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Foradil

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Foradil Aerolizer

Foradil Aerolizer

CLINICAL PHARMACOLOGY

Mechanism of Action

Formoterol fumarate is a long-acting 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 200-fold 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 beta2-agonists 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.

Pharmacodynamics

Systemic Safety and Pharmacokinetic/Pharmacodynamic Relationships

The major adverse effects of inhaled beta2-agonists occur as a result of excessive activation of the systemic betaadrenergic 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, and 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 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).

Pharmacokinetics

Information on the pharmacokinetics of formoterol in plasma has been obtained in healthy subjects by oral inhalation of doses higher than the recommended range and in Chronic Obstructive Pulmonary Disease (COPD) patients after oral inhalation of doses at and above the therapeutic dose. 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.

Absorption

Following inhalation of a single 120 mcg dose of formoterol fumarate by 12 healthy subjects, formoterol was rapidly absorbed into plasma, reaching a maximum drug concentration of 92 pg/mL within 5 minutes of dosing. In COPD patients treated for 12 weeks with formoterol fumarate 12 or 24 mcg twice daily, the mean plasma concentrations of formoterol obtained at 10 min, 2 h and 6 h post inhalation ranged between 4.0 and 8.8 pg/mL and 8.0 and 17.3 pg/mL, respectively..

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.

In a study in patients with asthma, when formoterol 12 or 24 mcg twice daily was given by oral inhalation for 4 weeks or 12 weeks, the accumulation index, based on the urinary excretion of unchanged formoterol ranged from 1.63 to 2.08 in comparison with the first dose. For COPD patients, when formoterol 12 or 24 mcg twice daily was given by oral inhalation for 12 weeks, the accumulation index, based on the urinary excretion of unchanged formoterol was 1.19 - 1.38. This suggests some 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. 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.

Distribution

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.

Metabolism

Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and Odemethylation 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. Four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) are involved in the O-demethylation 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.

Excretion

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. Following inhalation of a 12 mcg or 24 mcg dose by 16 patients with asthma, about 10% and 15%-18% of the total dose was excreted in the urine as unchanged formoterol and direct conjugates of formoterol, respectively. Following inhalation of 12 mcg or 24 mcg dose by 18 patients with COPD the corresponding values were 7% and 6-9% of the dose, respectively.

Based on plasma concentrations measured following inhalation of a single 120 mcg dose 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.

Special Populations

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 12 or 24 mcg was given twice daily by oral inhalation for 12 weeks, the accumulation index ranged from 1.18 to 1.84 based on urinary excretion of unchanged formoterol. Hence, the accumulation in children did not exceed that in adults, where the accumulation index ranged from 1.63 to 2.08 (see above). Approximately 6% and 6.5% to 9% of the dose was recovered in the urine of the children as unchanged and conjugated formoterol, respectively.

Hepatic/Renal Impairment

The pharmacokinetics of formoterol have not been studied in subjects with hepatic or renal impairment.

Animal Toxicology and/or Pharmacology

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.

Clinical Studies

Asthma

Adults and Adolescents 12 Years of Age and Older

In a placebo-controlled, single-dose clinical trial, the onset of bronchodilation (defined as a 15% or greater increase from baseline in FEV1) was similar for FORADIL AEROLIZER and albuterol 180 mcg by metered-dose inhaler.

In single-dose and multiple-dose clinical trials, the maximum improvement in FEV1 for FORADIL AEROLIZER 12 mcg generally occurred within 1 to 3 hours, and an increase in FEV1 above baseline was observed for 12 hours in most patients.

FORADIL AEROLIZER 12 mcg twice daily was compared to FORADIL AEROLIZER 24 mcg twice daily, albuterol 180 mcg four times daily by metered-dose inhaler, and placebo in a total of 1095 adult and adolescent patients 12 years of age and above with mild-to-moderate asthma (defined as FEV1 40%-80% of the patient's predicted normal value) who participated in two pivotal, 12-week, multi-center, randomized, double-blind, parallel group trials.

The results of both clinical trials showed that FORADIL AEROLIZER 12 mcg twice daily resulted in significantly greater post-dose bronchodilation (as measured by serial FEV1 for 12 hours post-dose) throughout the 12-week treatment period. There was no significant difference in post-dose bronchodilation between FORADIL AEROLIZER 12 mcg twice daily and FORADIL AEROLIZER 24 mcg twice daily, but serious asthma exacerbations occurred more commonly in the higher dose group [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Mean FEV1 measurements from both studies are shown below for the first and last treatment days (see Figures 1 and 2).

Figure 1a: Mean FEV1 from Clinical Trial A

Mean FEV1 from Clinical Trial A - Illustration

Figure : 1b

Mean FEV1 from Clinical Trial A - Illustration

Figure 2a: Mean FEV1 from Clinical Trial B

Mean FEV1 from Clinical Trial B - Illustration

Figure : 2b

Mean FEV1 from Clinical Trial B - Illustration

Compared with placebo and albuterol, patients treated with FORADIL AEROLIZER 12 mcg demonstrated improvement in many secondary efficacy endpoints, including improved combined and nocturnal asthma symptom scores, fewer nighttime awakenings, fewer nights in which patients used rescue medication, and higher morning and evening peak flow rates. FORADIL AEROLIZER 24 mcg twice daily did not provide any additional improvements in these secondary endpoints compared to FORADIL AEROLIZER 12 mcg twice daily.

