Triple therapy FDC inhalers for severe asthma

• Treatment options for severe asthma on the PBS that don’t require specialist referral have expanded over the past year with the listings of triple therapy FDC (fixed-dosed combination) inhalers.
  Previously, only tiotropium was available as an add-on treatment.
• On 1 April 2022, fluticasone with umeclidinium and vilanterol (Trelegy Ellipta) was listed on the PBS for severe asthma.
  It is the second triple therapy FDC inhaler to be listed on the PBS for this indication.
• Prescribers should be aware of flow-on changes to the PBS listings of indacaterol with glycopyrronium and mometasone (Enerzair Breezhaler) and tiotropium (Spiriva Respimat).
  It updated the clinical criteria for indacaterol with glycopyrronium and mometasone (Enerzair Breezhaler), and amended the listing to Authority Required (Streamlined). The clinical criteria for tiotropium was also updated, but its restriction type remains unchanged.
• In asthma, there is evidence of significant noncompliance and non-adherence to medicines.
  Triple therapy FDC inhalers may improve adherence by reducing the number of inhaler devices required for maintenance treatment, with fewer instructions and similar dosing regimens.

On 1 April 2022, fluticasone with vilanterol and umeclidinium (Trelegy Ellipta) was listed as Authority Required (Streamlined) for severe asthma.⁴

The clinical and population criteria specify that the patient must:⁴

• have experienced at least one severe asthma exacerbation in the 12 months prior to having first commenced treatment for severe asthma, which required systemic corticosteroid treatment despite each of:
  • receiving optimised asthma therapy
  • being assessed for adherence to therapy
  • being assessed for the correct inhaler technique
• be aged 18 years and older.

Optimised asthma therapy includes adherence to the maintenance of ICS (at least 800 micrograms budesonide per day or equivalent) + LABA.⁴

See the PBS website for complete details on each item.

Authorised nurse practitioners can prescribe these medicines on the PBS.⁵ See the PBS website for more information on nurse practitioner PBS prescribing.

On 1 April 2022, changes were made for two medicines listed on the PBS General Schedule (Section 85) for severe asthma:

• indacaterol with glycopyrronium and mometasone (Enerzair Breezhaler)
• tiotropium (Spiriva Respimat)

Flow-on changes to indacaterol with glycopyrronium and mometasone (Enerzair Breezhaler) from 1 April 2022 amended the listing to Authority Required (Streamlined) and updated the clinical criteria.⁴ It was first listed as a treatment option for severe asthma on 1 April 2021 as an Authority Required (telephone/online PBS authorities system) listing.⁵

The clinical criteria for tiotropium were also updated, but its restriction type remains as a Restricted Benefit.⁴ It was first listed as an add-on treatment option for severe asthma on 1 February 2017.⁶

At the March 2022 meeting, the PBAC considered a submission for a new PBS listing for beclometasone with formoterol and glycopyrronium (Trimbow) for severe asthma.⁷

Triple therapy FDC inhalers include:^8-10

• an ICS that reduces inflammation in the airways
• a LABA that dilates the airways by activating adenylate cyclase to relax airway smooth muscle cells
• a LAMA that dilates the airways by blocking the constricting effect of acetylcholine on airway smooth muscle cells.

The recommended dose of the PBS-listed triple therapy FDC inhalers is once daily via inhalation for severe asthma.^8,9

Table 1: Triple therapy FDC inhalers^7-11

^{a Product labelling and product information displayed as the delivered dose
b Product labelling and product information displayed as the metered dose
c must have experienced at least one severe exacerbation, which has required the documented use of systemic corticosteroids in the previous 12 months while receiving optimised asthma therapy, despite documented formal assessment of and adherence to a correct inhaler technique}

The conditions for TGA registration of indacaterol with glycopyrronium and mometasone (Enerzair Breezhaler) required changes to labelling and product information to display the delivered dose (the dose leaving the mouthpiece of the inhaler) rather than the metered dose (the dose leaving the valve of the inhaler).¹²

The clinical place of triple therapy FDC inhalers in the management of severe asthma is becoming more established. As a result, the PBS have expanded the treatment options for severe asthma that don’t require specialist referral.

In asthma, there is significant non-adherence to medicines. This could be due to the difficulty of following different treatment schedules or using multiple inhalers. Triple therapy FDC inhalers may improve treatment adherence by reducing the number of inhaler devices needed for maintenance treatment, with fewer instructions and similar dosing schedules.¹³

2022 Australian Asthma Handbook Version 2.2 guidelines for severe asthma

The guidelines recommend that pharmacological management of asthma involve stepping up (by increasing the dose or adding to the treatment regimen) when good control is not achieved. Before considering stepping up, check that:¹

• any symptoms are related to asthma
• the inhaler technique is correct
• adherence is adequate.

