(FLOO-tikka-zown, sal-MET-ah-roll)

This document has been updated since its original release.

PBS listing | Reason for PBS listing | Place in therapy | Safety issues | Dosing issues | Information for patients | References

PBS listing

Restricted benefit

Fluticasone with salmeterol was previously listed on the Pharmaceutical Benefits Scheme (PBS) as a restricted benefit for the treatment of asthma.¹ This listing has been extended to the symptomatic treatment of chronic obstructive pulmonary disease (COPD) in people with forced expiratory volume in 1 second (FEV₁) < 50% of predicted normal, and a history of repeated exacerbations with significant symptoms despite regular beta₂ agonist treatment. The listing only applies to fluticasone with salmeterol 250/25 metered-dose inhaler (MDI) and 500/50 dry powder inhaler (DPI) preparations (Table 1), reflecting the submission to the Pharmaceutical Benefits Advisory Committee (PBAC). Fluticasone with salmeterol is not listed for initiating bronchodilator therapy in people with COPD.²

Table 1: Available fluticasone with salmeterol products and PBS listing for COPD^2,3

Fluticasone with salmeterol doses (microgram/microgram)	Formulation	PBS listed for COPD
50/25	MDI
125/25	MDI
250/25	MDI
100/50	DPI
250/50	DPI
500/50	DPI

Reason for PBS listing

The PBAC recommended a restricted benefit listing on a cost-minimisation basis — that is, similar efficacy and cost — with fluticasone 500 micrograms and salmeterol 50 micrograms twice daily being considered equi-effective to tiotropium 18 micrograms inhaled once daily in the treatment of COPD. Tiotropium is the only long-acting bronchodilator monotherapy subsidised on the PBS for COPD¹ and thus was considered an appropriate comparator. However, anticholinergic bronchodilators (such as tiotropium) have a different mechanism of action to those of inhaled corticosteroids and/or long-acting beta₂ agonists. The PBAC did not accept that fluticasone with salmeterol was more cost-effective — that is, offered greater effectiveness warranting a higher cost — compared with tiotropium.

Place in therapy

Consider fluticasone with salmeterol for people with COPD who have FEV₁ < 50% of predicted normal and symptoms that are poorly controlled despite regular beta₂ agonist treatment. Fluticasone with salmeterol has been shown to improve FEV₁ and reduce exacerbations more than either fluticasone or salmeterol given alone in moderate to severe COPD.^4–6 However, there are no published head-to-head studies comparing these outcomes between fluticasone with salmeterol and tiotropium.

Clinical guidelines recommend stepped care for stable COPD

Drug treatments for COPD have not been shown to modify the decline in lung function, but they can improve symptoms and quality of life.^7,8

The usual stepped care approach^6–10 includes:

• Step 1: intermittent short-acting bronchodilators (beta₂ agonist or anticholinergic) as needed*
• Step 2: if there is no change in symptoms, regular inhaled bronchodilators (short- or long-acting anticholinergic with or without a beta₂ agonist^†). Discontinue treatment if there is no clinically significant response after 4–8 weeks. People with most response to long-acting beta₂ agonists have some reversible airflow limitation.¹¹
• Step 3: an inhaled corticosteroid^‡ is suggested for people with:
  • FEV₁ ≤ 50% of predicted normal and/or
  • more than 2 exacerbations per year requiring treatment with antibiotics or oral corticosteroids.

Discontinue treatment if there is no clinically significant response after 4–8 weeks.

Combining an inhaled corticosteroid with a long-acting beta₂ agonist may provide some additional benefit for people with moderate to severe COPD

Fluticasone with salmeterol has been shown to improve FEV₁ more than either fluticasone or salmeterol given alone in people with moderate to severe COPD.⁴

Combined therapy with an inhaled corticosteroid and a long-acting beta₂ agonist reduces acute exacerbations.⁶ A meta-analysis showed that combining an inhaled corticosteroid with a long-acting beta₂ agonist^§ reduced exacerbations in moderate to severe COPD by about 30% (relative risk 0.70, 95% confidence interval [CI] 0.62 to 0.78) — slightly more than the 20–25% reduction seen with either long-acting beta₂ agonists (RR 0.79, 95% CI 0.69 to 0.90) or inhaled corticosteroids, respectively (RR 0.76, 95% CI 0.72 to 0.80).⁵

The same meta-analysis showed that fluticasone with salmeterol had no effect on mortality.⁵ A recent 3-year study (in which about 40% of people discontinued treatment) showed a trend towards a reduced mortality for fluticasone with salmeterol (12.6%) compared with placebo (15.2%) but this did not reach statistical significance (RR 0.83, 95% CI 0.68 to 1.00, p = 0.052).¹²

Assess response to combined therapy by monitoring symptoms and FEV₁; stop if there is no clinically significant response after 4–8 weeks.^6–10 Only people who show clear and clinically significant benefit should continue treatment, because of the potential risks.

* Short-acting bronchodilators are subsidised on the PBS for COPD.¹

^† Long-acting beta₂ agonists are not subsidised on the PBS for initiation of bronchodilator therapy or for symptomatic relief in COPD. Tiotropium is the only long-acting bronchodilator subsidised on the PBS for COPD.¹

^‡ Inhaled corticosteroids are not approved by the TGA for COPD. They are listed on the PBS general schedule as unrestricted benefits and prescribers may write prescriptions in line with their clinical judgment.^1,3

^§ The combinations included were fluticasone with salmeterol, and budesonide with eformoterol.

