Budesonide with formoterol for mild asthma: New PBS listings

• On 1 June 2020, new listings for budesonide + formoterol fixed-dose combination (FDC) were added on the PBS General Schedule
  They can be prescribed under the PBS for adults and adolescents with mild asthma who require anti-inflammatory reliever therapy.
• The new listings are for low dose budesonide + formoterol FDC including Symbicort Turbuhaler 200/6, Symbicort Rapihaler 100/3 and DuoResp Spiromax
  Prescriptions are Authority Required (STREAMLINED) with two repeats.
• Budesonide + formoterol FDC can be prescribed when initiating management in mild asthma under the PBS
  Previously it could only be prescribed for patients who had frequent episodes and required single maintenance and reliever therapy.
• The new listings complement an upcoming update to the Australian guidelines and recent changes to international guidelines and TGA-registered indications
  They will provide prescribers with another treatment option under the PBS for mild asthma in adults and adolescents.
• A preview of the Australian guidelines update shows it provides 3 treatment options for mild asthma in adults and adolescents
  1) SABA as needed for only a few patients; while for most new patients 2) Regular daily ICS (low dose) and SABA reliever as needed; OR 3) Budesonide + formoterol FDC as needed

On 1 June 2020, new Authority Required (STREAMLINED) listings for budesonide + formoterol FDC were added to the PBS General Schedule (Section 85) for adults and adolescents with mild asthma who require anti-inflammatory reliever therapy.^1,2

Previously, budesonide + formoterol FDC was only listed for adults and adolescents with asthma who had frequent episodes and required single maintenance and reliever therapy.³

The new listings are for low-dose formulations:¹

• Budesonide 200 micrograms with formoterol fumarate dihydrate 6 micrograms per dose, 120 doses (Symbicort Turbuhaler 200/6 for 12 years and over; DuoResp Spiromax for 18 years and over). These two medicines are marked as equivalent for the purposes of substitution by the pharmacist at the point of dispensing (that is, ‘a’ flagged).
• Budesonide 100 micrograms with formoterol fumarate dihydrate 3 micrograms per dose, 120 doses (Symbicort Rapihaler 100/3 for 12 years and over).

Budesonide is an inhaled corticosteroid (ICS). It has a dose-dependent anti-inflammatory action in the airways that occurs within hours, resulting in reduced asthma symptoms and fewer exacerbations.^4,5

Formoterol is a long-acting beta₂ agonist (LABA) that has a duration effect of at least 12 hours after a single dose and also a rapid onset of effect within 1–3 minutes after inhalation.^4,5

The clinical criteria for the new listings are:¹

• Patient must have asthma and require an anti-inflammatory reliever therapy

AND

• Patient must not be on a concomitant single agent long-acting beta₂ agonist (LABA), including olodaterol, indacaterol, salmeterol, formoterol or vilanterol
• Device (inhaler) technique should be reviewed at each clinical visit and before initiating treatment with this medicine.

The listings include two repeats and prescribers are advised that the medicines are not PBS-subsidised for the treatment of chronic obstructive pulmonary disease (COPD), or for the treatment of allergen- or exercise-induced bronchoconstriction in the absence of asthma.¹

See the current PBS Schedule at the PBS website for the updated listings.

Budesonide + formoterol FDC may be prescribed by nurse practitioners.

Authorised nurse practitioners may prescribe this medicine on the PBS.

See the PBS website for more information on nurse practitioner PBS prescribing.¹

The PBAC recommended the new listings for mild asthma in adults and adolescents at its November 2019 meeting. This followed a submission that was rejected at the July 2019 PBAC meeting.^2,6

The recommendation was based on:²

• a review of the results from the key clinical evidence, the SYGMA 1 and SYGMA 2 studies, that adequately addressed concerns raised at the PBAC July 2019 meeting about non-inferiority claims, compared to ICS preventer and SABA reliever as needed. See ‘Clinical evidence’ below for more details.
• evidence from two other randomised controlled open-label trials, Novel START and PRACTICAL, supporting the use of budesonide + formoterol FDC as needed for mild asthma. See ‘Clinical evidence’ below for more details.
• support for the new listings from the National Asthma Council Australia, Asthma Australia and Lung Foundation Australia.
• cost-minimisation and financial issues from the PBAC July 2019 meeting being adequately addressed

