Key points from the evidence

The content of this evidence summary was up-to-date in September 2014. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Fostair is a combination inhaler containing beclometasone and formoterol which has been licensed for asthma since 2007. In April 2014, a licence extension was granted for the use of Fostair in people with severe chronic obstructive pulmonary disease (COPD) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodilators.

In a randomised controlled trial (RCT; n=718), beclometasone/formoterol was non-inferior to budesonide/formoterol in improving pre-dose morning lung function in people with severe COPD over 48 weeks. There was no significant difference between the treatments in the rate of COPD exacerbations/patient per year. The incidence of adverse events was similar between the treatments. This study also included a formoterol alone arm.

In a second RCT (n=419), beclometasone/formoterol statistically significantly improved the onset of bronchodilation in people with moderate-to-severe COPD compared with fluticasone/salmeterol, although it is unclear whether the improvement is clinically important. The treatments were equivalent in improving dyspnoea over 12 weeks. Serious adverse events were statistically significantly more common with fluticasone/salmeterol.

From the published data, beclometasone/formoterol appears to work as well in COPD as the 2 commonly used ICS/LABA combinations, its constituent ingredients have been available for many years so their safety profile is known, it costs less than most alternatives and it can be used with a spacer, which many people with COPD need.

Effectiveness

In 1 RCT (Calverley et al. 2010; n=718), compared with budesonide/formoterol, beclometasone/formoterol was:

  • non-inferior for improving pre-dose morning forced expired volume in 1 second (FEV1) over 48 weeks (difference 0.002 L, lower limit of 97.5% confidence interval [CI] −0.052 L).

  • similar in terms of the rate of COPD exacerbations/patient per year (0.414 compared with 0.423 respectively, not statistically significant).

In a second RCT (Singh et al. 2014; n=419), compared with fluticasone salmeterol, beclometasone/formoterol was

  • equivalent in terms of improvement in Transition Dyspnoea Index (TDI) scores over 12 weeks (mean 1.32 compared with 1.15, p=0.56).

  • statistically significantly faster for onset of bronchodilation (mean difference in area under the curve from 0−30 minutes [AUC0-30min] 0.07 L, p<0.001).

Safety

  • In the first RCT, the incidence of adverse events did not differ significantly between beclometasone/formoterol and budesonide/formoterol.

  • In the second RCT, serious adverse events occurred statistically significantly more often in the fluticasone/salmeterol group than the beclometasone/formoterol group (13 people [6.3%] compared with 4 people [1.9%], p=0.024).

  • According to the summary of product characteristics, adverse effects that have been reported commonly (in between 1 in 10 and 1 in 100 people) with beclometasone/formoterol in combination or as single constituents are pharyngitis, oral candidiasis, headache and dysphonia.

Patient factors

  • The NICE clinical guideline on COPD recommends that the choice of treatment should take into account the person's symptomatic response and preference.

  • Beclometasone/formoterol is supplied in a metered dose inhaler (which can be used with a spacer), budesonide/formoterol is in a Turbohaler, fluticasone/formoterol is in an Accuhaler and fluticasone/vilanterol is in an Ellipta inhaler.

  • Apart from fluticasone/vilanterol, which is administered once daily, these treatments are administered twice daily.

Resource implications

A 30-day inhaler costs:

  • £29.32 for beclometasone/formoterol.

  • £38.00 for budesonide/formoterol.

  • £40.92 for fluticasone/salmeterol.

  • £27.80 for fluticasone/vilanterol.

(Costs from the Drug Tariff and MIMS, June 2014).

Introduction and current guidance

According to the NICE clinical guideline on Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update) (NICE clinical guideline 101), a combination inhaler containing an inhaled corticosteroid (ICS) and a long-acting beta2 agonist (LABA) should be offered if FEV1 is less than 50% of predicted in people with COPD. An ICS/LABA may also be considered in people with stable COPD and an FEV1 of 50% or more of predicted who remain breathless or have exacerbations despite maintenance therapy with a LABA. See the NICE guideline or the NICE pathway on COPD for full details.

This evidence summary considers the best available evidence to support the use of the ICS/LABA (beclometasone/formoterol) combination inhaler, Fostair, for COPD.

Full text of Introduction and current guidance.

Product overview

Fostair (Chiesi) is a pressurised metered dose inhaler containing beclometasone dipropionate (BDP; an ICS) and formoterol fumarate dihydrate (a LABA). Each metered dose contains 100 micrograms of beclometasone and 6 micrograms of formoterol. The summary of product characteristics advises that the particles of BDP in Fostair are extrafine and more potent than in standard formulations of BDP: 100 micrograms of extrafine BDP in Fostair are equivalent to 250 micrograms of standard BDP.

Fostair has been licensed for asthma since 2007 and a licence extension for use in COPD was granted in April 2014. The summary of product characteristics states that Fostair is licensed for the symptomatic treatment of adults with severe COPD (FEV1 less than 50% of the predicted normal) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodilators.

Full text of Product overview.

Evidence review

  • This evidence review focuses on 2 RCTs that provide evidence for beclometasone/formoterol (Fostair 100/6 micrograms, 2 puffs twice daily) for managing COPD compared with the established ICS/LABA combinations, budesonide/formoterol (Symbicort 200/6 micrograms, 2 puffs twice daily) and fluticasone/salmeterol (Seretide 500/50 micrograms, 1 puff twice daily).

