Fluticasone Propionate

FLUTICASONE PROPIONATE- fluticasone propionate cream
Padagis Israel Pharmaceuticals Ltd

For Dermatologic Use Only. Not for Ophthalmic Use.

Rx Only

DESCRIPTION

Fluticasone Propionate Cream, 0.05% contains fluticasone propionate [(6α,11β,16α,17α)-6,9,-difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy)androsta-1,4-diene-17-carbothioic acid, S-fluoromethyl ester], a synthetic fluorinated corticosteroid, for topical dermatologic use. The topical corticosteroids constitute a class of primarily synthetic steroids used as anti-inflammatory and antipruritic agents.

Chemically, fluticasone propionate is C25 H31 F3 O5 S. It has the following structural formula:

Structural Formula
(click image for full-size original)

Fluticasone propionate has a molecular weight of 500.6. It is a white to off-white powder and is insoluble in water.

Each gram of Fluticasone Propionate Cream, 0.05% contains fluticasone propionate 0.5 mg in a base of ceteth-20, cetostearyl alcohol, citric acid, dibasic sodium phosphate, isopropyl myristate, mineral oil, propylene glycol, and purified water, with imidurea as a preservative.

CLINICAL PHARMACOLOGY

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 .

Fluticasone propionate is lipophilic and has a strong affinity for the glucocorticoid receptor. It has weak affinity for the progesterone receptor, and virtually no affinity for the mineralocorticoid, estrogen, or androgen receptors. The therapeutic potency of glucocorticoids is related to the half-life of the glucocorticoid-receptor complex. The half-life of the fluticasone propionate-glucocorticoid receptor complex is approximately 10 hours.

Studies performed with fluticasone propionate cream, 0.05% indicate that it is in the medium range of potency as compared with other topical corticosteroids.

Pharmacokinetics

Absorption –

The activity of Fluticasone Propionate Cream, 0.05% is due to the parent drug, fluticasone propionate. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusive dressing enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption.

In a human study of 12 healthy males receiving 12.5 g of 0.05% fluticasone propionate cream twice daily for 3 weeks, plasma levels were generally below the level of quantification (0.05 ng/mL). In another study of 6 healthy males administered 25 g of 0.05% fluticasone propionate cream under occlusion for 5 days, plasma levels of fluticasone ranged from 0.07 to 0.39 ng/mL.

In an animal study using radiolabeled 0.05% fluticasone propionate cream and ointment preparations, rats received a topical dose of 1 g/kg for a 24-hour period. Total recovery of radioactivity was approximately 80% at the end of 7 days. The majority of the dose (73%) was recovered from the surface of the application site. Less than 1% of the dose was recovered in the skin at the application site. Approximately 5% of the dose was absorbed systemically through the skin. Absorption from the skin continued for the duration of the study (7 days), indicating a long retention time at the application site.

Distribution –

Following intravenous administration of 1 mg fluticasone propionate in healthy volunteers, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The apparent volume of distribution averaged 4.2 L/kg (range, 2.3 to 16.7 L/kg). The percentage of fluticasone propionate bound to human plasma proteins averaged 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes. Fluticasone propionate is not significantly bound to human transcortin.

Metabolism –

No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone propionate incubated in a human skin homogenate. The total blood clearance of systemically absorbed fluticasone propionate averages 1,093 mL/min (range, 618 to 1,702 mL/min) after a 1-mg intravenous dose, with renal clearance accounting for less than 0.02% of the total. Fluticasone propionate is metabolized in the liver by cytochrome P450 3A4-mediated hydrolysis of the 5-fluoromethyl carbothioate grouping. This transformation occurs in 1 metabolic step to produce the inactive 17-β-carboxylic acid metabolite, the only known metabolite detected in man. This metabolite has approximately 2,000 times less affinity 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.

Excretion –

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).

INDICATIONS AND USAGE

Fluticasone Propionate Cream, 0.05% is a medium potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Fluticasone Propionate Cream, 0.05% may be used with caution in pediatric patients 3 months of age or older. The safety and efficacy of drug use for longer than 4 weeks in this population have not been established. The safety and efficacy of Fluticasone Propionate Cream, 0.05% in pediatric patients below 3 months of age have not been established.

CONTRAINDICATIONS

Fluticasone Propionate Cream, 0.05% is contraindicated in those patients with a history of hypersensitivity to any of the components in the preparation (see PRECAUTIONS).

PRECAUTIONS

Fluticasone Propionate Cream, 0.05% contains the excipient imidurea which releases formaldehyde as a breakdown product. Formaldehyde may cause allergic sensitization or irritation upon contact with the skin. Fluticasone Propionate Cream, 0.05% should not be used in individuals with hypersensitivity to formaldehyde as it may prevent healing or worsen dermatitis.

General –

Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal from treatment. Manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment.

Patients applying a potent topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free cortisol tests.

If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products.

Fluticasone propionate cream, 0.05% caused depression of A.M. plasma cortisol levels in 1 of 6 adult patients when used daily for 7 days in patients with psoriasis or eczema involving at least 30% of the body surface. After 2 days of treatment, this patient developed a 60% decrease from pretreatment values in the A.M. plasma cortisol level.

There was some evidence of corresponding decrease in the 24-hour urinary free cortisol levels. The A.M. plasma cortisol level remained slightly depressed for 48 hours but recovered by day 6 of treatment.

Fluticasone propionate cream, 0.05%, caused HPA axis suppression in 2 of 43 pediatric patients, ages 2 and 5 years old, who were treated for 4 weeks covering at least 35% of the body surface area. Follow-up testing 12 days after treatment discontinuation, available for 1 of the 2 subjects, demonstrated a normally responsive HPA axis (see PRECAUTIONSPediatric Use).

Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios (see PRECAUTIONSPediatric Use).

The following local adverse reactions have been reported with topical corticosteroids, and they may occur more frequently with the use of occlusive dressings and higher potency corticosteroids. These reactions are listed in an approximately decreasing order of occurrence: irritation, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infections, skin atrophy, striae, hypertrichosis, and miliaria.

Fluticasone Propionate Cream, 0.05% may cause local cutaneous adverse reactions (see ADVERSE REACTIONS).

If irritation develops, Fluticasone Propionate Cream, 0.05% should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing.

If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of Fluticasone Propionate Cream, 0.05% should be discontinued until the infection has been adequately controlled.

Fluticasone Propionate Cream, 0.05% should not be used in the presence of preexisting skin atrophy and should not be used where infection is present at the treatment site. Fluticasone Propionate Cream, 0.05% should not be used in the treatment of rosacea and perioral dermatitis.

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