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Mechanism of Action
Formoterol fumarate is a long-acting selective beta2-adrenergic receptor agonist (beta2-agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200fold greater agonist activity at beta2-receptors than at beta1-receptors. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10%-50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2agonists may have cardiac effects.
The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.
Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.
Information on the pharmacokinetics of formoterol in plasma has been obtained in asthma patients following inhalation of formoterol fumarate via FORADIL CERTIHALER (formoterol fumarate inhalation powder) at the therapeutic dose. In addition, information on the pharmacokinetics of formoterol in plasma has been obtained in healthy subjects by oral inhalation of formoterol fumarate doses via FORADIL® AEROLIZER® higher than the recommended dose. FORADIL AEROLIZER consists of a single-dose dry powder inhaler and capsules containing formoterol fumarate and lactose. Urinary excretion of unchanged formoterol was used as an indirect measure of systemic exposure. Plasma drug disposition data parallel urinary excretion, and the elimination half-lives calculated for urine and plasma are similar.
Formoterol was rapidly absorbed in patients with asthma treated with formoterol fumarate 10 mcg twice daily via FORADIL CERTIHALER (formoterol fumarate inhalation powder) for 12 weeks; the maximum mean drug concentration of 18 pg/mL (n=12) in plasma was reached by 10 minutes post-dosing, and the systemic exposure (AUC0-12h) at steady state was 67 pg.hr/mL (n=9). In this study of adult and adolescent patients, the mean accumulation index based on the urinary excretion of unchanged formoterol was 1.59 in comparison with the first dose. This suggests some limited accumulation of formoterol in plasma with multiple dosing. The excreted amounts of formoterol at steady-state were close to those predicted based on single-dose kinetics.
Following inhalation of a single 120 mcg dose of formoterol fumarate via FORADIL AEROLIZER by 12 healthy subjects, formoterol reached a maximum plasma drug concentration of 92 pg/mL within 5 minutes of dosing.
Following inhalation of 12 to 96 mcg of formoterol fumarate by 10 healthy males, urinary excretion of both (R,R)- and (S,S)-enantiomers of formoterol increased proportionally to the dose. Thus, absorption of formoterol following inhalation appeared linear over the dose range studied.
As with many drug products for oral inhalation, it is likely that the majority of the inhaled formoterol fumarate delivered is swallowed and then absorbed from the gastrointestinal tract.
The binding of formoterol to human plasma proteins in vitro was 61%-64% at concentrations from 0.1 to 100 ng/mL. Binding to human serum albumin in vitro was 31%-38% over a range of 5 to 500 ng/mL. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 120 mcg dose via FORADIL AEROLIZER.
Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. In vitro studies showed that multiple isozymes catalyze the glucuronidation (UGT1A1, 1A8, 1A9, 2B7 and 2B15 were the most predominant isozymes) and O-demethylation (CYP2D6, 2C19, 2C9, and 2A6) of formoterol. Formoterol did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both. Whether a deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects has not been adequately explored.
Following oral administration of 80 mcg of radiolabeled formoterol fumarate to 2 healthy subjects, 59%-62% of the radioactivity was eliminated in the urine and 32%-34% in the feces over a period of 104 hours. Renal clearance of formoterol from blood in these subjects was about 150 mL/min.
When adults and adolescents with asthma were treated with 10 mcg formoterol fumarate twice daily via FORADIL CERTIHALER (formoterol fumarate inhalation powder) for 12 weeks, 11.5% of the dose was excreted in the urine as unchanged formoterol. Renal clearance of formoterol from plasma was 330 mL/min, which is similar to that seen previously following treatment of healthy volunteers with FORADIL AEROLIZER (300 mL/min).
Based on plasma concentrations measured following inhalation of a single 120 mcg dose of formoterol fumarate via FORADIL AEROLIZER by 12 healthy subjects, the mean terminal elimination half-life was determined to be 10 hours. From urinary excretion rates measured in these subjects, the mean terminal elimination half-lives for the (R,R)- and (S,S)-enantiomers were determined to be 13.9 and 12.3 hours, respectively. The (R,R)- and (S,S)-enantiomers represented about 40% and 60% of unchanged drug excreted in the urine, respectively, following single inhaled doses between 12 and 120 mcg in healthy volunteers and single and repeated doses of 12 and 24 mcg in patients with asthma. Thus, the relative proportion of the two enantiomers remained constant over the dose range studied and there was no evidence of relative accumulation of one enantiomer over the other after repeated dosing.
Gender: After correction for body weight, formoterol pharmacokinetics did not differ significantly between males and females.
Geriatric and Pediatric: The pharmacokinetics of formoterol have not been studied in the elderly population, and limited data are available in pediatric patients.