If an adult with confirmed severe asthma continues to frequently experience symptoms or flare-ups despite optimised inhaler techniques and adherence and treatment of comorbidities, a trial of add-on treatment with a LAMA or montelukast (a leukotriene receptor antagonist) can be considered before referring for specialist assessment for monoclonal antibody therapy.¹

Montelukast is not PBS-listed for severe asthma.¹⁴ There is little evidence to support its use as add-on treatment for severe asthma.¹

LAMAs (as a single inhaler added to a ICS + LABA FDC inhaler or part of a triple therapy FDC inhaler) are listed as options in the current guidelines.¹ Explicit guidance of triple therapy FDC inhalers will be added to version 3.0 of the guidelines.

See the Australian Asthma Handbook for more information on severe asthma in adults and adolescents.

Find out more about using a systemic approach to assessing patients with difficult-to-treat and severe asthma. This resource was developed by NPS MedicineWise for health professionals.

2021 GINA global strategy

In 2021, GINA (Global Initiative for Asthma) updated the global pharmacological management strategy for patients with severe asthma. GINA expanded the treatment options by including triple therapy FDC inhalers in the previous recommendations for adding tiotropium.²

Severe asthma should be managed under specialist care or at a severe asthma clinic if possible. The clinical or inflammatory phenotype should be assessed, as this may guide the selection of treatment.²

If asthma is not well controlled with medium- or high-dose ICS + LABA, a LAMA may be prescribed as a treatment option:²

• as an add-on in a separate inhaler for patients aged 6 years and older (tiotropium)
• in a triple therapy FDC inhaler for patients aged 18 years and older (indacaterol with glycopyrronium and mometasone; fluticasone with umeclidinium and vilanterol; beclometasone with formoterol and glycopyrronium).

Clinical evidence

The evidence for the recommendations from GINA is based on data from several clinical trials conducted for the triple therapy FDC inhalers. The studies found that adding a LAMA to ICS + LABA modestly improves lung function compared to ICS + LABA.^15-18 In one study, add-on LAMA modestly increased the time to severe exacerbation requiring oral corticosteroids.¹⁶

Triple therapy FDC inhalers are a safe and effective therapeutic alternative for patients with poorly controlled asthma despite ICS + LABA treatment.^13,19,20

A 2021 systemic review and meta-analysis investigated asthma outcomes associated with triple therapy FDC inhalers compared to ICS + LABA. The authors concluded that among adults with moderate-to-severe asthma, triple therapy FDC inhalers were significantly associated with fewer asthma exacerbations and modest improvements in asthma control, compared to those with dual therapy.²⁰

Practical implications

Comparing clinical efficacy and safety of treatment options

There are no clinically meaningful differences in efficacy and safety between that indacaterol with glycopyrronium and mometasone (Enerzair Breezhaler) and ICS + LABA with tiotropium as an add-on when used for the treatment of severe asthma.¹²

The PBAC has recommended that indacaterol with glycopyrronium and mometasone (Enerzair Breezhaler) and fluticasone with umeclidinium and vilanterol (Trelegy Ellipta) should be treated as interchangeable on an individual patient basis.²¹ Please note that interchangeability in this context is different to ‘a’ flagging and brand substitution is not permitted at the point of dispensing.

Indacaterol with glycopyrronium and mometasone (Enerzair Breezhaler) is one of the first inhalers PBS listed for asthma and is the only triple therapy FDC inhaler that requires capsules to be loaded prior to use.^9,10 For many patients, this would be a new inhaler technique.¹²

Fluticasone with umeclidinium and vilanterol (Trelegy Ellipta) is a dry powder inhalation (DPI) device (Ellipta), which has a single-step activation procedure.²¹

Educating patients about the purpose of their medicine and its correct use is important to ensure they gain the greatest benefit from their treatment.¹³

Adherence and inhaler technique

Several patient-related factors, such as adherence, need to be considered carefully. The optimum place for triple therapy FDC inhalers within treatment guidelines must be established.¹³

Adherence rates are often significantly better in patients using a single inhaler than in patients using multiple inhalers.²² At the same time, a single FDC inhaler may reduce the flexibility to adjust the dose of each individual medicine, although some triple therapy FDC inhalers are available at different doses to provide added flexibility.^5,13

