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Inhaled Salmeterol

A Review of its Efficacy in Chronic Obstructive Pulmonary Disease

  • Adis Drug Evaluation
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Summary

Abstract

Inhaled salmeterol is a long-acting, selective β2-adrenoceptor agonist bronchodilator. The drug has been compared with placebo, ipratropium bromide and oral theophylline in patients with chronic obstructive pulmonary disease (COPD) in randomised, clinical trials.

Inhaled salmeterol 50µg twice daily produced significant improvement in forced expiratory volume in 1 second (FEV1), equivalent to that obtained with inhaled ipratropium bromide 40µg 4 times daily and greater than that obtained with placebo or oral theophylline in randomised trials. Use of as-needed salbutamol (albuterol) was significantly reduced during treatment with inhaled salmeterol or ipratropium bromide compared with placebo or oral theophylline. The time to first COPD exacerbation was significantly longer during 12 weeks of treatment with inhaled salmeterol 50µg twice daily than ipratropium bromide 40µg 4 times daily.

Compared with baseline and placebo, patients treated for 16 weeks with salmeterol 50µg (but not 100µg) twice daily reported significant improvement in total St George’s Respiratory Questionnaire (SGRQ) scores. Similarly, more patients treated with inhaled salmeterol 50µg twice daily or ipratropium bromide 40µg 4 times daily experienced an increase of ≥10 points in Chronic Respiratory Disease Questionnaire (CRQ) scores, the minimum clinically significant increment.

Compared with placebo, inhaled salmeterol 50µg twice daily alone, or concurrent with ipratropium bromide 40µg 4 times daily improved lung function and reduced symptoms in patients with stable COPD in a 12-week, randomised, double-blind study. Clinically meaningful improvement in CRQ scores was documented in significantly more patients treated with the combination of the 2 drugs than either salmeterol monotherapy or placebo.

Inhaled salmeterol 50µg twice daily plus oral theophylline had additive effects on lung function, increased the proportion of symptom-free days and decreased requirements for as-needed salbutamol compared with either agent alone according to a pooled analysis of 2 multicentre, randomised, double-blind studies.

Conclusion: When used at the optimal dosage, 50µg twice daily, salmeterol provides symptomatic relief and improves lung function and health-related quality of life in patients with COPD. Available evidence suggests that the drug is as effective as ipratropium bromide and more effective than oral theophylline in patients with COPD. Moreover salmeterol has additive effects when used in combination with inhaled ipratropium bromide or oral theophylline. These qualities make the drug suitable for first-line use in patients with COPD who require regular bronchodilator therapy to manage symptoms.

Pharmacodynamics and Pharmacokinetics

In single dose crossover studies, the long-acting selective β2-adrenoceptor agonist salmeterol consistently produced improvements in forced expiratory volume in 1 second (FEV1) in patients with chronic obstructive pulmonary disease (COPD) compared with baseline and placebo. There was no statistical difference in the mean peak FEV1 after inhalation of salmeterol 50µg, formoterol 6 or 12µg, salbutamol (albuterol) 200µg, oral bambuterol 20mg, ipratropium bromide 40µg (alone or in combination with salbutamol 200µg) or oxitropium bromide 200 or 400µg. The time required to achieve peak FEV1 tended to be somewhat longer with salmeterol than other bronchodilators, but the duration of action of a single dose of salmeterol was generally longer than other agents, with the exception of inhaled formoterol and oral bambuterol.

Bronchodilation was maintained throughout ≥12 weeks of treatment with salmeterol 50µg twice daily without any evidence of tachyphylaxis. In randomised, double-blind multicentre studies, salmeterol 50µg twice daily and ipratropium bromide 40µg 4 times daily produced greater improvements in FEV1 after 12 weeks compared with placebo. FEV1 was >12% higher than the baseline value 12 hours after inhalation of salmeterol on both the first and last days of treatment. Significant improvements in lung function were obtained in ‘reversible’ and ‘nonreversible’ patients

In patients with COPD and minimal reversibility of FEV1 after inhaling salbutamol (≤12%), significant bronchodilation was maintained throughout 12 weeks of treatment with twice daily inhaled salmeterol 50µg administered alone or concurrently with inhaled fluticasone propionate 250 or 500µg, or oral theophylline.

Use of salmeterol does not impair the response to short-acting bronchodilators in patients with COPD, as treatment for up to 12 weeks did not preclude a prompt statistically significant bronchodilator response to inhaled salbutamol or oxitropium bromide.

