Inhaled formoterol is a long-acting selective β2-adrenoceptor agonist, with an onset of action of 5 minutes postdose and a bronchodilator effect that lasts for at least 12 hours.
Statistically significant and clinically relevant (> 120ml) improvements in lung function [assessed using standardized/normalized area under the forced expiratory volume in 1 second (FEV1) versus time curve (AUC FEV1)] were observed with inhaled formoterol 12μg twice daily (the approved dosage in the US) compared with placebo in 12-week and 12-month, randomized, double-blind trials in patients with chronic obstructive pulmonary disease (COPD).
The bronchodilator efficacy of formoterol 12μg twice daily was greater than that of oral slow-release theophylline (individualized dosages) in a 12-month trial or inhaled ipratropium bromide 40μg four times daily in a 12-week trial. Improvement in AUC FEV1 with formoterol, but not theophylline, compared with placebo was observed in patients with irreversible or poorly-reversible airflow obstruction. Formoterol also significantly improved health-related quality of life compared with ipratropium bromide or placebo and significantly reduced symptoms compared with placebo. Combination therapy with formoterol 12μg twice daily plus ipratropium bromide 40μg four times daily was significantly more effective than albuterol (salbutamol) 200μg four times daily plus the same dosage of ipratropium bromide in a 3-week, randomized, double-blind, double-dummy, crossover trial.
Inhaled formoterol was well tolerated in clinical trials. The incidence of investigator-determined drug-related adverse events with inhaled formoterol 12μg twice daily was similar to that with placebo and inhaled ipratropium bromide 40μg four times daily but lower than that with oral slow-release theophylline (individualized dosages). Importantly, there were no significant differences between formoterol and placebo or comparator drugs in cardiovascular adverse events in patients with COPD and corrected QT interval values within the normal range.
In conclusion, inhaled formoterol improved lung function and health-related quality of life and reduced symptoms relative to placebo in clinical trials in patients with COPD. The drug had greater bronchodilator efficacy than oral slow-release theophylline or inhaled ipratropium bromide and showed efficacy in combination with ipratropium bromide. The adverse events profile (including cardiovascular adverse events) with formoterol was similar to that with placebo. Thus, inhaled formoterol may be considered as a first-line option for the management of bronchoconstriction in patients with COPD who require regular bronchodilator therapy for the management of symptoms.
Inhaled formoterol is a long-acting selective β2-adrenoceptor agonist (β2-agonist); it has a rapid onset of action (5 minutes in single- and multiple-dose studies) and, like salmeterol, maintains a bronchodilator effect for at least 12 hours. The onset of postdose bronchodilator action was faster with formoterol 12μg than with salmeterol 100μg in a double-blind, randomized, placebo-controlled trial.
Formoterol 6 to 24μg improved forced expiratory volume in 1 second (FEV1) compared with baseline and placebo in single-dose crossover trials in patients with chronic obstructive pulmonary disease (COPD), and was at least as effective as salmeterol 50 or 100μg or albuterol (salbutamol) 400μg at improving FEV1. Mean peak FEV1 was reached 1 hour after inhalation of formoterol 12μg; values for this parameter were 1 hour after albuterol 200μg, and 2 to 5 hours after salmeterol 50μg.
Formoterol 4.5 to 18μg twice daily for 1 week prolonged the time to exhaustion on a bicycle ergometer test compared with placebo; results were similar to those for ipratropium bromide 80μg three times daily.
All β2-agonists have the potential to increase heart rate and plasma glucose concentrations, and to decrease plasma potassium concentrations, through effects on extrapulmonary β2 receptors. Dose-dependent increases in heart rate, corrected QT (QTc) interval and plasma glucose concentrations, and dose-dependent decreases in plasma potassium concentrations, were observed with inhaled formoterol 24 to 96μg or salmeterol 100 to 400μg in a double-blind, placebo-controlled, crossover trial in 16 healthy volunteers. In patients with COPD, pre-existing mild to moderate cardiac arrhythmias and hypoxemia [PaO2 (arterial oxygen pressure) <60mm Hg], formoterol 12μg had similar systemic effects to salmeterol 50μg. Complex ventricular arrhythmias were observed in formoterol 12 and 24μg recipients, but not in salmeterol 50μg or placebo recipients.
The maximum plasma concentration (92 ng/L) of formoterol was reached within 5 minutes of inhalation of a single supraoptimal dose (120μg) in 12 healthy volunteers. Urinary excretion data suggest that absorption was linear with inhaled formoterol 12 to 96μg in ten healthy volunteers. In vitro plasma protein binding of formoterol was 61 to 64% at concentrations 0.1 to 100 μg/L.
Mean plasma concentrations of the drug at 10 minutes to 6 hours postinhalation were 4.0 to 8.8 ng/L and 8.0 to 17.3 ng/L, respectively, after multiple doses of formoterol 12 or 24μg administered twice daily for 12 weeks in patients with COPD, with some evidence of accumulation of formoterol in the plasma (accumulation index 1.19 to 1.38).
