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Formoterol
See also Beta 2 -adrenoceptor agonists
General information
Formoterol is a long-acting selective β 2 -adrenoceptor agonist that is more potent than salmeterol [ ] and has a similar duration of action (12 hours) but a rapid onset of effect similar to that of salbutamol. It is available as a multidose, pressurized aerosol and as a dry powder inhaler, delivering 0.006 or 0.012 mg per dose. The usual dose is 0.012 mg bd.
The pharmacokinetics and pharmacodynamics of a single oral dose of formoterol 168 mg have been studied in eight healthy men. Plasma concentrations reached a maximum of 94 pg/ml 70 minutes after administration. The biological effects peaked later, at 4 hours. Plasma potassium fell from 3.98 mmol/l to 2.33 mmol/l. There was a fall in blood eosinophil count from 277 × 10 6 /l to 47 × 10 6 /l [ ].
In a postmarketing surveillance study of the long-acting β 2 -adrenoceptor agonist formoterol in the UK using the technique of prescription event monitoring, exposure and outcome data in 5777 patients aged 3–96 years were collected [ ]. The most commonly reported events, excluding those related to respiratory disease, were headache, tremor, palpitation, cramp, and nausea and vomiting, events known to be associated with β 2 -adrenoceptor agonists [ ]. However, the frequencies of nausea and vomiting (1.3%) and pruritus (0.5%) differed from the frequencies reported in the premarketing trials.
Drug studies
Observational studies
The cardiovascular and metabolic responses to increasing doses of formoterol 12, 24, 48, and 96 mg administered from a dry powder inhaler have been assessed in a randomized, double-blind, crossover study in 20 patients with mild to moderate asthma. There was no difference in the maximum effects of formoterol 12 micrograms and placebo. The 24 micrograms dose significantly reduced plasma potassium (average fall 0.2 mmol/l) and increased blood glucose (average rise 1.8 mmol/l). After formoterol 96 micrograms the rise in heart rate was 9/minute greater than after placebo, systolic blood pressure rose by an average of 4 mmHg, and diastolic pressure fell by an average of 3 mmHg. Plasma potassium fell by an average of 0.5 mmol/l and blood glucose rose by an average of 2.6 mmol/l. The effects on extrapulmonary parameters would only be of clinical significance at the highest dose of formoterol studied [ ].
A 3-month, open, uncontrolled, multicenter trial has been carried out in 1380 patients with moderate to severe persistent asthma taking inhaled corticosteroids [ ]. Formoterol was given via a single-dose, breath-activated device (Foradil). There were significant increases in peak flow and a three-fold reduction in the need for rescue treatment with short acting β 2 -adrenoceptor agonists. By the end of the study, 72% of the patients were taking formoterol 12 micrograms bd and 29% were taking 24 micrograms bd. Physician evaluation indicated that tolerability was very good or good in 93% of the patients. There were only minor drug-related adverse events similar to those produced by other β 2 -agonists.
Comparative studies
Formoterol has been compared with various other β 2 -adrenoceptor agonists.
Fenoterol and salbutamol
Formoterol 24 micrograms, fenoterol 0.4 mg, and salbutamol 0.4 mg all caused an increase in heart rate and plasma glucose, and a fall in diastolic blood pressure and plasma potassium [ ]. Fenoterol had a greater maximum effect on heart rate than either salbutamol or formoterol. Formoterol and fenoterol caused a similar maximum reduction in plasma potassium greater than that seen with salbutamol.
Formoterol (12 + 12 micrograms via Aerolizer) has been compared with salbutamol (200 + 200 + 200 micrograms via spacer) each at 20-minute intervals in 60 patients with acute exacerbations of asthma in a double-blind, randomized, placebo-controlled study [ ]. Typical β 2 -adrenoceptor-mediated symptoms (reported as adverse events) occurred in 12 patients who used formoterol and 11 who used salbutamol. There was no significant difference in incidence of adverse events between the two groups: dry mouth (38% versus 36%), dizziness (16% versus 7.1%), headache (9.4% versus 7.1%).
The effects of formoterol Turbuhaler® (2 × 9 micrograms and 6 × 9 micrograms) and salbutamol Diskhaler® (3 × 400 micrograms and 9 × 400 micrograms) have been compared in 26 patients with asthma in a double-blind, crossover, randomized, placebo-controlled study [ ]. Maximum heart rate and palpitation and tremor scores were statistically significant greater after salbutamol. Other systemic effects were comparable and the effects were brief. These findings need to be interpreted with caution, given the small size of the study.