A 16-week, randomized, multi-center, double-blind, parallel-group trial enrolled 1568 patients 12 years of age and older with mild-to-moderate asthma (defined as FEV1 ≥ 40% of the patient's predicted normal value) in three treatment groups: FORADIL AEROLIZER 12 mcg twice daily, FORADIL AEROLIZER 24 mcg twice daily, and placebo. The trial's primary endpoint was the incidence of serious asthma-related adverse events. Serious asthma exacerbations occurred in 3 (0.6%) patients who received FORADIL AEROLIZER 12 mcg twice daily, 2 (0.4%) patients who received FORADIL AEROLIZER 24 mcg twice daily, and 1 (0.2%) patient who received placebo. The size of this trial was not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups. All serious asthma exacerbations resulted in hospitalizations. While there were no deaths in the trial, the duration and size of this trial were not adequate to quantify the rate of asthma-related death. See [WARNINGS AND PRECAUTIONS] for information about a trial that compared another long-acting beta2-adrenergic agonist to placebo.

Children 5-11 Years of Age

A 12-month, multi-center, randomized, double-blind, parallel-group, trial compared FORADIL AEROLIZER 12 mcg twice daily and FORADIL AEROLIZER 24 mcg twice daily to placebo in a total of 518 children with asthma (ages 5-12 years) who required daily bronchodilators and anti-inflammatory treatment. Efficacy was evaluated on the first day of treatment, at Week 12, and at the end of treatment.

FORADIL AEROLIZER 12 mcg twice daily demonstrated a greater 12-hour FEV1 AUC compared to placebo on the first day of treatment, after twelve weeks of treatment, and after one year of treatment. FORADIL AEROLIZER 24 mcg twice daily did not result in any additional improvement in 12-hour FEV1 AUC compared to FORADIL AEROLIZER 12 mcg twice daily.

Exercise-Induced Bronchospasm

The effect of FORADIL AEROLIZER on exercise-induced bronchospasm (defined as > 20% fall in FEV1) was examined in four randomized, single-dose, double-blind, crossover trials in a total of 77 patients 4 to 41 years of age with exercise-induced bronchospasm. Exercise challenge testing was conducted 15 minutes, and 4, 8, and 12 hours following administration of a single dose of study drug (FORADIL AEROLIZER 12 mcg, albuterol 180 mcg by metered-dose inhaler, or placebo) on separate test days. FORADIL AEROLIZER 12 mcg and albuterol 180 mcg were each superior to placebo for FEV1 measurements obtained 15 minutes after study drug administration. FORADIL AEROLIZER 12 mcg maintained superiority over placebo at 4, 8, and 12 hours after administration. Most subjects were protected from exercise-induced bronchospasm for up to 12 hours following administration of FORADIL AEROLIZER; however, some were not. The efficacy of FORADIL AEROLIZER in the prevention of exercise-induced bronchospasm when dosed on a regular twice daily regimen has not been studied.

COPD

In multiple-dose clinical trials in patients with COPD, FORADIL AEROLIZER 12 mcg was shown to provide onset of significant bronchodilation (defined as 15% or greater increase from baseline in FEV1) within 5 minutes of oral inhalation after the first dose. Bronchodilation was maintained for at least 12 hours.

FORADIL AEROLIZER was studied in two pivotal, double-blind, placebo-controlled, randomized, multi-center, parallel-group trials in a total of 1634 adult patients (age range: 34-88 years; mean age: 63 years) with COPD who had a mean FEV1 that was 46% of predicted. The diagnosis of COPD was based upon a prior clinical diagnosis of COPD, a smoking history (greater than 10 pack-years), age (at least 40 years), spirometry results (prebronchodilator baseline FEV1 less than 70% of the predicted value, and at least 0.75 liters, with the FEV1/VC being less than 88% for men and less than 89% for women), and symptom score (greater than zero on at least four of the seven days prior to randomization). These studies included approximately equal numbers of patients with and without baseline bronchodilator reversibility, defined as a 15% or greater increase FEV1 after inhalation of 200 mcg of albuterol sulfate. A total of 405 patients received FORADIL AEROLIZER 12 mcg, administered twice daily. Each trial compared FORADIL AEROLIZER 12 mcg twice daily and FORADIL AEROLIZER 24 mcg twice daily with placebo and an active control drug. The active control drug was ipratropium bromide in COPD Trial A, and slow-release theophylline in COPD Trial B (the theophylline arm in this study was open-label). The treatment period was 12 weeks in COPD Trial A, and 12 months in COPD Trial B.

The results showed that FORADIL AEROLIZER 12 mcg twice daily resulted in significantly greater post-dose bronchodilation (as measured by serial FEV1 for 12 hours post-dose; the primary efficacy analysis) compared to placebo when evaluated after 12 weeks of treatment in both trials, and after 12 months of treatment in the 12-month trial (COPD Trial B). Compared to FORADIL AEROLIZER 12 mcg twice daily, FORADIL AEROLIZER 24 mcg twice daily did not provide any additional benefit on a variety of endpoints including FEV1.

Mean FEV1 measurements after 12 weeks of treatment for one of the two major efficacy trials are shown in the figure below.

Figure 3 : Mean FEV1 after 12 Weeks of treatment from COPD Trial A

Mean FEV1 after 12 Weeks of treatment from COPD Trial A - Illustration

FORADIL AEROLIZER 12 mcg twice daily was statistically superior to placebo at all post-dose timepoints tested (from 5 minutes to 12 hours post-dose) throughout the 12-week (COPD Trial A) and 12-month (COPD Trial B) treatment periods.

In both pivotal trials compared with placebo, patients treated with FORADIL AEROLIZER 12 mcg demonstrated improved morning pre-medication peak expiratory flow rates and took fewer puffs of rescue albuterol.

Last reviewed on RxList: 4/2/2012
This monograph has been modified to include the generic and brand name in many instances.

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