ADVAIR DISKUS

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).

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 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).

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 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).

ADVAIR DISKUS is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

Hypersensitivity to any of the ingredients of these preparations contraindicates their use (see DESCRIPTION and ADVERSE REACTIONS: Observed During Clinical Practice: Non-Site Specific).

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