Short-term safety and tolerability of double-dose salmeterol/fluticasone propionate in adult asthmatic patients

Introduction: The incidence of asthma exacerbations in patients receiving salmeterol/fluticasone propionate (Seretide (TM) or Advair((R))) is low. However, when asthma control deteriorates, clinicians may instruct patients to double the dose of their inhaled corticosteroid medication for a short period. The purpose of this study was to demonstrate that doubling the dose of Seretide (TM) for a period of 2 weeks in subjects with persistent asthma is safe and well tolerated. Methods: This randomised, double-blind, parallel-group study was conducted in primary-care centres. Adults with a post-bronchodilator forced expiratory volume in 1 second (FEV1) of >= 70% predicted were stratified to receive a single dose of Seretide (TM) 50 mu g/100 mu g, 50 mu g/250 mu g or 50 mu g/500 mu g twice daily from a Diskus (TM) inhaler for a 4-week run-in period, dependent on the dose of inhaled corticosteroid on entry. Subjects were then randomised to receive either an extra inhalation of the same dose of Seretide (TM) received during the run-in (double dose) or an inhalation of matching placebo (single dose) for 14 days in a 2 : 1 ratio. Subjects were asked to record any adverse events, morning and evening heart rate (HR), peak flow and relief medication use in daily record cards. The primary endpoint was tremor as perceived by the subject. Clinic evaluations included HR, 12-lead ECG, and potassium and glucose levels. Results: 110 and 208 subjects received single- and double-dose Seretide (TM), respectively. Only one subject experienced tremor. This was classified as mild and occurred in a subject receiving double-dose Seretide (TM) (50 mu g/100 mu g). There was no difference between the treatment groups in the incidence of tremor (difference < 1%; 95% CI -6, 8). Other salmeterol-related adverse events (palpitations, muscle cramps and headache) and fluticasone propionate-related events (oral candidiasis and hoarseness) occurred in a similar percentage of subjects in each treatment group. The treatment differences for morning and evening HR measurements showed small differences between the two groups (< 2 beats/min). The adjusted mean treatment difference (double dose - single dose) in morning HR was 1.1 beats/min (95% CI 0.2, 2.0) and evening HR was 0.9 beats/min (95% CI 0.1, 1.7). Seven percent of subjects receiving single-dose Seretide (TM) and 8% receiving double-dose Seretide (TM) had a QTc change from baseline in the interval 30-59 msec. No increases above 59 msec were seen in either group. There were no clinically significant changes from baseline for potassium levels. Two percent of subjects in the single dose and < 1% in the double-dose group had a change from a non-clinically significant baseline blood glucose assessment to a clinically significant abnormality at the end of treatment. Conclusion: In circumstances in which a physician may be considering doubling the dose of Seretide (TM) for a short period of time in adult asthmatics, this study demonstrates that doubling the dose for a period of 2 weeks is safe and well tolerated.