Use of a single inhaler device may also enable step-up from ICS + LABA therapy in the same device, if required.¹⁵ Currently, indacaterol with glycopyrronium and mometasone (Enerzair Breezhaler) is PBS-listed for two different strengths,⁵ while fluticasone with umeclidinium and vilanterol (Trelegy Ellipta) is PBS-listed for asthma for the high dose only.²¹

At the November 2021 meeting, the PBAC recommended fluticasone with umeclidinium and vilanterol (Trelegy Ellipta) for PBS listing for maintenance therapy of severe asthma. The listing was only for one strength (the high dose) as a FDC inhaler.²¹ The recommendation was based on an assessment of the cost not exceeding the least expensive combination of currently PBS-listed components of triple therapy available for asthma with comparable doses.²¹

The PBAC considered the high dose of indacaterol with glycopyrronium and mometasone (Enerzair Breezhaler) and any high-dose ICS + LABA FDC inhalers with tiotropium as appropriate comparators of non-inferior effectiveness and safety to fluticasone with umeclidinium and vilanterol (Trelegy Ellipta). This was based on indirect comparisons using data from five trials.²¹

The decision for an Authority Required (Streamlined) listing was to provide consistency between triple therapy FDC inhalers across COPD and severe asthma. Flow-on changes to indacaterol with glycopyrronium and mometasone (Enerzair Breezhaler) were recommended to align it with this listing, amending the restriction type to Authority Required (Streamlined) and updating the clinical criteria. The update clarified that continuing patients do not need to experience severe exacerbations again every 12 months to qualify for continued treatment. The clinical criteria for tiotropium were also updated, but its restriction type remains as a Restricted Benefit.²¹

Safety issues

Serious effects may include paradoxical bronchospasm and cardiovascular effects. The ICS in triple therapy FDC inhalers may increase the incidence of pneumonia. Systemic corticosteroid effects (eg, Cushing’s syndrome) may occur from long-term high-dose ICS.^8-10

Ocular effects, such as glaucoma, may occur with the long-term use of ICS or LAMA. Consider a referral to an ophthalmologist for patients who develop ocular symptoms.^8-10

Fluticasone with umeclidinium and vilanterol (Trelegy Ellipta) is contraindicated in patients with severe milk-protein allergy.⁹

Dosing considerations

Once-daily dosing from a single device to deliver multiple inhaled medicines may improve adherence.¹⁵ However, having to learn different techniques for different inhalers may undermine adherence.

Indacaterol with glycopyrronium and mometasone (Enerzair Breezhaler) requires capsules to be loaded by the patient prior to use.¹² Instruct patients to administer the medicine correctly and re-check at each visit. If a patient does not experience an improvement in breathing, check if they are swallowing the capsule rather than inhaling it.⁸ For more information, see NPS MedicineWise In my practice: inhaler technique – it’s a repeat prescription.

Talk with patients and carers about these points:

• Patients may start using the triple therapy FDC inhaler at the next dose after taking a last dose of their current inhalers.^9,10
• Triple therapy FDC inhalers are for maintenance treatment. They do not ease symptoms of an asthma attack; tell patients to follow their asthma action plan.^9,10,23
• Start triple therapy FDC inhalers as a treatment trial. If asthma does not improve after an adequate trial, you may tell patients to stop the treatment.¹ Triple therapy FDC inhalers are not indicated for the initiation of treatment in asthma.^4,5
• After using the inhaler, patients should rinse their mouth with water without swallowing.^8-10
• Once removed from the tray, the patient can store fluticasone with umeclidinium and vilanterol (Trelegy Ellipta) for up to 1 month in a cool dry place below 30°C. If the patient stores it in the fridge, remind them to allow the inhaler to return to room temperature for at least an hour before use.⁹
• If monoclonal antibody therapy might help a patient with likely severe asthma, refer to a specialist without delay. The patient needs six months of treatment by a specialist before they can use monoclonal antibody therapy.¹

Visit Asthma Australia or the National Asthma Council Australia for more information and resources for patients.

Further patient information about asthma, asthma medicines and inhaler devices is available from NPS MedicineWise.

• NPS MedicineWise Systemic assessment of a patient with difficult-to-treat asthma
• Australian Asthma Handbook 2020 Severe asthma in adults and adolescents
• GINA 2021 Global strategy for asthma management and prevention
• Centre of Excellence in Severe Asthma Severe asthma toolkit