Fluticasoneinteractions

Fluticasone propionate and salmeterol inhalation powder has been used concomitantly with other drugs, including short-acting beta 2 -agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma or COPD without adverse drug reactions. No formal drug interaction trials have been performed with fluticasone propionate and salmeterol inhalation powder.

Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended. May increase risk of systemic corticosteroid and cardiovascular effects.

Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of salmeterol on vascular system.

Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm.

Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists.

7.1 Inhibitors of

Cytochrome P450 3A4 Fluticasone propionate and salmeterol, the individual components of Wixela Inhub ®, are substrates of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with Wixela Inhub ® is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur. Ritonavir Fluticasone Propionate A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Ketoconazole Fluticasone Propionate Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol. Salmeterol In a drug interaction trial in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and C max increased 1.4-fold). Three subjects were withdrawn due to beta 2 -agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.

7.2 Monoamine

Oxidase Inhibitors and Tricyclic Antidepressants Wixela Inhub ® should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of Wixela Inhub ®, on the vascular system may be potentiated by these agents.

7.3 Beta-adrenergic

Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of Wixela Inhub ®, but may also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

7.4 Non–Potassium-Sparing

Diuretics The ECG changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, such as salmeterol, a component of Wixela Inhub ®, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of Wixela Inhub ® with non–potassium-sparing diuretics.

Drug Interaction Studies In the repeat- and single-dose trials, there was no evidence of significant drug interaction in systemic exposure between fluticasone propionate and salmeterol when given alone or in combination via a dry powder inhaler. The population pharmacokinetic analysis from 9 controlled clinical trials in 350 subjects with asthma showed no significant effects on fluticasone propionate or salmeterol pharmacokinetics following co-administration with beta 2 -agonists, corticosteroids, antihistamines, or theophyllines. Inhibitors of Cytochrome P450 3A4 Ritonavir Fluticasone Propionate Fluticasone propionate is a substrate of CYP3A4. Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction trial in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (<10 pg/mL) in most subjects, and when concentrations were detectable peak levels (C max ) averaged 11.9 pg/mL (range: 10.8 to 14.1 pg/mL) and AUC (0-τ) averaged 8.43 pg

h/mL (range: 4.2 to 18.8 pg

h/mL). Fluticasone propionate C max and AUC (0-τ) increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg

h/mL (range: 1,207.1 to 5,662.0 pg

h/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in serum cortisol AUC. Ketoconazole Fluticasone Propionate In a placebo-controlled crossover trial in 8 healthy adult volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Salmeterol In a placebo-controlled, crossover drug interaction trial in 20 healthy male and female subjects, coadministration of salmeterol (50 mcg twice daily) and the strong CYP3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a significant increase in plasma salmeterol exposure as determined by a 16-fold increase in AUC (ratio with and without ketoconazole 15.76 [90% CI: 10.66, 23.31]) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations were increased by 1.4-fold (90% CI: 1.23, 1.68). Three out of 20 subjects (15%) were withdrawn from salmeterol and ketoconazole coadministration due to beta-agonist–mediated systemic effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, mean blood potassium, or mean blood glucose. Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration. Erythromycin Fluticasone Propionate In a multiple-dose drug interaction trial, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics. Salmeterol In a repeat-dose trial in 13 healthy subjects, concomitant administration of erythromycin (a moderate CYP3A4 inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase in salmeterol C max at steady state (ratio with and without erythromycin 1.4 [90% CI: 0.96, 2.03], P = 0.12), a 3.6-beat/min increase in heart rate ([95% CI: 0.19, 7.03], P <0.04), a 5.8-msec increase in QTc interval ([95% CI: -6.14, 17.77], P = 0.34), and no change in plasma potassium.