, Volume 67, Issue 16, pp 2383-2405
Date: 14 Sep 2012

Salmeterol/Fluticasone Propionate

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Summary

Abstract

Salmeterol/fluticasone propionate (Seretide®, Advair®, Viani®) administered using a multidose dry powder inhaler (Diskus®, Accuhaler®) is approved for use in the treatment of chronic obstructive pulmonary disease (COPD) in numerous countries.

Salmeterol/fluticasone propionate administered twice daily via dry powder inhaler is effective and generally well tolerated in patients with COPD. Although not associated with a statistically significant reduction in mortality versus placebo in the TORCH study (p = 0.052), salmeterol/fluticasone propionate reduced the rate of decline in lung function over the 3 years of the trial and was associated with lower exacerbation rates than the component monotherapies or placebo; other trials revealed clinically significant improvements in health status and dyspnoea scores with salmeterol/fluticasone propionate. Results of the INSPIRE trial suggest that salmeterol/fluticasone propionate is associated with a significantly lower mortality rate than tiotropium bromide monotherapy in patients with COPD; the two treatments had similar effects in terms of exacerbation rates and lung function. Thus, salmeterol/fluticasone propionate is an important option in the treatment of patients with COPD who are appropriate candidates for combination therapy with a long-acting bronchodilator and an inhaled corticosteroid.

Pharmacological Properties

Salmeterol is a highly selective β2-adrenoceptor agonist with, among other effects, long-acting bronchodilator activity, and fluticasone propionate is a corticosteroid with anti-inflammatory activity. Together, they appear to have additive, or even synergistic, effects. In patients with COPD, salmeterol/fluticasone propionate demonstrated beneficial effects on airway inflammation; fluticasone propionate alone may also have a beneficial effect on systemic inflammation in this patient group. The systemic effects of salmeterol/fluticasone propionate are similar to those of the individual agents, with no evidence of systemic pharmacodynamic interaction.

The pharmacokinetics of the salmeterol/fluticasone propionate combination product are similar to those of its individual components. Both salmeterol and fluticasone propionate are lipophilic and act locally in the lung, so plasma concentrations are not predictive of therapeutic effect. Hepatic clearance is predominantly responsible for the clearance of both salmeterol and fluticasone propionate, meaning that patients with hepatic disease who receive salmeterol/ fluticasone propionate should be closely monitored and caution is recommended when salmeterol/fluticasone propionate is co-administered with potent cytochrome P450 3A4 inhibitors.

Therapeutic Efficacy

A number of well designed trials have compared the efficacy of salmeterol/ fluticasone propionate 50μg/250μg or 50μg/500μg administered twice daily via dry powder inhaler with that of various comparators in patients with COPD.

Several randomised, double-blind, multicentre studies of 24 weeks to 3 years’ duration have compared twice-daily salmeterol/fluticasone propionate 50μg/ 250μg or 50μg/500μg with the component monotherapies and/or placebo in patients with COPD. Results of the 3-year TORCH study did not reveal a statistically significant difference in mortality between salmeterol/fluticasone propionate and either placebo or salmeterol alone, although there was a significantly lower probability of death with salmeterol/fluticasone propionate than with fluticasone propionate alone. In two studies comparing salmeterol/fluticasone propionate with the component monotherapies, including the TORCH study, significantly fewer moderate to severe exacerbations occurred with salmeterol/ fluticasone propionate than with the component monotherapies. The results of the 3-year TORCH study suggest that long-term therapy with salmeterol/fluticasone propionate in COPD reduced the rate of decline in lung function. In all studies, lung function improved to a significantly greater extent with salmeterol/fluticasone propionate than with component monotherapies or placebo. In addition, some trials revealed clinically significant improvements in health status and dyspnoea scores with salmeterol/fluticasone propionate.

Twice-daily salmeterol/fluticasone propionate 50μg/500μg had a similar effect to once-daily tiotropium bromide 18μg in terms of healthcare utilisation and symptom-based exacerbation rates and lung function in patients with severe COPD, according to the results of the 2-year, randomised, double-blind, multicentre INSPIRE trial. However, the relative probability of all-cause mortality was significantly lower with salmeterol/fluticasone propionate than with tiotropium bromide.

Twice-daily salmeterol/fluticasone propionate 50μg/250μg was more effective than four-times-daily salbutamol/ipratropium bromide 206μg/36μg, administered via metered-dose inhaler, in the treatment of COPD, according to the results of two randomised, double-blind, multicentre, 8-week studies. The change from baseline in morning predose forced expiratory volume in 1 second (FEV1) significantly favoured patients receiving salmeterol/fluticasone propionate in both studies, as did the 6-hour area under the FEV1 curve, morning peak expiratory flow (PEF), the percentage of symptom-free nights, the transitional dyspnoea index focal score and the overall combined daytime symptom score.

