ADVAIR DISKUS: Healthy Subjects: Cardiovascular Effects: Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four (4) studies were conducted in healthy adult subjects: (1) a single-dose crossover study using 2 inhalations of ADVAIR DISKUS 500/50, fluticasone propionate powder 500 mcg and salmeterol powder 50 mcg given concurrently, or fluticasone propionate powder 500 mcg given alone, (2) a cumulative dose study using 50 to 400 mcg of salmeterol powder given alone or as ADVAIR DISKUS 500/50, (3) a repeat-dose study for 11 days using 2 inhalations twice daily of ADVAIR DISKUS 250/50, fluticasone propionate powder 250 mcg, or salmeterol powder 50 mcg, and (4) a single-dose study using 5 inhalations of ADVAIR DISKUS 100/50, fluticasone propionate powder 100 mcg alone, or placebo. In these studies no significant differences were observed in the pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given as ADVAIR DISKUS, concurrently with fluticasone propionate from separate inhalers, or as salmeterol alone. The systemic pharmacodynamic effects of salmeterol were not altered by the presence of fluticasone propionate in ADVAIR DISKUS. The potential effect of salmeterol on the effects of fluticasone propionate on the HPA axis was also evaluated in these studies.

HPA Axis Effects: No significant differences across treatments were observed in 24-hour urinary cortisol excretion and, where measured, 24-hour plasma cortisol AUC. The systemic pharmacodynamic effects of fluticasone propionate were not altered by the presence of salmeterol in ADVAIR DISKUS in healthy subjects.

Asthma: Adults and Adolescent Patients: Cardiovascular Effects: In clinical studies with ADVAIR DISKUS in adult and adolescent patients 12 years of age and older with asthma, no significant differences were observed in the systemic pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given alone or as ADVAIR DISKUS. In 72 adolescent and adult patients with asthma given either ADVAIR DISKUS 100/50 or ADVAIR DISKUS 250/50, continuous 24-hour electrocardiographic monitoring was performed after the first dose and after 12 weeks of therapy, and no clinically significant dysrhythmias were noted.

HPA Axis Effects: In a 28-week study in adolescent and adult patients with asthma, ADVAIR DISKUS 500/50 twice daily was compared with the concurrent use of salmeterol powder 50 mcg plus fluticasone propionate powder 500 mcg from separate inhalers or fluticasone propionate powder 500 mcg alone. No significant differences across treatments were observed in serum cortisol AUC after 12 weeks of dosing or in 24-hour urinary cortisol excretion after 12 and 28 weeks.

In a 12-week study in adolescent and adult patients with asthma, ADVAIR DISKUS 250/50 twice daily was compared with fluticasone propionate powder 250 mcg alone, salmeterol powder 50 mcg alone, and placebo. For most patients, the ability to increase cortisol production in response to stress, as assessed by 30-minute cosyntropin stimulation, remained intact with ADVAIR DISKUS. One patient (3%) who received ADVAIR DISKUS 250/50 had an abnormal response (peak serum cortisol < 18 mcg/dL) after dosing, compared with 2 patients (6%) who received placebo, 2 patients (6%) who received fluticasone propionate 250 mcg, and no patients who received salmeterol.

In a repeat-dose, 3-way crossover study, 1 inhalation twice daily of ADVAIR DISKUS 100/50, FLOVENT® DISKUS® 100 mcg (fluticasone propionate inhalation powder, 100 mcg), or placebo was administered to 20 adolescent and adult patients with asthma. After 28 days of treatment, geometric mean serum cortisol AUC over 12 hours showed no significant difference between ADVAIR DISKUS and FLOVENT DISKUS or between either active treatment and placebo.

Pediatric Patients: HPA Axis Effects: In a 12-week study in patients with asthma aged 4 to 11 years who were receiving inhaled corticosteroids at study entry, ADVAIR DISKUS 100/50 twice daily was compared with fluticasone propionate inhalation powder 100 mcg administered twice daily via the DISKUS. The values for 24-hour urinary cortisol excretion at study entry and after 12 weeks of treatment were similar within each treatment group. After 12 weeks, 24-hour urinary cortisol excretion was also similar between the 2 groups.

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