###  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 include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose. 

Changes in serum potassium and serum glucose were evaluated in 12 COPD patients following inhalation of single doses of PERFOROMIST Inhalation Solution containing 10, 20 and 244 mcg of formoterol fumarate (calculated on an anhydrous basis) in a crossover study. At 1 hour after treatment with formoterol fumarate inhalation solution, mean (± standard deviation) serum glucose rose 26 ± 30, 29 ± 28, and 38 ± 44 mg/dL, respectively, and was not significantly different from baseline or trough level at 24 hours post-dose. At 1 hour after dosing with formoterol fumarate inhalation solution 244 mcg, serum potassium fell by 0.68 ± 0.4 mEq/L, and was not different from baseline or trough level at 24 hours post-dose.

Linear pharmacokinetic/pharmacodynamic (PK/PD) relationships between urinary formoterol excretion and decreases in serum potassium, increases in plasma glucose, and increases in heart rate were generally observed with another inhalation formulation of formoterol fumarate and hence would be expected with PERFOROMIST Inhalation Solution also. Following single dose administration of 10-fold the recommended clinical dose of the other formoterol fumarate inhalation formulation having comparable exposure to single dose of 244 mcg of PERFOROMIST Inhalation Solution (approximately 12-fold the recommended clinical dose) in healthy subjects, the formoterol plasma concentration was found to be highly correlated with the reduction in plasma potassium concentration. Data from this study showed that maximum reductions from baseline in plasma potassium ranged from 0.55 to 1.52 mmol/L with a median maximum reduction of 1.01 mmol/L. Generally, the maximum effect on plasma potassium was noted 1 to 3 hours after peak formoterol plasma concentrations were achieved. 

###  Electrophysiology

In the dose-ranging study of PERFOROMIST Inhalation Solution, ECG-determined heart rate increased by a mean of 6 ±3 beats per minute at 6 hours after a single dose of 244 mcg, but was back to predose level at 16-24 hours.

The effect of PERFOROMIST Inhalation Solution on heart rate and cardiac rhythm was studied in a 12-week clinical trial comparing PERFOROMIST Inhalation Solution to placebo and an active control treatment. COPD patients, including 105 patients exposed to PERFOROMIST Inhalation Solution, underwent continuous electrocardiographic (Holter) monitoring during two 24-hour periods (study baseline and after 8-12 weeks of treatment). ECGs were performed pre-dose and at 2 to 3 hours post-dose at study baseline (prior to dosing) and after 4, 8 and 12 weeks of treatment. Bazett’s and Fridericia’s methods were used to correct the QT interval for heart rate (QTcB and QTcF, respectively). The mean increase from baseline in QTcB interval over the 12-week treatment period was ≤ 4.8 msec for PERFOROMIST Inhalation Solution and ≤ 4.6 msec for placebo. The percent of patients who experienced a maximum change in QTc greater than 60 msec at any time during the 12-week treatment period was 0% and 1.8% for PERFOROMIST Inhalation Solution and placebo, respectively, based on Bazett’s correction, and 1.6% and 0.9%, respectively, based on Fridericia’s correction. Prolonged QT was reported as an adverse event in 1 (0.8%) patient treated with PERFOROMIST Inhalation Solution and 2 (1.8%) placebo patients. No occurrences of atrial fibrillation or ventricular tachycardia were observed during 24-hour Holter monitoring or reported as adverse events in patients treated with PERFOROMIST Inhalation Solution after the start of dosing. No increase in supraventricular tachycardia over placebo-treated subjects was observed. The mean increase in maximum heart rate from baseline to 8-12 weeks after the start of dosing was 0.6 beats per minute (bpm) for patients treated with PERFOROMIST Inhalation Solution twice daily compared to 1.2 bpm for placebo patients. There were no clinically meaningful differences from placebo in acute or chronic effects on heart rate, including QTcB and QTcF, or cardiac rhythm resulting from treatment with PERFOROMIST Inhalation Solution.

At an exposure from formoterol fumarate dry powder formulation comparable to approximately 12-fold the recommended dose of PERFOROMIST Inhalation Solution, a mean maximum increase of pulse rate of 26 bpm was observed 6 hours post dose in healthy subjects. This study showed that 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 to 24 hours post-dose. Formoterol plasma concentrations were weakly correlated with pulse rate and increase of QTc duration. The effects on pulse rate and QTc interval are known pharmacological effects of this class of study drug and were not unexpected at this supratherapeutic formoterol fumarate inhalation dose.

###  Tachyphylaxis / Tolerance

Tolerance to the effects of inhaled beta-agonists can occur with regularly-scheduled, chronic use. In a placebo-controlled clinical trial in 351 adult patients with COPD, the bronchodilating effect of PERFOROMIST Inhalation Solution was determined by the FEV1 area under the curve over 12 hours following dosing on Day 1 and after 12 weeks of treatment. The effect of PERFOROMIST Inhalation Solution did not decrease after 12 weeks of twice-daily treatment (Figures 1 and 2).