ADVAIR DISKUS ADVAIR - GlaxoSmithKline

significant increase in plasma salmeterol exposure (1.4-fold C max and 15-fold AUC).
There was no increase in salmeterol accumulation with repeat dosing. Three subjects
were withdrawn from salmeterol and ketoconazole co-administration due to QTc
prolongation or palpitations with sinus tachycardia. In the remaining 12 subjects, coadministration
of salmeterol and ketoconazole did not result in a clinically significant
effect on heart rate, blood potassium or QTc duration (see WARNINGS AND
PRECAUTIONS, and DRUG INTERACTIONS).
Fluticasone Propionate
Following intravenous administration, the pharmacokinetics of fluticasone propionate are
proportional to the dose. Fluticasone propionate is extensively distributed within the
body. The volume of distribution at steady state is approximately 300 litres and has a
very high clearance which is estimated to be 1.1 litre/minute indicating extensive hepatic
extraction.
Peak plasma fluticasone propionate concentrations are reduced by approximately 98%
within 3-4 hours and only low plasma concentrations are associated with the terminal
half-life, which is approximately 8 hours.
Following oral administration of fluticasone propionate, 87-100% of the dose is excreted
in the faeces. Following doses of either 1 or 16 mg, up to 20% and 75% respectively, is
excreted in the faeces as the parent compound. There is a non-active major metabolite.
Absolute oral bioavailability is negligible (< 1%) due to a combination of incomplete
absorption from the gastrointestinal tract and extensive first-pass metabolism.
The absolute bioavailability of fluticasone propionate has been estimated from within
study comparisons of inhaled and intravenous pharmacokinetic data. In healthy adult
subjects the absolute systemic bioavailability of fluticasone propionate from salmeterolfluticasone
propionate inhalation aerosol and from salmeterol-fluticasone propionate dry
powder for inhalation was 5.3% and 5.5% respectively. Systemic absorption of
fluticasone propionate occurs mainly through the lungs, and is initially rapid, then
prolonged.
The percentage of fluticasone propionate bound to human plasma proteins averages 99%.
Fluticasone propionate is extensively metabolised by CYP3A4 enzyme to an inactive
carboxylic acid derivative.
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