The PBAC also found that patients are likely to have more than one budesonide + formoterol inhaler in use at a time. Because of this, it recommended that the new listings include two repeats.²

Global Initiative for Asthma guidelines and TGA changes

The PBAC also noted changes in the 2019 Global Initiative for Asthma (GINA) guidelines that recommended low-dose budesonide + formoterol FDC as needed, instead of SABA as needed, for mild asthma in adolescents and adults.⁶

In July/August 2019, the TGA changed the registration of budesonide + formoterol FDC (Symbicort 200/6 Turbuhaler and Symbicort 100/3 Rapihaler) to include reliever therapy for mild asthma as an indication.² On 30 April 2020 the same change was made to the TGA registration of DuoResp Spiromax.⁷

See ‘Will the changes affect current prescribing?’ below for more details about the GINA guidelines changes.

Four studies were considered in the PBAC recommendation to list budesonide + formoterol FDC for mild asthma in adults and adolescents.²

SYGMA 1 and SYGMA 2 studies

The SYGMA 1 and SYGMA 2 studies, which were considered to be the key clinical evidence by the PBAC, evaluated budesonide + formoterol FDC as needed for:⁶

• safety
• effectiveness, as measured by asthma control and reduced asthma exacerbations.

The SYGMA 1 study (n = 3849) was a 52-week, double blind, randomised, multi-centre, parallel group, Phase III trial in patients 12 years and older with asthma. It compared:⁸

• budesonide + formoterol FDC (200 micrograms/6 micrograms) as needed
• SABA (terbutaline 0.5 mg) as needed
• ICS preventer (budesonide 200 micrograms) twice daily as well as SABA (terbutaline 0.5 mg) as needed (from here on called ICS and SABA).

The primary outcome was asthma control based on the percentage of well-controlled asthma weeks (WCAW) during the 52-week trial, comparing budesonide + formoterol FDC as needed versus SABA as needed. The study found budesonide + formoterol FDC as needed had 14% greater odds of achieving a WCAW (34.4% vs. 31.1%; CI 95% odds ratio (OR) 1.14 [1.00 to 1.30] P = 0.046).^6,8

A secondary outcome for severe asthma exacerbations, comparing budesonide + formoterol FDC as needed to SABA as needed, found a 64% reduced annualised exacerbation rate (0.07 vs. 0.20; CI 95%, rate ratio (RR) 0.36 [0.27 to 0.49]).⁸

In contrast, another secondary outcome for asthma control comparing budesonide + formoterol FDC as needed to ICS and SABA, found a 36% lower odds of achieving a WCAW (34.4% vs. 44.4%; CI 95%, OR 0.64 [0.57 to 0.73]).^6,8

The SYGMA 2 study (n = 4215) had the same design as SYGMA 1, but only compared budesonide + formoterol FDC as needed versus ICS and SABA.^6,9

The primary outcome was for severe asthma exacerbations (annualised rate), initially for superiority, but during the trial switched to non-inferiority, based on a prespecified limit of 1.2 for the upper one-sided 95% CI for the rate ratio (RR).^6,9

The study found there was no significant difference for budesonide + formoterol FDC as needed and claimed a non-inferiority; 0.11 (CI 95%, 0.10 to 0.13) versus 0.12 (CI 95%, 0.10 to 0.14) and a RR of 0.97 with a one-sided 95% upper CI of 1.16.^6,9

Novel START

Novel START was a 52-week, open-label, parallel group controlled trial of adults with mild asthma on SABA reliever alone (n = 668), who were randomised to either:¹⁰

• budesonide + formoterol FDC (200 micrograms/6 micrograms) as needed
• SABA (salbutamol 100 micrograms) as needed
• ICS preventer (budesonide 200 micrograms) twice daily and SABA (salbutamol 100 micrograms) as needed (ICS and SABA).

