Drug interactions between Advair Diskus and Biaxin

clarithromycin ↔ salmeterol

Applies to:Biaxin (clarithromycin) and Advair Diskus (fluticasone/salmeterol)

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the systemic levels and pharmacologic effects of salmeterol, which is primarily metabolized by the isoenzyme. Because salmeterol prolongs the QT interval in a dose-dependent manner, high systemic levels of salmeterol may increase the risk of ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, and torsade de pointes. In a placebo-controlled, crossover drug interaction study consisting of 20 healthy subjects, coadministration of salmeterol (50 mcg twice daily) and the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a 16-fold increase in plasma salmeterol exposure (AUC) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations (Cmax) were increased by 1.4-fold, and three out of 20 subjects (15%) were withdrawn from the combination due to salmeterol-mediated systemic effects (two with QTc prolongation and one with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, blood potassium, or blood glucose. Although there was no statistical effect on the mean QTc, the combination was associated with more frequent increases in QTc duration than salmeterol and placebo.

MANAGEMENT: The use of salmeterol in combination with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics is not recommended.

clarithromycin ↔ fluticasone

Applies to:Biaxin (clarithromycin) and Advair Diskus (fluticasone/salmeterol)

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the systemic exposure to fluticasone following intranasal administration or oral inhalation. Fluticasone undergoes extensive first-pass and systemic metabolism via hepatic and intestinal CYP450 3A4, thus inhibition of the isoenzyme may significantly increase systemic bioavailability of the drug. In 18 healthy subjects, administration of fluticasone propionate nasal spray (200 mcg once daily) in combination with the potent CYP450 3A4 inhibitor ritonavir (100 mg twice daily) for 7 days resulted in an approximately 25-fold increase in fluticasone peak plasma concentration (Cmax) and 350-fold increase in systemic exposure (AUC) compared to administration alone. These changes were accompanied by an 86% decrease in mean plasma cortisol AUC. In a different study, coadministration of a single dose of orally inhaled fluticasone propionate (1000 mcg) with the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone exposure and a 45% decrease in plasma cortisol AUC, but had no effect on urinary excretion of cortisol. In a study using intranasal fluticasone furoate, 6 of 20 subjects who were coadministered ketoconazole 200 mg once a day for 7 days had measurable but low levels of fluticasone furoate compared to 1 of 20 subjects who received placebo. There was an estimated 5% reduction in 24-hour serum cortisol levels with ketoconazole relative to placebo. Likewise, a study of 17 lung transplant patients found that mean fluticasone trough plasma level in subjects receiving fluticasone propionate (1 mg twice daily by oral inhalation for 14 days) with itraconazole was 2.5 times that observed in subjects not receiving itraconazole. Clinically, systemic glucocorticoid adverse effects may occur in association with the interaction. Adrenal suppression, Cushing's syndrome, osteoporosis, and exacerbation of diabetes mellitus have been reported during worldwide postmarketing use of orally inhaled or intranasal fluticasone, primarily in combination with ritonavir. However, there have also been a few case reports of adrenal suppression associated with concomitant use of inhaled fluticasone propionate and azole antifungal agents. Recovery of adrenal function was reportedly slow in some patients following discontinuation of fluticasone. Investigators suggest that this could be related to the highly lipophilic nature of fluticasone, which allows for prolonged seepage of drug into the circulation from fat stores.

MANAGEMENT: The use of orally inhaled fluticasone in combination with potent CYP450 3A4 inhibitors (e.g., clarithromycin, telithromycin, itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors) is not recommended unless the potential benefit outweighs the risk of systemic side effects. Alternatives to fluticasone should be considered whenever possible, particularly for long-term use. If an orally inhaled corticosteroid is necessary, a less potent, less lipophilic, and/or shorter-acting agent such as beclomethasone, budesonide, flunisolide or triamcinolone may be appropriate, although probably most, if not all, corticosteroids can interact with potent CYP450 3A4 inhibitors to some extent. The lowest effective dosage of orally inhaled corticosteroid should be used, and further adjustments made as necessary according to therapeutic response and tolerance. Intranasal fluticasone may be used cautiously in combination with potent CYP450 3A4 inhibitors except ritonavir. Patients should be monitored for signs and symptoms of hypercorticism such as acne, striae, thinning of the skin, easy bruising, moon facies, dorsocervical "buffalo" hump, truncal obesity, increased appetite, acute weight gain, edema, hypertension, hirsutism, hyperhidrosis, proximal muscle wasting and weakness, glucose intolerance, exacerbation of preexisting diabetes, depression, and menstrual disorders. Other systemic glucocorticoid effects may include adrenal suppression, immunosuppression, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation in children and adolescents. Following extensive use with a potent CYP450 3A4 inhibitor, a progressive dosage reduction may be required over a longer period if fluticasone is to be withdrawn from therapy, as there may be a significant risk of adrenal suppression. Signs and symptoms of adrenal insufficiency include anorexia, hypoglycemia, nausea, vomiting, weight loss, muscle wasting, fatigue, weakness, dizziness, postural hypotension, depression, and adrenal crisis manifested as inability to respond to stress (e.g., illness, infection, surgery, trauma). Systemic glucocorticoids may be necessary until adrenal function recovers.