Formoterol

Abstract

Formoterol, a selective β₂-adrenoceptor agonist, produces effective doseproportional bronchodilation, which persists for up to 12 hours, in patients with reversible obstructive respiratory disease. Bronchodilation is significant within minutes of inhalation, maximal within 2 hours, and at therapeutic doses is equivalent to that produced by standard doses of traditional β₂-agonists. In single-dose studies comparing the two long-acting β₂-agonists formoterol and salmeterol, significant broncho dilation is achieved more rapidly with formoterol than salmeterol. Duration of bronchodilation is similar with both drugs. The therapeutic efficacy of inhaled formoterol has been equal to or greater than that of salbutamol (albuterol), fenoterol and terbutaline in both short and long term clinical trials. Formoterol reduces symptoms of nocturnal asthma and reduces the need for rescue medication compared with salbutamol. Recent studies have shown that the addition of inhaled formoterol 12 or 24μg twice daily to existing inhaled corticosteroid regimens improves lung function and reduces asthma symptoms compared with placebo. In one well designed study, the frequency of severe exacerbations of asthma over 12 months was decreased by adding formoterol to existing regimens of inhaled corticosteroids. Tolerance to the bronchodilator response of formoterol has not been observed in long term clinical trials. Because of its long duration of action, formoterol offers significant therapeutic advantages over shorter-acting β₂-agonists in the treatment of nocturnal and exercise-induced asthma. Formoterol is effective in preventing exercise-induced asthma in adults and children and confers significantly more protection than salbutamol when administered 3 and 12 hours before exercise. In general, inhaled formoterol is well tolerated. The most commonly reported adverse effects, tremor and palpitations, are those traditionally associated with the use of β₂-agonists. Oral formoterol and high doses of inhaled formoterol are associated with more adverse events than are the recommended doses of 6 to 24μg. Formoterol is currently recommended for use as an alternative to increasing inhaled steroid dosage in patients whose symptoms are inadequately controlled despite therapy with low to moderate doses of inhaled steroids and intermittent short-acting β₂-agonists, and results of recent studies support therapeutic guidelines. Long term clinical studies comparing formoterol and salmeterol have not yet been published. Further studies to evaluate the earlier use of formoterol in patients with mild to moderate asthma are needed to determine the role and long term safety of formoterol in the management of asthma. The long-acting selective β₂-adrenoceptor agonist formoterol elicited dose-proportional bronchodilation in patients with asthma as measured by forced expiratory volume in 1 second (FEV₁), forced vital capacity (FVC), peak expiratory flow (PEF), and specific airways conductance (sGaw). As with salbutamol (albuterol), clinical effects of formoterol were detected within 1 minute after inhalation; however, the duration of bronchodilation with formoterol was significantly longer than with salbutamol. The onset of action of formoterol was more rapid than that of salmeterol, but the duration of effect (≈12 hours) was similar for both drugs. Formoterol usually produced maximum bronchodilation within 2 hours of inhalation. Dry powder capsule formulations of formoterol have been equipotent with formoterol administered from a metered-dose inhaler (MDI) in improving pulmonary function. Formoterol has exhibited some anti-inflammatory effects in vitro. Formoterol inhibited allergen-induced responses in animals and patients with asthma. In patients with moderate chronic obstructive pulmonary disease (COPD), the onset and duration of action of formoterol 24μg and salmeterol 50μg were similar. However, the effects of salmeterol persisted longer than those of formoterol in patients with severe COPD. Oral formoterol produced small dose-related increases in heart rate and decreases in blood pressure but cardiovascular effects were significant only after high doses administered by inhalation. The cardiovascular effects of formoterol and salbutamol were similar, but less than those associated with fenoterol. Rebound bronchial hyperresponsiveness has not been seen after stopping treatment with formoterol. Attenuation of the bronchodilator response, with a concomitant decrease in the density of β₂-receptors on peripheral blood lymphocytes, has been noted after 2 or 4 weeks of formoterol use. Formoterol exhibited a biphasic serum concentration after single-dose inhalation of 120μg, with an initial peak of 52 ng/L at 0.25 hours followed by a second peak of 40 ng/L at 1.58 hours. The mean plasma half-life of formoterol has been calculated as 3.4 hours after oral administration and 1.7 to 2.3 hours after inhalation. The therapeutic efficacy of inhaled and oral formoterol has been demonstrated in both short and long term studies in patients with stable asthma or chronic obstructive airways disease. In studies that provided relevant baseline data, mean FEV₁ was usually 60 to 67% of predicted value. In noncomparative and placebo-controlled trials, formoterol improved symptoms, produced clinically relevant increases in PEF and FEV₁, and reduced the need for rescue medication in patients with asthma. Improvements in lung function and control of asthma symptoms with formoterol were maintained during up to 5 years of treatment; there was no evidence of a reduced bronchodilator response or worsening of asthma control. Long term studies