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Formoterol

A Review of its Pharmacological Properties and Therapeutic Potential in Reversible Obstructive Airways Disease

  • Drug Evaluation
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Summary

Synopsis

Formoterol, a long-acting β2-selective adrenoceptor agonist, produces dose-proportional bronchodilation in patients with obstructive airways disease with a reversible component. A significant effect occurs within minutes of inhalation of a therapeutic formoterol dose and persists for approximately 12 hours. Oral formoterol has a slower onset of action than the inhaled formulations, but also produces prolonged bronchodilatory effects.

Inhaled formoterol has shown a therapeutic efficacy equivalent to or better than comparable dosages of the conventional β2-agonists salbutamol, fenoterol and terbutaline in short and long term trials, in both adults and children with asthma. Its prolonged duration of action permits a twice-daily dosage regimen and results in improved control of nocturnal symptoms by reducing the ‘morning dip’. Formoterol also compares well with oral slow release theophylline. In addition, significantly more patients with chronic obstructive airways disease (COAD) had an improvement in symptoms when treated with formoterol compared with salbutamol or fenoterol. Noncomparative studies indicate formoterol also provides effective prophylaxis of exercise-induced asthma. Development of tachyphylaxis has not been observed.

Formoterol is generally well tolerated. Adverse effects observed represent predictable extensions of its pharmacology. Tremor and palpitations are most frequently reported. The incidence of adverse events is dose-proportional and therefore related to the route of administration, being more frequent following oral than inhalation therapy.

The long-acting β2-agonists, including formoterol, represent a significant advance over current maintenance or prophylactic bronchodilator therapy with intermediate-acting β2-agonists such as salbutamol, fenoterol and terbutaline, predominantly because of the twice daily administration regimen. However, comparisons with other long-acting β2-agonists, such as salmeterol, evaluation of its role in improving symptom control in patients failing to respond to prophylactic therapy, and clarification of the optimal role of β2-agonists in asthma maintenance therapy are required to fully determine the value of formoterol in the management of obstructive airways disease.

Pharmacodynamic Properties

Formoterol is a long-acting selective fo-adrenoceptor agonist which has demonstrated significant bronchodilatory effects. In patients with asthma inhaled formoterol produced rapid, dose-proportional bronchodilation with increases in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR) and specific airways conductance (sGaw). Effective doses of inhaled formoterol significantly decreased specific airways resistance within minutes. Maximum bronchodilation was achieved within 2 hours, with effects persisting for approximately 12 hours, significantly longer than the bronchodilatory effects of equivalent doses of salbutamol, fenoterol or terbutaline. Oral formoterol had a slower onset of action than inhaled formoterol but also produced prolonged effects. Formoterol also demonstrated significant antiallergic activity in animals and in healthy volunteers, and in inhaled form had a protective effect in provocation tests in asthmatic patients.

Formoterol produced a dose-proportional increase in heart rate and a decrease in blood pressure in healthy volunteers and patients with asthma, but these changes were small and within physiological norms at therapeutic dosages.

Pharmacokinetic Properties

Following therapeutic doses formoterol concentrations in body tissues and fluids are often below the detection limits of currently available assays. An elimination half-life of 1.7 to 2.3 hours after formoterol inhalation has been calculated in humans. After oral formoterol 40μg or inhaled formoterol 24μg, 9.6% and 24%, respectively, of the dose was recovered from the urine over 24 hours and a glucuronic acid conjugate was identified. It is possible formoterol has a prolonged elimination half-life which has not yet been detected in humans.

Therapeutic Use

The therapeutic efficacy of inhaled or oral formoterol was demonstrated in several short term and a few long term studies of adults with asthma or chronic obstructive airways diseases (COAD) and children with asthma or non-asthmatic respiratory disorders. Noncomparative studies in patients with chronic bronchial asthma showed formoterol improved subjective clinical symptoms and lung function parameters. No evidence of tachyphylaxis was found in trials lasting up to 252 weeks, during which 70 to 100% of asthmatic adults showed some improvement. Reduction in the severity of clinical symptoms, and a significant increase in FEV1, resulted in decreased usage of ‘rescue’ medication.

Symptoms diminished in 64 to 100% of children receiving oral formoterol and in 79 to 87% when formoterol was administered by inhalation. FEV1 and airways resistance also improved during a 2-week study, and the mean frequency of nocturnal and diurnal asthma attacks decreased.

Overall efficacy of formoterol was at least equivalent to and in some trials significantly greater than, an equipotent dose of salbutamol, and diurnal variation in pre-bronchodilator PEFR was significantly less pronounced in patients taking formoterol (12jug twice daily) compared with salbutamol (200μg 4 times daily) [17 vs 42 L/min]. Patients receiving formoterol experienced fewer asthma attacks and required less rescue medication than those taking salbutamol. There was an overall patient preference for formoterol. In patients with nocturnal asthma, a single night-time dose of inhaled formoterol 12μg was more effective than salbutamol 200μg.