The primary outcome was annualised rate of asthma exacerbations. An exacerbation was defined as an urgent medical care consultation (eg primary care or emergency department visit, or hospital admission); a prescription of systemic corticosteroid for any duration; or an episode of high beta₂ agonist use > 16 actuations of salbutamol or > 8 actuations of budesonide + formoterol FDC over the course of 24 hours.¹⁰

The rate of asthma exacerbations for budesonide + formoterol FDC as needed was significantly lower than SABA as needed (CI 95%, relative rate (RR) 0.49 [0.33 to 0.72], p <0.001), but did not differ significantly from ICS and SABA (CI 95%, RR 1.12 [0.70, 1.79]).^2,10

However the number of severe exacerbations for budesonide + formoterol FDC as needed during the 52-week trial period was lower than for both SABA as needed (9 vs 23; CI 95%, relative risk, 0.40 [0.18 to 0.86] and ICS and SABA (9 vs 21; CI 95%, relative risk 0.44 [0.20 to 0.96]).^2,10

PRACTICAL

PRACTICAL was a 52-week, open-label, parallel group controlled trial of adults with mild to moderate asthma (n = 885) either on SABA reliever with or without maintenance low-dose inhaled ICS, who were randomised to either:^2,11

• budesonide + formoterol FDC (200 micrograms/6 micrograms) as needed
• ICS preventer (budesonide 200 micrograms) twice daily and SABA (terbutaline 250 micrograms) as needed (ICS and SABA).

The primary outcome was the rate of severe asthma exacerbations per patient per year, defined as use of systemic corticosteroids for at least 3 days because of asthma, or admission to hospital or an emergency department visit because of asthma requiring systemic corticosteroids.¹¹

The study found severe asthma exacerbations were lower for budesonide + formoterol FDC as needed, compared to ICS and SABA (CI 95%, relative rate 0.69 [0.48 to 1.00] p= 0.049). The combined moderate and severe asthma exacerbation rate was also lower (CI 95%, relative rate, 0.70 [0.51 to 0.95]).^2,11

In addition, the 31% reduction in severe asthma exacerbation was achieved despite the fact that participants who were taking budesonide + formoterol FDC as needed used 60% less ICS, compared to the ICS and SABA participants.^2,11

PBAC – July 2019 meeting

The PBAC accepted that ICS and SABA was the appropriate main comparator when considering the place in therapy for the proposed listing of budesonide + formoterol FDC for mild asthma. It did not consider SABA as needed was a relevant comparator.⁶

The PBAC noted that the claim of non-inferior comparative safety (versus both ICS and SABA and SABA as needed) in the SYGMA studies was reasonable.⁶

However the PBAC found that it was uncertain about the claim of non-inferior clinical effectiveness when comparing budesonide + formoterol FDC as needed to ICS and SABA. This was due to concerns it had about:^2,6

• asthma control results in the SYGMA 1 study, which found a 36% lower odds of achieving a WCAW
• severe asthma exacerbation results in the SYGMA 2 study, based on the upper 95% CI for the rate ratio, where 97.5% CI was considered more appropriate by the PBAC when using one-sided CI, which would have resulted in the prespecified limit of 1.2 not being met.

PBAC – November 2019 meeting

PBAC considered its concerns about the non-inferiority claims of the SYGMA studies were adequately addressed in a resubmission from the sponsor.²

The PBAC noted that the use of WCAW as a measure of asthma control inherently biases against budesonide + formoterol FDC as needed when comparing to ICS and SABA.²

The reasoning was that under ‘as needed’ treatment, budesonide + formoterol FDC is not taken unless a patient experiences symptoms, whereas in the ICS and SABA treatment, the ICS is taken as a preventer (twice daily). As a result, the largest difference between budesonide + formoterol as needed and ICS and SABA in the SYGMA 1 study was seen for the ‘as needed’ use component, in favour of ICS and SABA.²

The PBAC considered that removal of the ‘as needed’ use component in a review of the results, improved the likelihood of patients who were using budesonide + formoterol FDC achieving a WCAW, although the results continued to favour ICS and SABA. Instead of a 36% lower odds, it had a 22% lower odds of achieving a WCAW compared to ICS and SABA during the study period (46.6% vs 52.9%; CI 95%, OR 0.78 [0.69 to 0.88]).²

With respect to the severe asthma exacerbations in the SYGMA 2 study, the PBAC noted the sponsor’s argument, including reference to the TGA and PBAC guidelines and previous submissions for other medicines, against the use of 97.5% CI and the acceptance of 95% CI, to determine that the prespecified limit of 1.2 for non-inferiority had been met.^2,6

As a result, the PBAC concluded that on balance, with the support of the Novel START and PRACTICAL trials, the body of the clinical evidence supported the new listings for budesonide + formoterol FDC for mild asthma in adults and adolescents.²

The new listings for budesonide + formoterol FDC as needed for mild asthma in adults and adolescents will provide prescribers with another treatment option for these patients under the PBS.²

This will complement changes to the treatment guidelines for mild asthma in adults and adolescents.

