In clinical trials with patients with asthma, the mean daily need for albuterol by 166 adult and adolescent patients 12 years of age and older using ADVAIR DISKUS was approximately 1.3 inhalations/day, and ranged from 0 to 9 inhalations/day. Five percent (5%) of patients using ADVAIR DISKUS in these trials averaged 6 or more inhalations per day over the course of the 12 week trials. No increase in frequency of cardiovascular adverse reactions was observed among patients who averaged 6 or more inhalations per day.
In a COPD clinical trial, the mean daily need for albuterol for patients using ADVAIR DISKUS 250/50 was 4.1 inhalations/day. Twenty six percent (26%) of patients using ADVAIR DISKUS 250/50 averaged 6 or more inhalations per day over the course of the 24 week trial. No increase in frequency of cardiovascular adverse reactions was observed among patients who averaged 6 or more inhalations of albuterol per day.
The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by adult and adolescent patients 12 years of age and older receiving ADVAIR DISKUS has not been completely evaluated. In clinical trials with patients with asthma, 39 patients receiving ADVAIR DISKUS 100/50, 250/50, or 500/50 twice daily concurrently with a theophylline product had adverse event rates similar to those in 304 patients receiving ADVAIR DISKUS without theophylline. Similar results were observed in patients receiving salmeterol 50 mcg plus fluticasone propionate 500 mcg twice daily concurrently with a theophylline product (n = 39) or without theophylline (n = 132).
In a COPD clinical trial, 17 patients receiving ADVAIR DISKUS 250/50 twice daily concurrently with a theophylline product had adverse event rates similar to those in 161 patients receiving ADVAIR DISKUS without theophylline. Based on the available data, the concomitant administration of methylxanthines with ADVAIR DISKUS did not alter the observed adverse event profile.
Fluticasone Propionate Nasal Spray
In adult and adolescent patients 12 years of age and older taking ADVAIR DISKUS in clinical trials, no difference in the profile of adverse events or HPA axis effects was noted between patients taking FLONASE® (fluticasone propionate) Nasal Spray, 50 mcg concurrently (n = 46) and those who were not (n = 130).
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 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.
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.
Inhibitors of Cytochrome P450
Fluticasone propionate is a substrate of cytochrome P450 3A4. A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a highly 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 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 plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should be exercised when ADVAIR DISKUS is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.
No deaths occurred in rats given an inhaled single-dose combination of salmeterol 3.6 mg/kg (approximately 290 and 140 times, respectively, the maximum recommended daily inhalation dose in adults and children on a mg/m2 basis) and 1.9 mg/kg of fluticasone propionate (approximately 15 and 35 times, respectively, the maximum recommended daily inhalation dose in adults and children on a mg/m2 basis).
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 inhalation aerosol was 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 (>4,100 and >9,600 times, respectively, the maximum recommended daily inhalation dose in adults and children on a mg/m2 basis). In rats the subcutaneous median lethal dose was >1,000 mg/kg (>8,100 and >19,200 times, respectively, the maximum recommended daily inhalation dose in adults and children on a mg/m2 basis).
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 240 and 110 times, respectively, the maximum recommended daily inhalation dose in adults and children on a mg/m2 basis) and in dogs at an inhalation dose of 0.7 mg/kg (approximately 190 and 90 times, respectively, the maximum recommended daily inhalation dose in adults and children 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, respectively, the maximum recommended daily inhalation dose in adults and children on a mg/m2 basis) and in rats at 1,000 mg/kg (approximately 81,000 and 38,000 times, respectively, the maximum recommended daily inhalation dose in adults and children on a mg/m2 basis).