GENEMIST Nasal spray, suspension Ref.[115274] Active ingredients: Fluticasone furoate

Absorption

Fluticasone furoate undergoes incomplete absorption and extensive first-pass metabolism in the liver and gut resulting in negligible systemic exposure. The intranasal dosing of 110 μg once daily does not typically result in measurable plasma concentrations (<10 ug/ml). The absolute bioavailability for intranasal fluticasone furoate administered as 880 μg three times per day (2 640 μg total daily dose) is 0,50%.

Distribution

The plasma protein binding of fluticasone furoate is greater than 99%. Fluticasone furoate is widely distributed with volume of distribution at steady-state of, on average, 608 L.

Metabolism

Fluticasone furoate is rapidly cleared (total plasma clearance of 58,7 L/h) from systemic circulation principally by hepatic metabolism to an inactive 17β-carboxylic metabolite (GW694301X), by the cytochrome P450 enzyme CYP3A4. The principal route of metabolism was hydrolysis of the S-fluoromethyl carbothioate function to form the 17β-carboxylic acid metabolite. In vivo studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone.

Elimination

Elimination was primarily via the faecal route following oral and intravenous administration indicative of excretion of fluticasone furoate and its metabolites via the bile. Following intravenous administration, the elimination phase half-life averaged 15,1 hours. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered dose, respectively.

Children

Fluticasone furoate is typically not quantifiable (<10 ug/mL) following intranasal dosing of 110 μg once daily. Quantifiable levels were observed in <16% of paediatric patients following intranasal dosing of 110 μg once daily and only <7% of paediatric patients following 55 μg once daily. There was no evidence for a higher incidence of quantifiable levels of fluticasone furoate in younger children (less than 6 years of age).

Elderly

Only a small number of elderly subjects (n = 23/872; 2,6%) provided pharmacokinetic data. There was no evidence for a higher incidence of subjects with quantifiable fluticasone furoate concentrations in the elderly, when compared with the younger subjects.

Renal impairment

Fluticasone furoate is not detectable in urine from healthy volunteers after intranasal dosing. Less than 1% of dose-related material is excreted in urine and therefore renal impairment would not be expected to affect the pharmacokinetics of fluticasone furoate.

Hepatic impairment

There are no data on intranasal fluticasone furoate in subjects with hepatic impairment. Data are available following inhaled administration of fluticasone furoate (as fluticasone furoate or fluticasone furoate/vilanterol) to subjects with hepatic impairment that are also applicable for intranasal dosing. A study of a single 400 μg dose of oral inhaled fluticasone furoate in patients with moderate hepatic impairment (Child-Pugh B) resulted in increased C_max (42%) and AUC_(0-∞) (172%) compared to healthy subjects. Following repeat dosing of orally inhaled fluticasone furoate/vilanterol for 7 days, there was an increase in fluticasone furoate systemic exposure (on average two-fold as measured by AUC_(0–24)) in subjects with moderate or severe hepatic impairment (Child-Pugh B or C) compared with healthy subjects. The increase in fluticasone furoate systemic exposure in subjects with moderate hepatic impairment (fluticasone furoate/vilanterol 200/25 μg) was associated with an average 34% reduction in serum cortisol compared with healthy subjects. There was no effect on serum cortisol in subjects with severe hepatic impairment (fluticasone furoate/vilanterol 100/12,5 μg). Based on these findings the average predicted exposure for 110 μg of intranasal fluticasone furoate in this patient population would not be expected to result in suppression of cortisol.

No further information of relevance available.