COPD fixed-dose combination (FDC) inhalers: PBS listing changes

• On 1 March 2020, the FEV₁ < 50% threshold was removed from the clinical criteria in PBS listings of COPD fixed-dose combination (FDC) inhalers
  The COPD FDC inhalers include triple therapy (Trelegy Ellipta) and all ICS + LABAs.

• The FEV₁ threshold removal made the PBS listings consistent with recent evidence
  FEV₁ threshold lacks precision to be used clinically as a predictor of exacerbations or mortality in patients with COPD.

• The role of spirometry for COPD diagnosis was included in the triple therapy PBS listing
  The change aims to ensure that removal of the FEV₁ threshold does not undermine the importance of spirometry in COPD diagnosis.

• The FEV₁ < 50% threshold removal was also accompanied by strengthening of the clinical criteria
  Patients must have experienced at least one severe COPD exacerbation (requiring hospitalisation), or ≥ 2 moderate exacerbations in the previous 12 months.

• The PBAC found that triple therapy had greater efficacy than the comparator, LAMA + LABA, but also an increased incidence of pneumonia and oral candidiasis
  As a result the PBAC considered that the appropriate place of triple therapy was after inadequate control was experienced with LAMA + LABA or ICS + LABA.

Triple therapy FDC inhaler

On 1 March 2020, changes were made to the PBS listing of fluticasone furoate with umeclidinium and vilanterol (Trelegy Ellipta) for chronic obstructive pulmonary disease (COPD). The main change was removal of the threshold of FEV₁ < 50% predicted from the clinical criteria.^1,2

Fluticasone furoate with umeclidinium and vilanterol is the only TGA-registered and PBS-listed triple therapy fixed-dose combination (FDC) inhaler for COPD in Australia³ and will be referred to as the triple therapy FDC inhaler in this article.

This Authority Required (STREAMLINED) medicine contains an inhaled corticosteroid, a long-acting beta₂ agonist and a long-acting muscarinic antagonist (ICS + LAMA + LABA).²

The removal of the FEV₁ < 50% threshold was accompanied by a strengthening of the clinical criteria for prescribing the triple therapy FDC inhaler.²

The clinical criteria specify that the patient:¹

• must have experienced at least one severe COPD exacerbation, which required hospitalisation, or two or more moderate exacerbations in the previous 12 months, with significant symptoms despite regular bronchodilator therapy with LAMA + LABA or ICS + LABA, or
• has been stabilised on a combination of a LAMA, a LABA and an ICS for this condition (that is, has been using more than one inhaler).

The FEV₁ threshold removal was also accompanied by an addition to the PBS listing that emphasised the importance of spirometry in the diagnosis of COPD.^1,2

See the PBS website for complete details for this item.

ICS + LABA FDC inhalers

On 1 March 2020 all ICS + LABA FDC inhalers for COPD also had the FEV₁ < 50% predicted threshold removed from the clinical criteria of their Authority Required (STREAMLINED) PBS listings.^1,2

The ICS + LABA FDC medicines affected by this change include:¹

• budesonide 200 micrograms and formoterol 6 micrograms (Symbicort Rapihaler 200/6)
• budesonide 400 micrograms and formoterol 12 micrograms (Symbicort Turbuhaler 400/12, DuoResp Spiromax)
• fluticasone 250 micrograms and salmeterol 25 micrograms (Seretide Accuhaler, Seretide MDI, Fluticasone + Salmeterol Cipla, Pavtide, SalplusF Inhaler)
• fluticasone and vilanterol (Breo Ellipta)

The FEV₁ threshold removal was also accompanied by strengthening of the clinical criteria² specifying that the patient must have experienced at least one severe COPD exacerbation, which required hospitalisation, or two or more moderate exacerbations in the previous 12 months, in addition to significant symptoms despite regular beta₂ agonist bronchodilator therapy.^1,2

See the PBS website for complete details for these items.

Triple therapy FDC inhaler

At its March 2019 meeting, the PBAC recommended removing the FEV₁ threshold from the PBS listing of the triple therapy FDC inhaler for COPD to make it consistent with the 2018 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.²

This recommendation was based on an assessment of the medicine’s acceptable cost-effectiveness versus LAMA + LABA inhalers. The removal then led to additional listing changes.²

2018 GOLD guidelines and evidence

Prior to 2017, the GOLD guidelines recommended pharmacotherapy using spirometry criteria based on early evidence that patients with ‘severe’ lung function impairment (FEV₁ < 50% predicted) were prone to repeated exacerbations and hospitalisation.²

The PBAC considered that the 2018 update to the GOLD guidelines reflected evidence indicating that the FEV₁ threshold lacks precision to be used clinically as a predictor of exacerbations or mortality in patients with COPD.²

Many patients with COPD can be adequately treated with long-acting bronchodilator monotherapy using either a LABA or LAMA. Others may require dual therapy containing an ICS + LABA or LAMA + LABA. However a proportion of patients may need to escalate to triple therapy (ICS + LABA + LAMA).⁴

The 2018 GOLD guidelines recommended a stepwise approach to pharmacotherapy based on exacerbation history and symptoms, irrespective of FEV₁ thresholds. All patients are categorised into one of 4 groups (A, B, C or D) based on an assessment of their exacerbation history and symptoms.⁵

