Tolerability of short-term, high-dose formoterol in healthy volunteers and patients with asthma.

Background: Formoterol is a long-acting (>or=12 hours) beta(2)-receptor agonist with a rapid onset of action (1-3 minutes). It is approved in the United States, delivered via a single-dose dry-powder inhaler (DPI), for use in combination with anti-inflammatory therapy for the maintenance treatment of asthma and for the prevention of exercise-induced bronchospasm. Potential exposure of patients to higher doses than are currently approved is an important consideration in assessing the safety profile of formoterol.

Objective: This article reviews data from clinical trials investigating the effects of short-term use (4-48 hours) of high doses of formoterol (maximum, 228 microg).

Methods: Comparative and noncomparative studies of the effects of short-term, high-dose formoterol, inhaled via metered-dose inhaler (MDI) or single-dose DPI, were identified through searches of the literature indexed on MEDLINE, EMBASE, Current Contents, and Science Citation Index from their inception through August 15, 2003.

Results: This review included 1 open-label noncomparative study of high-dose formoterol in 12 healthy volunteers (mean age, 29 years), 1 placebo-controlled dose-escalation study of formoterol in 20 patients with asthma (mean age, 30 years), and 3 comparative studies of formoterol and short-acting beta(2)-agonists. The latter included a dose-escalation study in 13 patients with asthma (mean age, 47.2 years), a high-dose study in 12 healthy volunteers (mean age, 27 years), and a dose-escalation study in 9 children with asthma (mean age, 10 years). In the study in healthy volunteers, the metabolic and cardiovascular effects of high single doses of formoterol (maximum, 120 microg) were small and had no clinical consequences. In the placebo-controlled dose-escalation study in patients with asthma, however, the metabolic effects of formoterol at doses from 24 to 96 microg and the cardiovascular effects of formoterol at doses from 48 to 96 microg differed significantly from those of placebo (P < 0.05 to P <0.001) but were unlikely to result in clinically significant adverse effects. In the studies comparing formoterol with short-acting beta(2)-agonists in patients with stable asthma, the cardiovascular and metabolic effects of short-term, high-dose formoterol (cumulative dose, up to 228 microg) were comparable to those of high-dose albuterol (salbutamol) (cumulative dose, up to 3800 microg). Studies of high-dose formoterol delivered via multidose DPI (not available in the United States) have reported a safety profile similar to those of high-dose terbutaline and albuterol.

Conclusion: In studies of the short-term use of high-dose formoterol delivered via an MDI or single-dose DPI, this agent had a safety profile comparable to that of short-acting beta(2)-agonists.