunteers, fluticasone propionate showed polyexponential kinetics and had an average terminal half-life of 7.2 hours (range, 3.2 to 11.2 hours).

The apparent elimination half-life of fluticasone propionate after iv administration is approximately 3 hours.

[DB08906] and [DB00588] are cleared from hepatic metabolism by cytochrome P450 3A4. Both are hydrolysed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite.

Fluticasone propionate is rapidly metabolized in the liver by the cytochrome P-450 isoenzyme CYP3A4; the principal metabolite is the inactive 17beta-carboxylic acid derivative. ... Of the total radioactivity recovered in urine, 18% represented the inactive 17beta-carboxylic acid derivative of fluticasone propionate, 12% represented a less polar metabolite, and the remainder represented more polar metabolites. ... The 17beta-carboxylic acid metabolite of fluticasone propionate accounted for 3-40% of fecal excretion.

The inactive /17beta-carboxylic acid derivative/ had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone propionate incubated in a human skin homogenate.

CUT2W21N7U

FLUTICASONE

Established Pharmacologic Class [EPC] - Corticosteroid

Mechanisms of Action [MoA] - Corticosteroid Hormone Receptor Agonists

Fluticasone is a Corticosteroid. The mechanism of action of fluticasone is as a Corticosteroid Hormone Receptor Agonist.

Substances that reduce or suppress INFLAMMATION.

Agents that cause an increase in the expansion of a bronchus or bronchial tubes.

Drugs used to treat or prevent skin disorders or for the routine care of skin.

Agents that are used to treat allergic reactions. Most of these drugs act by preventing the release of inflammatory mediators or inhibiting the actions of released mediators on their target cells. (From AMA Drug Evaluations Annual, 1994, p475)

Intranasal exposure of [DB08906] 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%. Intranasal bioavailability of [DB00588] is <2%, and oral bioavailability is <1%. Intranasal exposure results in the majority of the dose being swallowed. Topical absorption of [DB00588] is very low but can change depending on a number of factors including integrity of the skin and the presence of inflammation or disease. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 9.0%.

[DB08906] is eliminated ≥90% in the feces and 1-2% in the urine. [DB00588] is mainly eliminated in the feces with <5% eliminated in the urine.

608L at steady state for intravenous administration of [DB08906]. 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. The volume of distribution of intravenous [DB00588] is 4.2L/kg. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 577L following intravenous administration.

57.8L/h for [DB08906]. A study of 24 healthy Caucasian males showed a clearance of 71.8L/h following intravenous administration. 1093mL/min for [DB00588]. A study of 24 healthy Caucasian males showed a clearance of 63.9L/h following intravenous administration.

Fluticasone propionate is poorly absorbed from the respiratory and GI tracts following nasal inhalation of the drug as an aqueous spray. Based on indirect calculations, intranasal fluticasone propionate has an absolute systemic bioavailability of less than 2%. A major portion of an intranasal dose of corticosteroids is swallowed and undergoes extensive first-pass metabolism in the liver. In patients with allergic rhinitis receiving intranasal fluticasone propionate for 2-3 weeks, plasma concentrations were above the level of detection of the assay (50 pg/mL) only when recommended dosages were exceeded, and in those instances, only in occasional samples at low concentrations.

Limited data from studies in which radiolabeled fluticasone propionate has been administered orally indicate that the drug is poorly absorbed from the GI tract and undergoes rapid first-pass metabolism in the liver. Preliminary data from a dose-ranging study suggests that the amount of unchanged fluticasone propionate in plasma increases with dose following oral administration, but the bioavailability of the radiolabeled drug averaged about 1% or less after oral doses of 1-40 mg.

Relieve inflammatory and pruritic symptoms of dermatoses and psoriases, intranasally to manage symptoms of allergic and non-allergic rhinitis, and orally for the treatment of asthma /Fluticasone propionate/

Fluticasone propionate is claimed to exert a topical effect on the lungs without significant systemic effects, due to its low systemic bioavailability. /Fluticasone propionate/

THERAP CAT: Antiallergic; antiasthmatic; anti-inflammatory /Fluticasone propionate/

Medication

Use (kg; approx.) in Germany (2009): >75；Consumption (g per capita; approx.) in Germany (2009): 0.000916；Calculated removal (%): 2

6alpha,9-difluoro-11beta-hydroxy-16alpha-methyl-3-oxo-17-propanoyloxy)androsta-1,4-diene-17beta-carboxylic acid

[(6alpha,9-difluoro-11beta-hydroxy-16alpha-methyl-3-oxo-17-(propanoyloxy)androsta-1,4-dien-17beta-yl]carbonyl]sulphenic acid

6alpha,9-difluoro-17-[[(fluoromethyl)sulpanyl]carbonyl]-11beta-hydroxy-16alpha-methyl-3-oxoandrosta-1,4-dien-17alpha-yl acetate

6alpha,9-difluoro-17-[(methylsulphanyl)carbonyl]-11beta-hydroxy-16alpha-methyl-3-oxoandrosta-1,4-dien-17alpha-yl propanoate

For more Impurities (Complete) data for Fluticasone (9 total), please visit the HSDB record page.

Fluticasone propionate nasal spray is an aqueous suspension of microfine fluticasone propionate for topical administration to the nasal mucosa by means of a metering, atomizing spray pump. Fluticasone propionate nasal spray also contains microcrystalline cellulose and carboxymethylcellulose sodium, dextrose, 0.02% w/w benzalkonium chloride, polysorbate 80, and 0.25% w/w phenylethyl alcohol, and has a pH between 5 and 7. /Fluticasone propionate/

Each gram of fluticasone propionate cream contains fluticasone propionate 0.5 mg in a base of propylene glycol, mineral oil, cetostearyl alcohol, Ceteth-20, isopropyl myristate, dibasic sodium phosphate, citric acid, purified water, and imidurea as preservative. /Fluticasone propionate/

Each gram of fluticasone propionate ointment contains fluticasone propionate 0.05 mg in a base of liquid paraffin, microcrystalline wax, propylene glycol, and sorbitan sesquioleate. /Fluticasone propionate/

Fluticasone propionate Diskus is a specially designed plastic inhalation delivery system containing a double-foil blister strip of a powder formulation of fluticasone propionate intended for oral inhalation only. The Diskus inhalation unit, which is the delivery component, is an integral part of the drug product. Each blister on the double-foil strip within the unit contains 50 mcg of microfine fluticasone propionate in 12.5 mg of formulation containing lactose (which contains milk proteins). /Fluticasone propionate/

Fluticasone propionate HFA inhalation aerosols (44, 110, 220 ug) are pressurized metered-dose aerosol units fitted with a counter. ... Each unit contains a microcrystalline suspension of fluticasone propionate (micronized) in propellant HFA-134a (1,1,1,2-tetrafluoroethane). It contains no other excipients. /Fluticasone propionate/