  • Calverley et al. (2010) found that, over 48 weeks, beclometasone/formoterol, budesonide/formoterol and formoterol alone improved pre-dose morning FEV1 (the first primary outcome) by 0.077 L, 0.080 L and 0.026 L respectively in 718 people with severe COPD (FEV1 between 30% and 50% of predicted). These changes in FEV1 are less than the improvement that the full NICE guideline on COPD considers to be clinically important (0.100 L or more). In the intention-to-treat analysis, beclometasone/formoterol was shown to be non-inferior to budesonide/formoterol (the lower limit of the 97.5% CI was −0.052 L, which is within the pre-specified non-inferiority margin of −0.100 L) and statistically significantly better than formoterol alone (p=0.046). Similar results were reportedly obtained in the per-protocol analysis.

  • In this study, the mean rate of COPD exacerbations/patient per year (the second primary outcome) was not statistically significantly different between the treatments (beclometasone/formoterol 0.414, budesonide/formoterol 0.423 and formoterol alone 0.431). The number of patients with exacerbations leading to hospitalisation was statistically significantly higher in the beclometasone/formoterol group compared with the budesonide/formoterol and formoterol alone groups (13 [5.6%] compared with 7 [2.9%, p<0.001] and 8 [3.4%, p=0.008] respectively). However, the numbers of exacerbations were lower than expected and these analyses may have been underpowered.

  • Singh et al. (2014) found that beclometasone/formoterol and fluticasone/salmeterol statistically significantly improved Transition Dyspnoea Index scores (a measure of breathlessness; the first primary outcome) by 1.32 units respectively and 1.15 units over 12 weeks in 419 people with moderate-to-severe COPD. The full NICE guideline on COPD considers an improvement of 1 unit to be clinically important. The combination treatments were found to be equivalent in the intention-to-treat analysis (the 95% CI for the difference [−0.39 to 0.72] was entirely within the pre-specified ±1 equivalence margins). However, both intention-to-treat and per-protocol analyses should be undertaken in equivalence analyses to confirm the findings and it is unclear whether a per-protocol analysis was undertaken in this study.

  • As assessed by the change in FEV1 from pre-dose in the first 30 minutes after drug inhalation (the secondary primary outcome), in this study beclometasone/formoterol had a statistically significantly faster onset of action than fluticasone/salmeterol (AUC0-30min adjusted means at 12 weeks 0.18 L compared with 0.11 L respectively, p<0.001). It is unclear whether this difference is clinically important.

  • Calverley et al. (2010) found that the incidence of adverse events did not differ significantly between beclometasone/formoterol, budesonide/formoterol and formoterol alone. The most commonly reported adverse event was exacerbation or worsening of COPD, which occurred in 27−28% of participants. Pneumonia was reported by 5 people (2.1%) in the beclometasone/formoterol group, 7 people (2.9%) in the budesonide/formoterol group and 1 person (0.4%) in the formoterol group (statistical significance of differences not reported).

  • In Singh et al. (2014), serious adverse events occurred statistically significantly more often in the fluticasone/salmeterol group than the beclometasone/formoterol group (13 people [6.3%] compared with 4 people [1.9%], p=0.024). Pneumonia was reported in 3 people (1.4%) treated with fluticasone/salmeterol and none treated with beclometasone/formoterol.

Full text of Evidence review.

Context

The cost of a beclometasone/formoterol inhaler (£29.32; Drug Tariff, June 2014) is less than a budesonide/formoterol or fluticasone/salmeterol inhaler (£38.00 and £40.92 respectively; Drug Tariff, June 2014) and is slightly higher than that of a fluticasone/vilanterol inhaler (£27.80; MIMS, June 2014). All inhalers last for 30 days at usual dosages.

Full text of Context.

Estimated impact for the NHS

The NICE clinical guideline on COPD recommends that the choice of treatment should take into account the person's symptomatic response and preference, and the medicine's potential to reduce exacerbations, side effects and costs.

Beclometasone/formoterol has been compared to the most commonly used ICS/LABA combinations for COPD, budesonide/formoterol and fluticasone/salmeterol. It was found to be similar to budesonide/formoterol in terms of change in pre-dose morning lung function (a disease orientated outcome) over 48 weeks, rate of COPD exacerbations/patient per year and incidence of adverse events, and similar to fluticasone/salmeterol in terms of change in dyspnoea scores over 12 weeks. The onset of bronchodilation was statistically significantly faster with beclometasone/formoterol compared with fluticasone/salmeterol, although it is unclear whether the improvement is clinically important. Serious adverse events were statistically significantly more common with fluticasone/salmeterol, which may be due to the higher BDP equivalent dose of ICS in this combination (see the evidence review section of this evidence summary for more information on the relative ICS doses in the treatments assessed).

The type of inhaler device may affect the choice of treatment for an individual person. A metered dose inhaler is the most appropriate device for people who need to use a spacer. Beclometasone/formoterol is administered using a metered dose inhaler; budesonide/formoterol is administered using a Turbohaler; fluticasone/formoterol is administered using an Accuhaler; and fluticasone/vilanterol is administered using an Ellipta device. Apart from fluticasone/vilanterol, which is administered once daily, these treatments are administered twice daily.

Local decision makers will need to take these factors into account when considering the likely place in therapy of beclometasone/formoterol for COPD.

Full text of Estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.