Salmeterol
The relative efficacy of the long-acting β 2 -adrenoceptor agonists formoterol and salmeterol has been studied in a randomized, double-blind, crossover trial in 15 patients with asthma taking regular corticosteroids and salbutamol [ ]. The patients had methacholine challenges performed after varying single doses of formoterol (12, 60, and 120 micrograms) and salmeterol (50, 250, and 500 micrograms). The maximal protective effect of salmeterol against methacholine challenge was reached at 250 micrograms, whereas formoterol showed a dose–response relation, with maximum protection at the highest dose. This confirmed the authors’ hypothesis that salmeterol is a partial agonist at β-adrenoceptors compared with formoterol. The higher affinity of formoterol for β-adrenoceptors also produced more adverse effects and reactions. There was a significant fall in serum potassium concentration after 60 micrograms of formoterol but not after 250 micrograms of salmeterol. The serum potassium concentration was also significantly lower with the highest dose of formoterol compared with the highest dose of salmeterol (minimum concentration 3.1 mmol/l). The highest dose of formoterol also resulted in more tremor than the highest dose of salmeterol. The increases in heart rate and QT interval were similar with the two drugs. It should be noted that the doses used in this study were higher than recommended. It is unclear whether the partial agonist activity of salmeterol is clinically important, but this seems unlikely.
Terbutaline
In 12 stable asthmatic patients who took high doses of formoterol or terbutaline, terbutaline had significantly greater systemic effects than formoterol, as indicated by pulse, blood pressure, and heart rate. Baseline serum potassium concentrations were all within the reference range (3.7–5.3 mmol/l). There was no significant difference between the mean potassium-lowering effects of formoterol 72 micrograms and terbutaline 6 mg. Mean maximal systolic blood pressure rose from 150 to 155 mmHg with formoterol 72 micrograms and from 139 to 153 mmHg with terbutaline 6 mg. The difference between treatment groups, 5 mmHg, was statistically significant. Diastolic blood pressure fell significantly with both formoterol (from 86 to 70 mmHg) and terbutaline (from 85 to 66 mmHg). Heart rate rose from 61/minute to 79/minute on day 3 in patients taking formoterol 72 micrograms/day compared with a rise from 63/minute to 86/minute with terbutaline 6 mg; this difference was statistically significant.
Formoterol 120 micrograms had significantly smaller effects than terbutaline 10 mg/day on serum potassium concentrations, pulse, and heart rate. During treatment with formoterol 120 micrograms/day, potassium concentrations were under 3.7 mmol/l in 10 patients on day 1, six patients on day 2, and five patients on day 3. With terbutaline 10 mg the corresponding numbers were 12, 10, and 9. However, the effect of terbutaline 10 mg was significantly greater than formoterol 120 micrograms over the three treatment days. Formoterol 120 micrograms/day caused a rise in baseline systolic blood pressure from 134 to 145 mmHg; terbutaline 10 mg produced a rise from 131 to 141 mmHg. The difference between the groups, 0.6 mmHg, was not statistically significant. With formoterol 120 micrograms/day the heart rate rose from 65/minute to 78/minute, and with terbutaline 10 mg/day it rose from 63/minute to 86/minute. The difference in mean heart rate rise of 8/minute was statistically significant. A patient taking formoterol 72 micrograms/day developed atrial fibrillation on day 1. Minor adverse events occurred in seven patients taking formoterol 72 micrograms/day and six patients taking terbutaline 6 mg/day. Eight patients reported adverse events when taking formoterol 120 micrograms/day, as did 10 patients taking terbutaline 10 mg/day. Minor adverse reactions included headache, muscle cramps, fatigue, and tremor with all four treatments. Tremor was reported in two of 12 patients taking terbutaline 6 mg and in five of 15 patients taking terbutaline 10 mg. The corresponding numbers for formoterol were none with formoterol 72 micrograms and one of 15 with formoterol 120 micrograms [ ].
High-dose formoterol (Oxis Turbuhaler) and terbutaline (Bricanyl Turbuhaler) have been compared in a randomized, double-blind trial in 48 patients with obstructive airways disease (mean FEV 1 0.98 liters or 33% predicted) [ ]. Patients with acute bronchoconstriction received either a cumulative dose of 90 micrograms inhaled formoterol or 10 mg inhaled terbutaline (corresponding to 20 puffs each) within the first 3 hours of admission. Treatment included intravenous prednisolone 40 mg after 1.5 hours and oxygen during the first 3 hours. FEV 1 improved similarly in both treatment groups, serum potassium concentration fell in both groups but to the same extent, and the mean 12-hour pulse rate was significantly higher with terbutaline. The authors concluded that formoterol is at least as safe and equally well tolerated as terbutaline.
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