As acute reversibility of FEV1 after inhalation of salbutamol 200µg did not reliably predict the response to inhaled salmeterol, reversibility testing is a poor predictor of the potential response to salmeterol in patients with COPD.

Compared with placebo, significant increases in FEV1 and forced vital capacity (FVC), and decreases in functional residual capacity, residual lung volume and breathlessness scores were observed 4 hours after inhaling salmeterol 50µg.

A comprehensive treatment program, which addressed the reduction in ventilatory capacity (with salmeterol), reduced ventilatory demand (through exercise training) and strengthened weakened inspiratory muscles, was effective in relieving dyspnoea in patients with COPD.

Despite significant increases in FEV1 after inhalation of single doses of inhaled β2-adrenergic agonists, small, statistically significant and transient decreases in arterial oxygen tension, which are unlikely to be of clinical significance, were detected in patients with COPD.

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-adrenoceptors. Salmeterol 50 or 100µg twice daily for 3 days had no significant effect on heart rate, systolic or diastolic blood pressure or the frequency of supraventricular or premature ventricular complexes and produced no electrocardiographic abnormalities during continuous Holter monitoring in patients with reversible airway obstruction.

In COPD patients with pre-existing cardiac arrhythmias and hypoxaemia, salmeterol 50µg and formoterol 12µg had a higher ‘safety margin’ than formoterol 24µg.

Plasma levels of salmeterol have no bearing on the therapeutic efficacy of salmeterol; the drug exerts its therapeutic effects through local action on β2 receptors in the lung.

Therapeutic Use

Inhaled salmeterol has been evaluated in patients with COPD in multicentre, randomised, placebo-controlled parallel-group trials of ≥3 months’ duration.

Versus Placebo

After 16 weeks of treatment, FEV1 increased by a greater extent in recipients of salmeterol 50 or 100µg than placebo in 674 patients with COPD and minimal reversibility (5 to 15%) to inhaled salbutamol. Salmeterol recipients used less supplemental salbutamol and the severity of symptoms during day and night was ameliorated compared with placebo recipients. Compared with baseline and placebo, patients treated with salmeterol 50µg twice daily, but not 100µg twice daily, reported a significant improvement (i.e. reduction) in total St George’s Respiratory Questionnaire (SGRQ) scores.

Versus Inhaled Ipratropium Bromide

Both salmeterol 50µg twice daily and ipratropium bromide 40µg 4 times daily improved FEV1 compared with placebo in two 12-week, randomised, double-blind studies. Improvements in the area under the 12-hour FEV1 versus time curve (FEV1 AUC12h) were evident in patients with American Thoracic Society stage 1 (FEV1 ≥50% predicted), 2 (FEV1 35 to 49% predicted) or 3 (FEV1 <35% predicted) disease during treatment with salmeterol. Both ‘responders’ and ‘nonresponders’ to salbutamol experienced improvements in FEV1 during treatment with inhaled salmeterol and there was no evidence of tachyphylaxis after 12 weeks of treatment.

The use of as-needed salbutamol decreased significantly in salmeterol and ipratropium bromide compared with placebo recipients, but there was no between-group differences in the distance walked or Borg Dyspnoea Scores before or after a 6-minute walk test.

Fewer than one-third of patients enrolled in any group experienced exacerbations in either study. Kaplan-Meier survival analysis revealed that the time to first COPD exacerbation was significantly longer in salmeterol- than ipratropium bromide-treated patients in 1 study.

Compared with placebo recipients, health-related quality of life (HRQoL) scores improved in recipients of salmeterol or ipratropium bromide. In 1 study, significantly more patients treated with salmeterol (46%) or ipratropium bromide (39%) experienced an increase of ≥10 points in Chronic Respiratory Disease Questionnaire (CRQ) scores, the minimum clinically significant increment (vs 27% in the placebo group). There were no significant differences among groups in the other study, in which 46, 41 and 38% of salmeterol, ipratropium bromide and placebo recipients experienced an increase of ≥10 points in CRQ scores.

Salmeterol Plus Ipratropium Bromide

Concurrent treatment with inhaled salmeterol 50µg twice daily plus ipratropium bromide 40µg 4 times daily improved lung function and reduced symptoms in patients with stable COPD to a greater extent than placebo in a 12-week, randomised, double-blind study. Significant reductions in daytime symptom scores, the percentage of days with minimal symptoms and use of as-needed salbutamol were obtained in patients treated with inhaled salmeterol alone or with ipratropium bromide compared with placebo. The frequency of COPD exacerbations was also lower in recipients of active therapy compared with placebo. There were no significant differences between active treatment groups for any of these outcomes or for morning peak expiratory flow (PEF).