In a study of children with asthma who were 5 to 12 years of age, when formoterol fumarate 10 mcg was given twice daily by oral inhalation via FORADIL CERTIHALER (formoterol fumarate inhalation powder) for 8 weeks, the maximum mean drug concentration of 17 pg/mL (n=13) in plasma was seen at 10 minutes post-dosing and the systemic exposure (AUC0-12h) at steady state was 82 pg.hr/mL (n=8), while the mean accumulation index was 1.58 based on urinary excretion of unchanged formoterol. Hence, rate of absorption and accumulation in children were similar to those in adults. About 12% of the dose was recovered in the urine of the children as unchanged formoterol.
Hepatic/Renal Impairment: The pharmacokinetics of formoterol have not been studied in subjects with hepatic or renal impairment.
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 via FORADIL AEROLIZER (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 effects of FORADIL CERTIHALER (formoterol fumarate inhalation powder) were compared with those of albuterol and placebo in two 12-week double-blind studies of adult and adolescent patients with asthma. ECGs were performed pre-dose and 90 minutes post-dose on the first day of treatment and after 12 weeks of treatment. A total of 166 patients were treated with FORADIL CERTIHALER (formoterol fumarate inhalation powder) 10 mcg twice daily in these two studies. There were no statistically significant differences between FORADIL CERTIHALER and placebo treatment groups for QTc at any timepoint assessed (for both Bazett's and Fridericia's formulae).
Additionally, the electrocardiographic effects of FORADIL CERTIHALER (formoterol fumarate inhalation powder) were compared with those of placebo in a 12-week double-blind study of pediatric patients with asthma. ECGs were performed pre-dose and 90 minutes post-dose on the first day of treatment and after 12 weeks of treatment. In this study, 127 patients were treated with FORADIL CERTIHALER (formoterol fumarate inhalation powder) 10 mcg twice daily. There were no significant differences between treatments in mean QTc interval at any timepoint assessed using Bazett's formula. Similar results were found using Fridericia's formula, with the exception of the post-dose week 12 value where a significant decrease in QTc interval was observed with FORADIL CERTIHALER (formoterol fumarate inhalation powder) compared to placebo.
Continuous electrocardiographic monitoring was not included in the clinical studies of FORADIL CERTIHALER (formoterol fumarate inhalation powder) . However, in two 12-week double-blind studies that studied FORADIL AEROLIZER (FORADIL AEROLIZER consists of a single-dose dry powder inhaler and capsules containing formoterol fumarate and lactose) in 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.
In a clinical study in 19 adult patients with mild asthma, the bronchoprotective effect of formoterol via FORADIL AEROLIZER, 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.
Adolescent and Adult Asthma Trials
In two 12-week, multi-center, randomized, double-blind, parallel group studies, FORADIL CERTIHALER (formoterol fumarate inhalation powder) 10 mcg twice daily was compared to albuterol 180 mcg four times daily by pressurized metered-dose inhaler, and placebo in a total of 504 adult and adolescent patients 13 years of age and above with persistent asthma (defined as FEV1 greater than, or equal to 40% of the patient's predicted normal value).
The results of both studies showed that FORADIL CERTIHALER (formoterol fumarate inhalation powder) 10 mcg twice daily resulted in significantly greater post-dose bronchodilation (as measured by 12 hour AUC of FEV1 post-dose) than placebo throughout the 12week treatment period. Mean FEV1 in liters from both studies are shown below for the first and last treatment days (see Figures 1 and 2).
Figures 1a and 1b: Mean (adjusted) FEV1 from Clinical Trial A
Figure 1a : Clinical Trail A- Adjusted means First Treatment
Figure 1b : Clinical Trail A- Adjusted means Last Treatment
Figure 2a : Clinical Trail B- Adjusted means First Treatment
Figure 2b : Clinical Trail B- Adjusted means Last Treatment
FORADIL CERTIHALER (formoterol fumarate inhalation powder) 10 mcg demonstrated an onset of bronchodilation (defined as a 15% or greater increase from baseline in FEV1) comparable to albuterol, as demonstrated by FEV1 measurements at the early post-dose time points.
Compared with placebo, patients treated with FORADIL CERTIHALER (formoterol fumarate inhalation powder) 10 mcg also demonstrated improvement in the following secondary efficacy endpoints: increased morning and evening peak flow and reduction in rescue medication usage over a 24 hour period.
Pediatric Asthma Trial
A 12-week, multi-center, randomized, double-blind, parallel-group, study compared FORADIL CERTIHALER (formoterol fumarate inhalation powder) 10 mcg and placebo in a total of 249 children with persistent asthma (ages 5-12 years) who required daily bronchodilators. Efficacy was evaluated on the first day of treatment, after one month, and at the end of treatment.
FORADIL CERTIHALER (formoterol fumarate inhalation powder) 10 mcg twice daily demonstrated a greater 12hour FEV1 AUC compared to placebo on the first day of treatment, after one month of treatment, and after three months of treatment. Mean FEV1 in liters is shown below for the first and last treatment days.
Figures 3a and 3b: Mean (adjusted) FEV1 from Pediatric Clinical Trial
Figure 3a : Adjusted means First Treatment day
Figure 3b : Adjusted means Last Treatment day
Last reviewed on RxList: 6/29/2010
This monograph has been modified to include the generic and brand name in many instances.
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