ADVAIR DISKUS has been used concomitantly with other drugs, including short-acting beta2-agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma or COPD, without adverse drug reactions. No formal drug interaction studies have been performed with ADVAIR DISKUS.
Inhibitors of Cytochrome P450 3A4
Fluticasone propionate and salmeterol, the individual components of ADVAIR DISKUS, are substrates of CYP 3A4. The use of strong CYP 3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with ADVAIR DISKUS is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur.
Fluticasone Propionate: A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology]. 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 syndrome and adrenal suppression.
Fluticasone Propionate: Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased plasma fluticasone propionate exposure and reduced plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.
Salmeterol: In a drug interaction study 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 Cmax increased 1.4-fold). Three (3) subjects were withdrawn due to beta2-agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia).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.
Monoamine Oxidase Inhibitors and Tricyclic Antidepressants
ADVAIR DISKUS 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 ADVAIR DISKUS, on the vascular system may be potentiated by these agents.
Beta-Adrenergic Receptor Blocking Agents
Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR DISKUS, but may produce severe bronchospasm in patients with reversible obstructive airways disease. Therefore, patients with asthma and 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.
The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical relevance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics.
No human overdosage data has been reported for ADVAIR DISKUS.
No deaths occurred in rats given an inhaled single-dose combination of salmeterol 3.6 mg/kg (approximately 290 and 140 times the MRHD for adults and children, respectively, on a mg/m2 basis) and 1.9 mg/kg of fluticasone propionate (approximately 15 and 35 times the MRHD for adults and children, respectively, on a mg/m2 basis).
Fluticasone Propionate: Chronic overdosage with fluticasone propionate may result in signs/symptoms of hypercorticism [see Warnings and Precautions]. Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate inhalation aerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated. Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.
No deaths were seen in mice given an oral dose of 1,000 mg/kg (4,100 and 9,600 times the MRHD dose for adults and children, respectively, on a mg/m2 basis). No deaths were seen in rats given an oral dose of 1,000 mg/kg (8,100 and 19,200 times the MRHD for adults and children, respectively, on a mg/m2 basis).
Salmeterol: The expected signs and symptoms with overdosage of salmeterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the following: seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Overdosage with salmeterol can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias. Other signs of overdosage may include hypokalemia and hyperglycemia.
As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of salmeterol.
Treatment consists of discontinuation of salmeterol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of salmeterol. Cardiac monitoring is recommended in cases of overdosage.
No deaths were seen in rats given salmeterol at an inhalation dose of 2.9 mg/kg (approximately 240 and 110 times the MRHD for adults and children, respectively, on a mg/m2 basis) and in dogs at an inhalation dose of 0.7 mg/kg (approximately 190 and 90 times the MRHD for adults and children, respectively, on a mg/m2 basis). By the oral route, no deaths occurred in mice at 150 mg/kg (approximately 6,100 and 2,900 times the MRHD for adults and children, respectively, on a mg/m2 basis) and in rats at 1,000 mg/kg (approximately 81,000 and 38,000 times the MRHD for adults and children, respectively, on a mg/m2 basis).