Escalation to triple therapy was reserved for group D patients, who are at high risk of exacerbations (≥ 2 moderate exacerbations or ≥ 1 severe exacerbation, which required hospitalisation, in the past 12 months) and with significant symptoms, as measured by a dyspnoea score of the Modified British Medical Research Council (mMRC) questionnaire ≥2 and comprehensive symptom assessment score of the COPD Assessment Test (CAT) ≥10).⁵

The PBAC didn’t consider that incorporating the mMRC or CAT scores in the PBS listing clinical criteria would be appropriate because prescribers are not familiar with them. It instead advised that the restriction continue to specify the need for a patient to be experiencing significant symptoms, despite regular LAMA + LABA or ICS + LABA therapy, or be stabilised on a combination of LAMA, LABA or ICS.²

The PBAC also considered that the restriction for the triple therapy FDC inhaler should include a reference to the use of spirometry for the diagnosis of COPD so that the removal of the FEV₁ threshold would not undermine the importance of spirometry in diagnosis. This would also be consistent with the PBS listings of LAMA + LABA and ICS + LABA FDC inhalers for COPD.²

Cost-effectiveness

The PBAC assessment of cost-effectiveness was based on the 2018 Informing the Pathway of COPD Treatment (IMPACT) trial, with LAMA + LABA therapy considered the appropriate comparator.²

The IMPACT trial was a 52-week, randomised, double blind, 3-arm parallel group study, comparing the efficacy, safety and tolerability of fluticasone furoate with umeclidinium and vilanterol to two dual therapy FDCs administered once daily to subjects with COPD (n = 10,355). The FDCs were:

1. fluticasone furoate and vilanterol (ICS + LABA), and
2. umeclidinium and vilanterol (LAMA + LABA). 

The primary efficacy outcome was the annual rate of moderate or severe COPD exacerbations during treatment.⁶

The PBAC considered that the IMPACT trial found that fluticasone furoate with umeclidinium and vilanterol was associated with greater efficacy in terms of lung function and exacerbations versus LAMA + LABA.² However it had reduced safety because of an increased incidence of pneumonia and oral candidiasis.²

The PBAC found that the triple therapy FDC inhaler was likely to be associated with an increased risk of harms over LAMA + LABA and its appropriate place should be after a patient experiences inadequate control with dual therapy (LAMA + LABA and ICS + LABA).²

ICS + LABA FDC inhalers

The March 2019 PBAC meeting decided that the FEV₁ threshold removal from the PBS listing clinical criteria for the triple therapy FDC inhaler was also applicable to all ICS + LABA inhalers for COPD. The PBAC recommended flow-on additional changes were appropriate² in order to maintain consistency with the triple therapy FDC inhaler and with the guidelines and evidence.²

It’s expected that more patients will be able to access the triple therapy FDC inhaler and all ICS + LABA FDC inhalers for COPD since a barrier to the next lines of therapies, the FEV₁ threshold that was previously part of their PBS listing clinical criteria, has been removed. This may lead to increased use of these medicines.²

The PBAC also highlighted a number of quality use of medicines concerns, including:²

• removal of the FEV₁ threshold could be seen to undermine the importance of spirometry in the diagnosis of COPD²
• prescribing the triple therapy FDC inhaler may occur earlier in the treatment pathway than intended and there was a risk of concomitant use of triple therapy FDC and other mono or dual therapy inhalers for COPD.²

Spirometry

Diagnosis of COPD should continue to include measurement of airflow obstruction using spirometry, with confirmation of post-bronchodilator airflow obstruction, regardless of the removal of the FEV₁ threshold from the PBS listings of the medicines.²

Safety

For every 100 patients treated with the triple therapy FDC inhaler over 52 weeks, approximately 3 more patients would experience pneumonia and 2 more patients would experience oral candidiasis.²

Adherence

Factors that contribute to adherence among COPD patients include ease of inhaler use, treatment complexity, such as dosing frequency, and the number of inhalers. In patients with poor adherence, a switch from two or three inhalers to a single triple therapy device may improve adherence,⁴ as well as achieve safety benefits.²

Conversely, patients with COPD, who rely on their inhalers to control their symptoms and reduce the risk of exacerbations, can find change disconcerting, which may have a negative impact on adherence. It’s recommended that patients with COPD and, when appropriate, relatives and carers, are trained, counselled and educated about starting on a new inhaler.⁴

Inhaler technique

Having to learn different techniques for different inhalers may undermine adherence. Many patients fail to use even one inhaler correctly.⁴ Poor inhaler technique is associated with reduced symptom control.⁷

Provide instructions on and demonstrate correct inhaler technique to patients, and re-check at each visit that they are continuing to use their inhalers correctly.⁸ For more information see NPS MedicineWise In my practice: inhaler technique – it's a repeat prescription.

Non-pharmacological treatments

Management of COPD is not limited to medicines alone and should be complemented by appropriate non-pharmacological treatments, including self-management, education, smoking cessation and physical activity.⁸

• Starting the triple therapy FDC inhaler can be done at the next dose after taking a last dose of the patient’s current inhalers.¹⁰
• The dose for the triple therapy FDC inhaler is one inhalation, once daily, either morning or evening, but at the same time every day.¹⁰
• After inhalation, patients need to rinse their mouth out with water without swallowing to prevent oral candidiasis.¹⁰
• Advise patients to see their doctor if they are getting breathless or wheezy more often than normal, or using a quick-acting inhaler (eg SABA) more than usual.¹¹
  

• Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines
• COPD-X Plan: Australian and New Zealand Guidelines for the management of Chronic Obstructive Pulmonary Disease