Fluticasone furoate is cleared by extensive first-pass metabolism mediated by the cytochrome P450 isozyme CYP3A4. In a drug interaction study of intranasal fluticasone furoate and the CYP3A4 inhibitor ketoconazole given as a 200-mg once-daily dose for 7 days, 6 of 20 subjects receiving fluticasone furoate and ketoconazole had measurable but low levels of fluticasone furoate compared with 1 of 20 receiving fluticasone furoate and placebo. Based on this study and the low systemic exposure, there was a 5% reduction in 24-hour serum cortisol levels with ketoconazole compared to placebo. The data from this study should be carefully interpreted because the study was conducted with ketoconazole 200 mg once daily rather than 400 mg, which is the maximum recommended dosage. Therefore, caution is required with the co-administration of VERAMYST Nasal Spray and ketoconazole or other potent CYP3A4 inhibitors.
Based on data with another glucocorticoid, fluticasone propionate, metabolized by CYP3A4, co-administration of VERAMYST Nasal Spray with the potent CYP3A4 inhibitor ritonavir is not recommended because of the risk of systemic effects secondary to increased exposure to fluticasone furoate. High exposure to corticosteroids increases the potential for systemic side effects, such as cortisol suppression.
Enzyme induction and inhibition data suggest that fluticasone furoate is unlikely to significantly alter the cytochrome P450-mediated metabolism of other compounds at clinically relevant intranasal dosages.
Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions] There are no data on the effects of acute or chronic overdosage with VERAMYST Nasal Spray. Because of low systemic bioavailability and an absence of acute drug-related systemic findings in clinical studies (with dosages of up to 440 mcg/day for 2 weeks [4 times the maximum recommended daily dose]), overdose is unlikely to require any therapy other than observation.
Intranasal administration of up to 2,640 mcg/day (24 times the recommended adult dose) of fluticasone furoate was administered to healthy human volunteers for 3 days. Single- and repeat-dose studies with orally inhaled fluticasone furoate doses of 50 to 4,000 mcg have shown decreased mean serum cortisol at doses of 500 mcg or higher. The oral median lethal dose in mice and rats was >2,000 mg/kg (approximately 74,000 and 147,000 times, respectively, the maximum recommended daily intranasal dose in adults and 52,000 and 105,000 times, respectively, the maximum recommended daily intranasal dose in children, on a mcg/m2 basis).
Acute overdosage with the intranasal dosage form is unlikely since 1 bottle of VERAMYST Nasal Spray contains approximately 3 mg of fluticasone furoate, and the bioavailability of fluticasone furoate is <1% for 2.64 mg/day given intranasally and 1% for 2 mg/day given as an oral solution.