There was a poor correlation between improvements in FEV1 and HRQoL in this study and no significant differences in HRQoL were detected, by either the CRQ or SGRQ, between recipients of salmeterol mono therapy and placebo. However, a clinically meaningful difference (i.e. ≥4 units) in mean scores for Symptoms in the SGRQ was detected between recipients of the combination and either salmeterol monotherapy or placebo, and clinically meaningful improvement as determined by the CRQ (improvement by ≥0.5 units in mean scores) was documented in approximately 40% of patients treated with the combination, but ≤13% of patients treated with salmeterol monotherapy or placebo.

Salmeterol versus Oral Theophylline

Inhaled salmeterol 50µg twice daily provided greater improvements in lung function and greater reductions in symptoms than oral theophylline in 2 randomised, nonblind studies. Improvements in FEV1, morning and evening PEF, and FVC in salmeterol recipients exceeded those in theophylline-treated patients. Among recipients of salmeterol, the median proportion of days and nights without symptoms, and the number of days and nights in which no as-needed salbutamol was used were significantly greater than in theophylline recipients. Statistically significant improvements in HRQoL were documented in both treatment groups compared with baseline.

Salmeterol plus Oral Theophylline

Inhaled salmeterol plus concurrent oral theophylline provide additive effects on lung function in patients with COPD according to the pooled results of 2 large multicentre, double-blind, parallel-group studies. Among patients randomised to twice daily inhaled salmeterol 50µg plus oral theophylline, FEV1 AUC12h was greater, both after the first dose of inhaled salmeterol and after 12 weeks of treatment, than in patients randomised to monotherapy with either agent. Recipients of concurrent therapy reported a significantly greater increase in the percentage of symptom-free days and a significantly greater decrease in requirements for as-needed salbutamol compared with theophylline recipients.

Pharmacoeconomic Considerations

The addition of inhaled salmeterol 50µg twice daily to ‘usual care’ (i.e. placebo) resulted in a higher proportion of successfully-treated patients (i.e. a 5% increase in FEV1), a higher percentage of symptom-free nights and a higher proportion of patients with clinically significant improvements in HRQoL than in those randomised to 16 weeks of placebo. The mean daily direct healthcare costs from the perspective of the UK healthcare payer were £1.72 and £0.91 (1998 sterling) in patients randomised to inhaled salmeterol and usual care, respectively. The cost per symptom-free night was £2.87 in salmeterol recipients and £2.00 in those receiving usual care; the incremental cost required to achieve an additional symptom-free night with inhaled salmeterol was estimated to be £5.67.

Direct medical costs associated with COPD were somewhat lower among users of inhaled salmeterol than inhaled ipratropium bromide in a preliminary US analysis of a medical claims database.

Tolerability

Salmeterol was generally well tolerated in patients with COPD enrolled in controlled trials. The frequency of adverse events was similar in patients treated with salmeterol 50µg twice daily or placebo in a 16-week trial. However, the incidence of adverse events in patients receiving salmeterol 100µg twice daily (24%) was greater than that in patients treated with salmeterol 50µg twice daily (18%) or placebo (16%); largely because of an increased frequency of tremor in patients treated with the higher dosage of salmeterol.

The frequency of adverse events was similar among patients randomised to 12 weeks’ treatment with salmeterol 50µg twice daily, ipratropium bromide 40µg 4 times daily or placebo. Fewer patients treated with salmeterol, than either ipratropium bromide or placebo withdrew because of adverse events.

In the UK, a large scale prescription event monitoring survey in patients treated with salmeterol showed that headache, tremor and palpitations were the most common adverse events associated with the drug.

Dosage and Administration

The recommended dosage of salmeterol in patients with COPD is 50µg twice daily approximately 12 hours apart. Higher dosages are unlikely to provide further improvements in lung function and have not resulted in improvements in HRQoL. Hence, the recommended dosage should not be exceeded.

Patients should be advised that salmeterol is not suitable for the relief of acute shortness of breath because of its relatively long onset of action.

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    Blair Jarvis & Anthony Markham

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Jarvis, B., Markham, A. Inhaled Salmeterol. Drugs & Aging 18, 441–472 (2001). https://doi.org/10.2165/00002512-200118060-00006

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