There was no significant difference between patients receiving salmeterol/ fluticasone propionate 50μg/500μg twice daily or fluticasone propionate 500μg plus oral sustained-release theophylline, both administered twice daily, in the change from baseline in FEV1 after 4 months of treatment in a randomised nonblind study in patients with COPD. However, the reductions from baseline in the visual analogue scale score for dyspnoea and rescue medication use significantly favoured salmeterol/fluticasone propionate.

Administering twice-daily salmeterol/fluticasone propionate 50μg/500μg in combination with once-daily tiotropium bromide 18μg did not confer additional enefit to patients with COPD in terms of exacerbation rates (vs once-daily tiotropium bromide 18μg alone), although some benefits were seen in terms of hospitalisation rates (vs once-daily tiotropium bromide 18μg alone), lung function (vs twice-daily salmeterol/fluticasone propionate 50μg/500μg alone or once-daily tiotropium bromide 18μg alone) and health status (vs once-daily tiotropium bromide 18μg alone), according to the results of three randomised, double-blind trials.

Withdrawing fluticasone propionate resulted in a significant, albeit small, decline in FEV1 in patients with COPD who had been receiving salmeterol/ fluticasone propionate 50μg/500μg twice daily for 3 months according to the results of a randomised, double-blind, multicentre trial. Moreover, significantly greater reductions from baseline in FEV1: forced vital capacity and PEF were seen with salmeterol alone versus salmeterol/fluticasone propionate, although results were mixed in terms of other endpoints.

Tolerability

In general, adverse events occurring with salmeterol/fluticasone propionate were those that would be expected with the component drugs. In the TORCH study, the most commonly occurring adverse events in salmeterol/fluticasone propionate recipients included COPD exacerbation, upper respiratory tract infection, nasopharyngitis, pneumonia, candidiasis, bronchitis, headache, back pain, sinusitis, cough and hypertension.

In the TORCH and INSPIRE studies, there were no significant between-group differences in fracture incidence. An additional safety analysis conducted in a subgroup of patients from the TORCH trial revealed that there were no significant between-group differences in the change from baseline in bone mineral density of the hip or lumbar spine. In the TORCH study, there was no significant difference between patients receiving salmeterol/fluticasone propionate, salmeterol alone, fluticasone propionate alone or placebo in the incidence of eye disorders, including the development of cataracts. The incidence of pneumonia was significantly higher with salmeterol/fluticasone propionate or fluticasone propionate alone than with placebo in the TORCH study, and with salmeterol/fluticasone propionate than with tiotropium bromide in the INSPIRE study.

Pharmacoeconomic Considerations

Salmeterol/fluticasone propionate was a cost-effective option in the treatment of COPD, according to the results of a pharmacoeconomic analysis conducted in conjunction with the TORCH study; the analysis was conducted from the perspective of the UK National Health Service. The incremental cost-effectiveness ratio (ICER) for salmeterol/fluticasone propionate versus placebo was £17 000 (95% CI 8100, 41 700) per quality-adjusted life-year (QALY) gained (year of costing not stated). Results of a modelling study conducted from the perspective of the Canadian Ministry of Health also found salmeterol/fluticasone propionate to be a potentially cost-effective option in the treatment of patients with poorly reversible COPD and frequent exacerbations. The ICER for salmeterol/fluticasone propionate versus placebo was $Can74 887 per QALY gained (2002 values).

Various sections of the manuscript reviewed by: J. Bourbeau, Respiratory Epidemiology and Clinical Research Unit, McGill University Health Center, Montreal, Quebec, Canada; M. Cazzola, Unit of Respiratory Diseases, Department of Internal Medicine, University of Rome ‘Tor Vergata’, Rome, Italy; N.A. Hanania, Section of Pulmonary and Critical Care Medicine, Asthma Clinical Research Center, Baylor College of Medicine, Houston, Texas, USA; P.K. Jeffery, Lung Pathology, Royal Brompton Hospital, London, England; P. Santus, Institute of Lung Disease, Respiratory Unit, San Paolo Hospital, University of Milan, Milan, Italy; E.F.M. Wouters, Department of Respiratory Medicine, University Hospital Maastricht, Maastricht, The Netherlands.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘salmeterol/fluticasone’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘salmeterol/fluticasone’ and (‘chronic obstructive pulmonary disease’ or ‘COPD’). Searches were last updated 15 October 2007.
Selection: Studies in patients with chronic obstructive pulmonary disease who received salmeterol/fluticasone propionate. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Salmeterol, fluticasone propionate, chronic obstructive pulmonary disease, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.