showed no difference in lung function in patients using formoterol with or without concomitant anti-asthma therapy. Results of comparative trials showed inhaled formoterol to be generally superior to salbutamol in improving lung function and asthma symptoms. In a representative study, formoterol 12μg twice daily was associated with a greater decrease in diurnal variation in pre-bronchodilator PEF (from 56 to 17 L/min) than salbutamol 200μg 4 times daily (from 45 to 42 L/min); morning FEV₁ and PEF were higher with formoterol than with salbutamol, even though salbutamol recipients used more rescue medication. Nocturnal asthma symptoms were better controlled by formoterol than by salbutamol. As with MDIs, dry powder formulations of formoterol were at least as effective as those of salbutamol. Formoterol 6 or 12μg twice daily via Turbuhaler® (a multidose inspiratory flow-driven dry powder inhalation device) was more effective than terbutaline 500μg 4 times daily at increasing morning and evening PEF and reducing day and night-time symptoms in studies involving more than 600 patients with stable asthma. Formoterol and fenoterol similarly improved lung function, but formoterol was more efficacious in relieving nocturnal asthma. Effects on lung function of formoterol and a combined regimen of fenoterol and ipratropium bromide were similar, but the overall efficacy of formoterol was considered to be better. A recent well designed double-blind study demonstrated that the addition of inhaled formoterol 12μg twice daily to inhaled budesonide 100 or 400μg twice daily reduced the frequency of severe exacerbation of asthma, improved PEF and symptom control and reduced the need for β₂-agonist rescue medication compared with placebo. Similarly, formoterol 24μg twice daily was more effective than placebo in improving morning PEF and asthma symptom score and reducing the need for rescue medication when added to existing therapy with inhaled corticosteroids. Initial results from a nonblind study indicate that the addition of formoterol 12μg twice daily to inhaled beclomethasone 250μg twice daily resulted in a significantly greater increase in PEF than doubling the dosage of the inhaled corticosteroid. In asthma patients receiving regular inhaled corticosteroid therapy, improvement in quality of life after 6 months was slightly greater after the addition of formoterol 12μg twice daily via Aerolizer® inhaler (a single-dose inspiratory flow-driven dry powder inhalation device) compared with salmeterol 50μg twice daily via Diskhaler®, although this difference did not reach statistical significance. A single dose of formoterol 12μg by inhalation provided significantly greater protection against exercise-induced asthma (EIA) than salbutamol 200 or 400μg when administered 3 to 12 hours before exercise. Postexercise FEV₁ decreased by 9% (median) at 3 hours compared with 17% after salbutamol and by 8 to 11% when formoterol was inhaled 12 hours before exercise. In children, formoterol 12μg conferred about 75% protection against EIA when inhaled 3 hours before exercise, compared with the 46 and 17% protection provided by inhaled salbutamol 400 and 200μg, respectively. Similar results were obtained when dry powder capsule formulations of formoterol and salbutamol were compared in patients with EIA. In patients with chronic obstructive airways disease, formoterol was more effective in increasing FEV₁ and improving symptoms than fenoterol and salbutamol. These results need to be confirmed in long term studies. When inhaled via Turbuhaler® significant changes in lung function compared with placebo were elicited by formoterol 6μg twice daily. However, in studies of patients using other dry powder inhalation devices, the duration of action of formoterol 6μg was less than that of formoterol 12 and 24μg. All formulations of formoterol are well tolerated, with the fewest adverse events associated with inhaled formoterol. The most commonly reported adverse effects with inhaled formoterol have been tremor and palpitation, traditionally associated with the use of β₂-agonists. Headache, muscle cramps, nausea and anxiety have also been reported. In long term studies in adults, the incidence of adverse events associated with inhaled formoterol ranged from 0 to 11%. Clinically significant cardiac or metabolic effects were extremely rare. Higher doses of inhaled formoterol (48μg) increased heart rate and tremor amplitude. Formoterol has been as well tolerated as terbutaline and salbutamol in short and long term comparative studies. Elderly patients have tolerated formoterol as well as salbutamol, with no significant changes in electrocardiogram tracings, heart rate, blood pressure, or laboratory values with either drug. The current recommended use for formoterol is as an alternative to increasing inhaled corticosteroid dosage in patients in whom asthma symptoms are not adequately controlled with beclomethasone or budesonide 200 to 800μg daily or fluticasone 100 to 400μg daily and as-required short-acting β2-agonists. Inhaled formoterol 6 μg twice daily via Turbuhaler®, or 12μg twice daily via Aerolizer®, other dry powder devices or MDI should initially be added to the above regimen, and may be increased to 24μg twice daily if necessary. In Europe, formoterol dosage is expressed as that delivered to the patient, 4.5 to 18μg twice daily, rather than the metered dose of 6 to 24μg twice daily. Formoterol is intended as maintenance therapy and is not recommended as rescue treatment for severe exacerbations of asthma. Patients should be advised not to discontinue steroids while on formoterol therapy, although dosage adjustments may be possible.