Safety issues

Only high-dose inhaled corticosteroids are effective in moderate to severe COPD^13,14; high doses increase the risk of adverse effects, including:

• oropharyngeal candidiasis and dysphonia.^3,14,15
• adrenal impairment, skin thinning and bruising, osteoporosis, cataracts and glaucoma, particularly in older people.^3,6,15 Recent data from people with moderate to severe COPD suggested there were no differences in fracture rates or cataract development between those receiving fluticasone with salmeterol and those receiving placebo.¹²
• pneumonia. Recent data in people with moderate to severe COPD showed that for every 17 people treated for 3 years with fluticasone (instead of salmeterol alone), 1 extra person will develop pneumonia (19.6% compared with 13.3%)¹² — the elderly who take inhaled corticosteroids have a higher risk of pneumonia hospitalisation.¹⁶

Report suspected adverse reactions to the Adverse Drug Reactions Advisory Committee (ADRAC) online or by using the 'Blue Card' distributed with Australian Prescriber. For information about reporting adverse reactions, see the Therapeutic Goods Administration website.

Dosing issues

The usual starting dose for fluticasone in COPD is 250 micrograms by inhalation, twice daily.⁶ Fluticasone should be titrated to the lowest dose at which effective control of symptoms is maintained.³ The usual dose for salmeterol in COPD is 50 micrograms by inhalation, twice daily.⁶ However, the PBS-listed dose is fluticasone 500 micrograms with salmeterol 50 micrograms inhaled twice a day.² This can be delivered as either 250/25 micrograms via MDI or 500/50 micrograms via DPI preparations.¹⁵

Combination inhalers have limited dosing flexibility

COPD is a condition that changes over time, so dose adjustments may be required that are not possible with the combination MDI or DPI.⁶ Ideally, treatment should be initiated with single-ingredient preparations of fluticasone and salmeterol to allow assessment of response and dose adjustment of each drug (as recommended by guidelines^6–10 before moving to the combination MDI or DPI. Some people may be better managed with separate fluticasone and salmeterol inhalers; however, these are not PBS listed for COPD.¹

Information for patients

Advise patients:

• that adverse effects of the combination MDI or DPI appear to be similar to those of the individual components
• to rinse their throat and mouth with water and spit out after each dose to reduce the risk of oral candida infection and/or systemic absorption of fluticasone
• to use a spacer if using an MDI, to reduce the risk of adverse effects
• to use this medicine as prescribed every day, even if feeling well, and not to stop taking it suddenly.

Suggest or provide the Seretide consumer medicine information (CMI) leaflet.

An NPS Medicine Update leaflet on fluticasone with salmeterol is available for consumers. Medicine Update helps consumers to ask the right questions about new medicines, and helps them compare the potential benefits and harms of a new medicine with other medicines.

References

1. Australian Government Department of Health and Ageing. PBS for Health Professionals. Canberra, 2007. http://www.pbs.gov.au (accessed 12 April 2007).
2. Pharmaceutical Benefits Advisory Committee. March 2007 Positive recommendations. Canberra: Australian Government Department of Health and Ageing, 2007. http://www.health.gov.au/internet/wcms/publishing.nsf/Content/pbacrec-mar07-positive (accessed 24 April 2007).
3. Rossi S, ed. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2007.
4. Anonymous. Are Seretide and Symbicort useful in COPD? Drug Ther Bull 2004;42:18–21. [PubMed]
5. Sin DD, McAlister FA, Man SFP, et al. Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA 2003;290:2301–12. [PubMed]
6. Respiratory Writing Group. Therapeutic Guidelines: Respiratory, 2005. Updated 2007 (eTG complete CD -ROM). Melbourne: Therapeutic Guidelines Ltd, 2005.
7. Australian Lung Foundation and Thoracic Society of Australia and New Zealand. The COPD-X Plan: Australian and New Zealand Guidelines for the management of Chronic Obstructive Pulmonary Disease. Brisbane: The Australian Lung Foundation, 2007. http://www.copdx.org.au (accessed 12 April 2007).
8. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease, 2006. http://www.goldcopd.org/Guidelineitem.asp?l1=2&l2=1&intId=989 (accessed 12 April 2007).
9. National Institute for Clinical Excellence (NICE). Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care. London: NICE, 2004. http://www.nice.org.uk/pdf/CG012_niceguideline.pdf (accessed 12 April 2007).
10. Prodigy Guidance. Chronic obstructive pulmonary disease. Newcastle: Department of Health (UK), 2007. http://www.cks.library.nhs.uk/copd (accessed 12 April 2007).
11. Appleton S, Poole B, Smith B, et al. Long-acting beta₂ agonists for poorly reversible chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006;(3):CD001104. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD001104/frame.html
12. Calverley PMA, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–89. [PubMed]
13. Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. Am J Med 2002;113:59–65. [PubMed]
14. Burge PS, Calverley PMA, Jones PW, et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297–303. [PubMed]
15. GlaxoSmithKline Australia Pty Ltd. Seretide product information. 15 March 2007.
16. Ernst P, Gonzalez AV, Brassard P, et al. Inhaled corticosteroid use in COPD and the risk of hospitalization for pneumonia. Am J Respir and Crit Care Med 2007;doi:10.1164/rccm.200611-1630OC.

Revision history

Correction August 2008: Footnote on PBS listing of inhaled corticosteroids revised. 

Updated December 2007: Added link to Medicine Update.

First released: 1 August 2007