Formoterol is metabolized primarily in the liver by four cytochrome P450 (CYP) isoenzymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6). These enzymes were not inhibited by the drug at therapeutic concentrations. Following inhalation of formoterol 12 or 24μg by 18 patients with COPD, 7% of the total dose was excreted in the urine as unchanged drug and 6 to 9% of the total dose was eliminated as direct conjugates of formoterol. The mean terminal elimination half-life was determined to be 10 hours (based on plasma concentrations) following inhalation of single-dose formoterol 120μg by 12 healthy volunteers.
Currently, there are no pharmacokinetic data for the use of formoterol in patients with hepatic or renal impairment or in elderly individuals.
Inhaled formoterol has been evaluated as monotherapy or combination therapy for the management of patients with COPD. In clinical trials, COPD was diagnosed using the American Thoracic Society guidelines.
The bronchodilator effect [measured as normalized area under the FEV1 versus time curve (AUC FEV1)] with formoterol 12μg twice daily (n = 194) was significantly greater than that with ipratropium bromide 40μg four times daily (n = 194; p = 0.001) or placebo (n = 200; p < 0.001) in a randomized, double-blind, 12-week trial in patients with COPD. Significant improvements were also observed in mean morning premedication peak expiratory flow (PEF; p < 0.001) and health-related quality of life [all three subsections of the St. George’s Respiratory Questionnaire (SGRQ); p ≤ 0.036], and significant reductions were reported for the use of rescue medication (p ≤ 0.014) and the percentage of ‘bad days’ (days with at least two individual symptom scores of ≥2 and/or a reduction in PEF from baseline of >20%; p < 0.001) in formoterol compared with ipratropium bromide recipients. The differences in health-related quality of life between the two treatments were clinically relevant (exceeding 4 points) for the Activity and the Impacts domains of the SGRQ.
Compared with oral slow-release theophylline (individualized dosages targeted at plasma concentrations of 8 to 20 mg/L), formoterol 12μg twice daily significantly increased standardized AUC12h FEV1 (primary end-point; p = 0.026) and mean morning premedication PEF (p ≤ 0.020) and reduced the percentage of ‘bad days’ (p ≤ 0.035) in a randomized, double-blind (with the exception of the theophylline arm), 12-month trial. A subgroup analysis in this trial indicated that at 3 (p = 0.007) and 12 months (p = 0.002), formoterol (n = 118), but not oral slow-release theophylline (n = 105), produced significant bronchodilation compared with placebo (n = 117) in patients with irreversible or poorly-reversible airflow obstruction (i.e. patients whose FEV1 values increased <15% after receiving albuterol). Both formoterol (p ≤ 0.026) and oral slow-release theophylline (p ≤ 0.013) were significantly more effective than placebo at managing COPD during the night (measured as morning premedication FEV1).
In these two monotherapy trials, inhaled formoterol 24μg twice daily did not provide any additional benefit over the 12μg twice daily dosage in patients with COPD.
The combined efficacy of inhaled formoterol 12μg twice daily plus inhaled ipratropium bromide 40μg four times daily for 3 weeks has been compared with that of albuterol 200μg four times daily for 3 weeks via a pressurized metered-dose inhaler plus inhaled ipratropium bromide 40μg four times daily in a randomized, double-blind, double-dummy, crossover trial in 172 patients with COPD. Formoterol combination therapy was significantly more effective than albuterol combination therapy at increasing mean morning premedication PEF (primary endpoint; p = 0.0003). Combination therapy with formoterol was also more effective according to secondary endpoints, significantly increasing postmedication FEV1 to 6 hours (p< 0.0001), peak postmedication FEV1 (p < 0.0001) and AUC FEV1 (p < 0.0001) and improving symptoms of COPD (measured as mean total symptoms score, p = 0.0042) and the SGRQ symptoms score (p = 0.0408) relative to albuterol combination therapy.
Inhaled formoterol was well tolerated in clinical trials in patients with COPD. The percentage of patients experiencing at least one adverse event with inhaled formoterol 12μg twice daily was similar to that with placebo, inhaled ipratropium bromide 40μg four times daily or oral slow-release theophylline (individualized dosages targeted at plasma concentrations of the drug of 8 to 20 mg/L) in randomized, double-blind, comparative trials of 12 weeks’ and 12 months’ duration. Viral infection, exacerbation of COPD, bronchitis, upper respiratory tract infection, dyspnea and headache were the most commonly reported adverse events (i.e. occurring in >5% of formoterol 12μg twice daily recipients); however, the incidence of these events was not significantly different compared with oral slow-release theophylline or placebo.
Drug-related adverse events, serious adverse events and events leading to withdrawal from the study occurred with a similar incidence with inhaled formoterol, placebo or ipratropium bromide. In contrast, drug-related adverse events and withdrawal because of adverse events occurred with a higher incidence in patients receiving oral slow-release theophylline in the 12-month trial.
