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ADVAIR DISKUS ADVAIR - GlaxoSmithKline

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Pharmacodynamics<br />

The pharmacodynamic effects and pharmacokinetics of the combination product in the<br />

<strong>DISKUS</strong> ® powder inhaler were investigated in healthy adult male and female volunteers<br />

after single and repeat-dose administration.<br />

Those studies showed that the systemic pharmacodynamic effects of salmeterol xinafoate<br />

and fluticasone propionate are essentially unchanged when the two drugs are<br />

administered in combination, when compared with the component drugs given alone or<br />

concurrently.<br />

There was no evidence that the systemic exposure to salmeterol was altered by<br />

concomitant exposure to fluticasone propionate. In one study, the salmeterol plasma C max<br />

and T max were not significantly different when compared between the groups receiving<br />

salmeterol xinafoate 100 mcg and fluticasone propionate 500 mcg twice daily in the<br />

combination product (C max 0.23 ng/mL) or salmeterol xinafoate 100 mcg twice daily as a<br />

single agent (C max 0.22 ng/mL).<br />

When fluticasone propionate alone or the salmeterol xinafoate/fluticasone propionate<br />

product are administered at the same dosage, there is similar systemic exposure to<br />

fluticasone propionate.<br />

Pharmacokinetics<br />

There is no evidence in animal or human subjects that the administration of salmeterol<br />

xinafoate and fluticasone propionate together by the inhaled route affects the<br />

pharmacokinetics of either component. For pharmacokinetic purposes therefore each<br />

component can be considered separately.<br />

Salmeterol Xinafoate<br />

Salmeterol acts locally in the lung; therefore, plasma levels are not an indication of<br />

therapeutic effect. Because of the low therapeutic dose, systemic levels of salmeterol are<br />

low or undetectable after inhalation of recommended doses (50 mcg twice daily).<br />

Salmeterol is predominantly cleared by hepatic metabolism; liver function impairment<br />

may lead to accumulation of salmeterol in plasma. Therefore, patients with hepatic<br />

disease should be closely monitored.<br />

An in vitro study showed that salmeterol is extensively metabolised to α-<br />

hydroxysalmeterol (aliphatic oxidation) by cytochrome P450 3A4 (CYP3A4). A repeat<br />

dose study with salmeterol and erythromycin in healthy volunteers showed no clinically<br />

significant changes in pharmacodynamic effects at 500 mg three times daily doses of<br />

erythromycin. However, a salmeterol-ketoconazole interaction study resulted in a<br />

significant increase in plasma salmeterol exposure (see WARNING AND<br />

PRECAUTIONS, and DRUG INTERACTIONS).<br />

In a placebo-controlled, crossover drug interaction study in 15 healthy subjects, coadministration<br />

of salmeterol (50 mcg twice daily inhaled) and the cytochrome P450 3A4<br />

(CYP3A4) inhibitor, ketoconazole (400 mg once daily orally), for 7 days, resulted in a<br />

July 29, 2014<br />

Page 30 of 67

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