DRUG INTERACTIONS
Short-Acting Beta2-Agonists
In three 12-week US clinical trials, the mean daily need for additional beta2-agonist use in 277 patients receiving ADVAIR HFA was approximately 1.2 inhalations/day and ranged from 0 to 9 inhalations/day. Two percent (2%) of patients receiving ADVAIR HFA in these trials averaged 6 or more inhalations per day over the course of the 12-week trials. No increase in frequency of cardiovascular events was observed among patients who averaged 6 or more inhalations per day.
Methylxanthines
The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving ADVAIR HFA has not been completely evaluated. In five 12-week clinical trials (3 US and 2 non-US), 45 patients receiving ADVAIR HFA 45/21, 115/21, or 230/21 twice daily concurrently with a theophylline product had adverse event rates similar to those in 577 patients receiving ADVAIR HFA without theophylline.
Fluticasone Propionate Nasal Spray
In patients receiving ADVAIR HFA in three 12-week US clinical trials, no difference in the profile of adverse events or HPA axis effects was noted between patients receiving FLONASE® (fluticasone propionate) Nasal Spray, 50 mcg concurrently (n = 89) and those who were not (n = 192).
Monoamine Oxidase Inhibitors and Tricyclic Antidepressants
ADVAIR HFA 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 HFA, 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 HFA, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma 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 in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
Diuretics
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 significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics.
Inhibitors of Cytochrome P450
Fluticasone propionate and salmeterol are substrates of cytochrome P450 3A4.
Fluticasone propionate
A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Fluticasone Propionate: Drug Interactions). 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. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
In a placebo-controlled, crossover study 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 systemic fluticasone propionate exposure, a reduction in plasma cortisol AUC, and 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. Due to the potential increased risk of cardiovascular adverse events, the concomitant use of salmeterol with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) is not recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Salmeterol Xinafoate: Drug Interactions).
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OVERDOSAGE
ADVAIR HFA Inhalation Aerosol
No deaths occurred in rats given a single-dose combination of salmeterol 3.6 mg/kg and fluticasone propionate 1.9 mg/kg given as the inhalation powder (approximately 290 and 15 times, respectively, the maximum recommended human daily inhalation dose on a mg/m2 basis).
Fluticasone Propionate
Chronic overdosage with fluticasone propionate may result in signs/symptoms of hypercorticism (see PRECAUTIONS: General: Metabolic and Other Effects). 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 CFC inhalation aerosol were well tolerated. Fluticasone propionate given by inhalation aerosol at doses 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. In mice the oral median lethal dose was >1,000 mg/kg (>4,400 times the maximum recommended human daily inhalation dose on a mg/m2 basis). In rats the subcutaneous median lethal dose was >1,000 mg/kg (>8,800 times the maximum recommended human daily inhalation dose 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 signs and symptoms listed under ADVERSE REACTIONS, e.g., 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 may be expected to result in exaggeration of the pharmacologic adverse effects associated with beta-adrenoceptor agonists, including tachycardia and/or arrhythmia, tremor, headache, and muscle cramps. 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 280 times the maximum recommended human daily inhalation dose on a mg/m2 basis) and in dogs at an inhalation dose of 0.7 mg/kg (approximately 230 times the maximum recommended human daily inhalation dose on a mg/m2 basis). By the oral route, no deaths occurred in mice at 150 mg/kg (approximately 7,200 times the maximum recommended human daily inhalation dose on a mg/m2 basis) and in rats at 1,000 mg/kg (approximately 97,000 times the maximum recommended human daily inhalation dose on a mg/m2 basis).
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