Pharmacotherapeutic Group: Corticosteroid, potent (Group III). ATC Code: D07AC.
Pharmacology: Pharmacodynamics: Mechanism of Action: Topical corticosteroids have anti-inflammatory, antipruritic, and vasoconstrictive properties. They act as anti-inflammatory agents via multiple mechanisms to inhibit late phase allergic reactions, including decreasing the density of mast cells, decreasing chemotaxis and activation of eosinophils, decreasing cytokine production by lymphocytes, monocytes, mast cells and eosinophils, and inhibiting the metabolism of arachidonic acid.
Fluticasone propionate is a glucocorticoid with high topical anti-inflammatory potency but low HPA-axis suppressive activity after dermal administration. It therefore has a therapeutic index which is greater than most of the commonly available steroids.
It shows high systemic glucocorticoid potency after subcutaneous administration but very weak oral activity, probably due to metabolic inactivation. In vitro studies show a strong affinity for, and agonist activity at, human glucocorticoid receptors.
Pharmacodynamic Effects: Fluticasone propionate has no unexpected hormonal effects, and no overt, marked effects upon the central and peripheral nervous systems, the gastrointestinal system, or the cardiovascular or respiratory systems.
Pharmacokinetics: Absorption: Bioavailability is very low after topical or oral administration, due to limited absorption through the skin or from the gastrointestinal tract, and because of extensive first pass metabolism.
Oral bioavailability approaches zero, due to poor absorption and extensive first pass metabolism. Therefore systemic exposure of fluticasone propionate from any ingestion of CUTIVATE Cream will be low.
Distribution: Distribution studies have shown that only minute traces of orally administered compound reach the systemic circulation, and that any systemically available fluticasone propionate is rapidly eliminated in the bile and excreted in the faeces.
Fluticasone propionate does not persist in any tissue, and does not bind to melanin.
Metabolism: Pharmacokinetic data for the rat and dog indicate rapid elimination and extensive metabolic clearance. In man too, metabolic clearance is extensive, and elimination is consequently rapid. Thus drug entering the systemic circulation via the skin will be rapidly inactivated. The major route of metabolism is hydrolysis to a carboxylic acid, which has very weak glucocorticoid or anti-inflammatory activity.
Elimination: In all test animal species the route of excretion was independent of the route of administration of fluticasone propionate. Excretion is predominantly faecal and is essentially complete within 48 hours.
Toxicology: Pre-Clinical Safety Data: Carcinogenesis/Mutagenesis: Carcinogenesis: Long-term topical and oral studies in animals to investigate the carcinogenic potential of fluticasone propionate did not show any evidence of carcinogenicity.
Genotoxicity: Fluticasone propionate was not shown to be mutagenic in a range of in vitro bacterial and mammalian cell assays.
Fertility: In a fertility and general reproductive performance study in rats, fluticasone propionate administered subcutaneously to females at up to 50 micrograms/kg per day and to males up to 100 micrograms/kg per day (later reduced to 50 micrograms/kg per day) had no effect upon mating performance or fertility.
Pregnancy: Subcutaneous administration of fluticasone propionate to mice (150 micrograms/kg/day), rats (100 micrograms/kg/day) or rabbits (300 micrograms/kg/day) during pregnancy produced foetal abnormalities including cleft palate. Oral administration did not produce foetal abnormalities, consistent with the low bioavailability of fluticasone propionate by the oral route.