There were no significant differences in the incidence of cardiovascular adverse events with inhaled formoterol (0.5% of patients) compared with inhaled placebo (2.5%) or ipratropium bromide (2.6%) after 12 weeks’ treatment or in the incidence of serious cardiovascular adverse events with inhaled formoterol (2.4% of patients) compared with placebo (0.9%) or oral slow-release theophylline (2.4%) after 12 months’ treatment in patients with COPD and QTc interval values within the normal range; heart rate and rhythm disorders were infrequent. The incidences of QTc interval prolongation (>0.46s), ECG abnormalities or clinically relevant changes in serum potassium or fasting plasma glucose concentrations were similar with inhaled formoterol 12μg twice daily compared with placebo, inhaled ipratropium bromide or oral slow-release theophylline in clinical trials.
Dosage and Administration
Formoterol, inhaled orally using an Aerolizer™1 inhaler, is indicated in the US for the long-term maintenance treatment of bronchoconstriction associated with COPD (including chronic bronchitis and emphysema). The recommended dosage of formoterol in this patient group is 12μg twice daily approximately 12 hours apart; the total daily dose should not exceed 24μg.
Formoterol should be used with caution in patients with cardiovascular disorders (especially coronary insufficiency, cardiac arrhythmias or hypertension), convulsive disorders or thyrotoxicosis, or hypersensitivity to sympathomimetic amines. Extreme caution is advised if formoterol is used concomitantly with monoamine oxidase inhibitors, tricyclic antidepressants or drugs that are known to prolong the QTc interval, and caution is recommended with the concomitant use of formoterol and non-potassium-sparing diuretics.
KeywordsChronic Obstructive Pulmonary Disease Salmeterol Formoterol Albuterol Ipratropium Bromide
- 3.Pauwels RA, Buist AS, Calverley PMA, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD): Executive Summary. Respir Care 2001 Aug; 46(8): 798–825PubMedGoogle Scholar
- 5.Celli BR, Snider GL, Heffner J, et al. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152 (5 Pt 2): S77–120Google Scholar
- 6.The COPD Guidelines Group of the Standards of Care Committee of the BTS. BTS guidelines for the management of chronic obstructive pulmonary disease. Thorax 1997; 52Suppl. 5: S1–28Google Scholar
- 13.Novartis Pharmaceuticals. Foradil aerolizer: formoterol fumarate inhalation powder [web page]. Available from URL: http://www.pharma.us.novartis.com/product/pi/pdf/foradil.pdf [Accessed 2002 Mar 4]
- 15.Cazzola M, Di Perna F, Califano C, et al. Formoterol Turbuhaler (F) vs salbutamol Diskus (S) in patients with partially reversible stable COPD. Am J Respir Crit Care Med 1999; 159 (3 Suppl. 2): A798Google Scholar
- 17.Kottakis J, Cioppa GD, Creemers J, et al. Faster onset of bronchodilation with formoterol than with salmeterol in patients with stable, moderate to severe COPD: results of a randomized, double-blind, clinical study. Can Res J 2002; 9(2): 107–15Google Scholar
- 19.Kottakis I, Bouros D, Siafakas N, et al. Effects of formoterol and salmeterol on inspiratory capacity: results from a single-dose, 5-period cross-over study in stable, poorly reversible, stage II and III COPD patients [abstract]. Am J Respir Crit Care Med 2001 Apr; 163(Suppl. 2): S278Google Scholar
- 25.Liesker JWW, van de Velde V, Meysmann M, et al. The effects of formoterol on excercise capacity in COPD patients [abstract]. Eur Respir J 1999; 14: 3795Google Scholar
- 33.D’Urzo AD, De Salvo MC, Ramirez-Rivera A, et al. In patients with COPD, treatment with a combination of formoterol and ipratropium is more effective than a combination of salbutamol and ipratropium: a 3-week, randomized, double-blind, within-patient, multicenter study. Chest 2001 May; 119(5): 1347–56PubMedCrossRefGoogle Scholar
- 34.Novartis Pharmaceuticals Corporation. Novartis’ Foradil gains FDA approval for the treatment of chronic obstructive pulmonary disease (COPD). Media Rel 2001 Sep 27Google Scholar
- 46.Hanania NA, Ramsdell J, Payne K, et al. Improvements in airflow and dyspnea in COPD patients following 24 weeks treatment with salmeterol 50μg and fluticasone propionate 250μg alone or in combination via the Diskus [abstract no. 884786]. Am J Respir Crit Care Med 2001 Apr; 163Suppl. 2: A279Google Scholar
- 48.Mahler DA, Wong E, Giessel G, et al. Improvements in FEV1 and symptoms in COPD patients following 24 weeks of twice daily treatment with salmeterol 50/fluticasone propionate 500 combination [abstract no. 884785]. Am J Respir Crit Care Med 2001 Apr; 163Suppl. 2: 279Google Scholar