Formoterol and fenoterol produced similar improvements in pulmonary function, but formoterol significantly reduced the number of nocturnal asthma attacks from baseline by the third week of treatment whereas fenoterol did not. Formoterol was at least as effective as terbutaline and provided better control of symptoms of nocturnal asthma. Formoterol showed a similar duration of action to slow release theophylline in patients with nocturnal asthma, and demonstrated superior tolerability, although sleep disturbance caused by asthma was more frequent in patients taking formoterol. Combined fenoterol plus ipratropium bromide induced bronchodilation to a similar extent as formoterol monotherapy and both agents were well tolerated. However from 4 to 12 hours after administration, formoterol produced a significantly better effect.

The few published studies assessing prophylaxis of exercise-induced asthma (EIA) have indicated that inhaled formoterol 24μg gives complete protection even when administered up to 8 hours before 5 to 8 minutes of strenuous exercise. Both inhaled formoterol 24/ug and fenoterol 400μg prevented EIA when administered 15 minutes before 6 minutes of exercise. Similarly, formoterol 12μg and salbutamol 200μg prevented EIA when given 2 hours before 5 to 8 minutes of exercise. However, when administered 4 hours prior to exercise, formoterol provided a protective efficacy significantly greater than that of salbutamol.

A number of small noncomparative Japanese trials have shown oral formoterol to reduce symptom severity in 75 to 100% of children with non-asthmatic respiratory disorders. Symptoms disappeared within 1 week of starting therapy in all patients administered formoterol syrup 3 to 4μg/kg/day. A large study of adults with COAD demonstrated therapeutic efficacy in 90% of patients, and 83% preferred formoterol to prior therapy. Significantly more patients with COAD experienced improvement whilst treated with formoterol compared to fenoterol or salbutamol in 2 large parallel studies. FEV1 increased significantly in formoterol recipients during the 2- and 4-week trials but not in patients receiving fenoterol or salbutamol. Further well designed, long term studies in large numbers of patients are required to confirm the above results.

Tolerability

Formoterol is tolerated well in adults and children, the adverse effects experienced being those seen with other β2-agonists. The most frequently reported effects were tremor and palpitation which occurred in 10.7% and 11.5% of asthmatic adults receiving oral formoterol 20 to 40μg once to 4 times daily. Inhaled formoterol 12/ug twice daily was associated with tremor in 6.4% and palpitation in 0.4% of 236 patients. Tachycardia occurred in 1.6% of patients receiving oral formoterol, however in 1 trial with oral formoterol the incidence was 15% (3/20 patients). This was resolved when the oral dosage was reduced from 120 to 60 Mg/day. Headache, cough, dizziness, dry mouth and nausea were occasionally reported.

Overall, the range and incidence of adverse effects observed with formoterol did not appear to be significantly different from that of other β2-agonists. However, it must be emphasised that only limited numbers of patients have been involved in comparative studies to date. As with other β2-agonists, high doses of formoterol may cause marked hypokalaemia.

Dosage and Administration

Inhaled formoterol 12 or 24μg (1 or 2 puffs) twice daily should be used as maintenance therapy. It has recently been recommended that long-acting β2-agonists be reserved for use in asthma patients with symptoms inadequately controlled by inhaled corticosteroids. The manufacturer also recommends that inhaled formoterol may be used as rescue medication, and for prophylaxis against exercise- or allergen-induced bronchoconstriction. No more than 2 puffs in 6 hours should be taken. The maximum recommended daily dose is 6 puffs (72μg). Tablet and dry syrup formulations are available in some countries. Recommended dosage of formoterol tablets is 80/ig 2 or 3 times daily in adults and 1.5 μg/kg 2 or 3 times daily in children. In children, formoterol 4 μg/kg/day in 2 or 3 doses, orally as a dry syrup, has also provided effective control of symptoms. Alternative or additional therapy is required if reduced efficacy of formoterol is noted, as this generally indicates worsening of asthma.

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    Diana Faulds, Lisa M. Hollingshead & Karen L. Goa

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Various sections of the manuscript reviewed by: P.J. Barnes, National Heart and Lung Institute, London, England; A.B. Becker, Section of Allergy and Clinical Immunology, Health Services Centre, Winnipeg, Manitoba, Canada; R.C. Bone, Department of Medicine, Rush Medical College, Chicago, Illinois, USA; G.K. Crompton, Respiratory Medicine Service, Respiratory Unit, Northern General Hospital, Edinburgh, Scotland; N.J. Gross, Hines, Illinois, USA; S. Kesten, Asthma Centre, Toronto Hospital, Toronto, Ontario, Canada; F.P.V. Maesen, De Wever Ziekenhuis, Heerlen, The Netherlands; C.P. Page, Biomedical Sciences Division, Kings College London, University of London, London, England; R. Pauwels, Department of Respiratory Disease, University Hospital, Ghent, Belgium; A.S. Rebuck, Asthma Centre, Toronto Hospital, Toronto, Ontario, Canada; A.E. Tattersfield, Faculty of Medicine, Respiratory Medicine Unit, City Hospital, Nottingham, England; J.H. Toogood, Allergy Clinic, Victoria Hospital, London, Ontario, Canada; M. Yamakido, Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima, Japan.

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Faulds, D., Hollingshead, L.M. & Goa, K.L. Formoterol. Drugs 42, 115–137 (1991). https://doi.org/10.2165/00003495-199142010-00007

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