###  Systemic Safety and Pharmacokinetic/Pharmacodynamic Relationships

The major adverse effects of inhaled beta2-agonists occur as a result of excessive activation of the systemic beta-adrenergic receptors. The most common adverse effects in adults and adolescents include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose.

Pharmacokinetic/pharmacodynamic (PK/PD) relationships between heart rate, ECG parameters, and serum potassium levels and the urinary excretion of formoterol were evaluated in 10 healthy male volunteers (25 to 45 years of age) following inhalation of single doses containing 12, 24, 48, or 96 mcg of formoterol fumarate. There was a linear relationship between urinary formoterol excretion and decreases in serum potassium, increases in plasma glucose, and increases in heart rate.

In a second study, PK/PD relationships between plasma formoterol levels and pulse rate, ECG parameters, and plasma potassium levels were evaluated in 12 healthy volunteers following inhalation of a single 120 mcg dose of formoterol fumarate (10 times the recommended clinical dose). Reductions of plasma potassium concentration were observed in all subjects. Maximum reductions from baseline ranged from 0.55 to 1.52 mmol/L with a median maximum reduction of 1.01 mmol/L. The formoterol plasma concentration was highly correlated with the reduction in plasma potassium concentration. Generally, the maximum effect on plasma potassium was noted 1 to 3 hours after peak formoterol plasma concentrations were achieved. A mean maximum increase of pulse rate of 26 bpm was observed 6 hours post dose. The maximum increase of mean corrected QT interval (QTc) was 25 msec when calculated using Bazett's correction and was 8 msec when calculated using Fridericia's correction. The QTc returned to baseline within 12-24 hours post-dose. Formoterol plasma concentrations were weakly correlated with pulse rate and increase of QTc duration. The effects on plasma potassium, pulse rate, and QTc interval are known pharmacological effects of this class of study drug and were not unexpected at the very high formoterol dose (120 mcg single dose, 10 times the recommended single dose) tested in this study. These effects were well-tolerated by the healthy volunteers. 

The electrocardiographic and cardiovascular effects of FORADIL AEROLIZER were compared with those of albuterol and placebo in two pivotal 12-week double-blind studies of patients with asthma. A subset of patients underwent continuous electrocardiographic monitoring during three 24-hour periods. No important differences in ventricular or supraventricular ectopy between treatment groups were observed. In these two studies, the total number of patients with asthma exposed to any dose of FORADIL AEROLIZER who had continuous electrocardiographic monitoring was about 200.

Continuous electrocardiographic monitoring was performed in an 8-week, randomized, double-blind, placebo controlled trial in 204 COPD patients treated with FORADIL AEROLIZER 12 mcg twice daily or placebo. Holter monitoring was used to evaluate predefined proarrhythmic events. Non-sustained ventricular tachycardia occurred in 2 (2.2%) of FORADIL AEROLIZER treated patients compared to none in the placebo group. An increase in ventricular premature beats (VPB) occurred in 3 (3.3 %) of FORADIL AEROLIZER treated patients compared to 2 (1.9%) in the placebo group. There were no events of sustained of ventricular tachycardia, ventricular flutter or fibrillation, or symptomatic runs of VPB. One patient in the FORADIL AEROLIZER group had a serious adverse event of atrial flutter.

The electrocardiographic effects of FORADIL AEROLIZER were evaluated versus placebo in a 12-month pivotal double-blind study of patients with COPD. An analysis of ECG intervals was performed for patients who participated at study sites in the United States, including 46 patients treated with FORADIL AEROLIZER 12 mcg twice daily, and 50 patients treated with FORADIL AEROLIZER 24 mcg twice daily. ECGs were performed predose, and at 5-15 minutes and 2 hours post-dose at study baseline and after 3, 6 and 12 months of treatment. The results showed that there was no clinically meaningful acute or chronic effect on ECG intervals, including QTc, resulting from treatment with FORADIL AEROLIZER.

###  Tachyphylaxis/Tolerance

In a clinical study in 19 adult patients with mild asthma, the bronchoprotective effect of formoterol, as assessed by methacholine challenge, was studied following an initial dose of 24 mcg (twice the recommended dose) and after 2 weeks of 24 mcg twice daily. Tolerance to the bronchoprotective effects of formoterol was observed as evidenced by a diminished bronchoprotective effect on FEV1 after 2 weeks of dosing, with loss of protection at the end of the 12 hour dosing period.

Rebound bronchial hyper-responsiveness after cessation of chronic formoterol therapy has not been observed.

In three large clinical trials in patients with asthma, while efficacy of formoterol versus placebo was maintained, a slightly reduced bronchodilatory response (as measured by 12-hour FEV1 AUC) was observed within the formoterol arms over time, particularly with the 24 mcg twice daily dose (twice the daily recommended dose). A similarly reduced FEV1 AUC over time was also noted in the albuterol treatment arms (180 mcg four times daily by metered-dose inhaler).