GINA guidelines

In April 2019 the Global Initiative for Asthma (GINA) published new recommendations on the use of SABA alone as needed, and the use of ICS with formoterol FDC as needed. These recommendations were described as the most important change in asthma management in 30 years.^12,13

The GINA guidelines on asthma management are based on a 5-step approach. In Step 1, for patients with symptoms less than twice a month, the focus is on recommending a ‘controller’ medicine to prevent exacerbations and control symptoms rather than on a reliever medicine.^6,12

The GINA guidelines recommendation is for low-dose ICS with formoterol FDC as needed rather than SABA alone as needed. Budesonide is the recommended ICS because it has available data from studies. If ICS with formoterol FDC is not available, the other recommended option is taking a low-dose ICS whenever a SABA is taken.^6,12

Low-dose ICS + formoterol FDC as needed is also recommended as the preferred reliever for all patients with asthma, from Step 1 to Step 5.¹²

The reason for this change from SABA only as needed was that overuse of SABA was found to be associated with harms; increased risk of severe exacerbations and, when ≥ 12 canisters are dispensed in a year, increased risk of asthma-related death.^6,12

The standout reason for the change to ICS with formoterol FDC as needed was the evidence from the SYGMA 1 and SYGMA 2 studies. The GINA guidelines noted that budesonide was the only ICS that had evidence to support its use for mild asthma in adults and adolescents.^6,12

Also of particular concern to GINA was the paradoxical switch in messaging for patients and clinicians between Step 1 and Step 2 in the previous guidelines. In Step 1 symptom relief was the priority and SABA use was encouraged. But then in Step 2 patients were told that they should reduce what was to them a familiar, effective, low-cost treatment, and that to achieve this, they should take a daily maintenance treatment even when asymptomatic.^12,13

Australian Asthma Handbook guidelines

The 2019 Australian Asthma Handbook guidelines, developed by the National Asthma Council (NAC), are based on a stepped approach to management, like the GINA guidelines.^14,15

The guidelines are currently under review. This will involve a rigorous review of the evidence, and also take into consideration the Australian health system and implementation in primary care. The National Asthma Council expects a full update to be released in coming weeks.¹⁶

A preview of the update was released by NAC on 1 June 2020. 

Unlike the GINA guidelines,¹⁵ the Australian Asthma Handbook provides three medicine options for the treatment of mild asthma in adults and adolescents.^16,17

Option 1: SABA alone as needed. This is Step 1 for patients who have symptoms less than twice a month and no risk factors for flareups. It’s expected that only ‘a few’ patients will use this option. It is unchanged from the 2019 guidelines.

Step 2 is considered a suitable starting treatment for ‘most new patients’. Management is either:

Option 2: Regular daily maintenance ICS (low dose) and SABA reliever as needed. This is unchanged from the 2019 guidelines

OR

Option 3: Budesonide + formoterol (low dose) as needed. This is a new addition to the guidelines.

The addition of budesonide + formoterol FDC as needed as a treatment option means that firm and clear diagnosis and assessment, which are essential for selecting the most appropriate treatment, are more important than ever.

Selecting the option that is most appropriate for each person with mild asthma will involve weighing up clinical and patient factors, such as history of flareups and exacerbations, day-to-day symptoms, patient preferences for treatment and potential issues with adherence or use of specific inhaler devices.

Healthcare professionals will also need to consider the different management regimens in the updated Australian Asthma Handbook guidelines for Steps 2 and 3 for budesonide + formoterol FDC.

As described above, patients at Step 2 may now start on low-dose budesonide + formoterol FDC as needed, or take regular daily low-dose ICS and SABA as needed. Patients at Step 3 may take either low-dose budesonide + formoterol FDC as a maintenance and reliever therapy, or low-dose ICS with LABA FDC as maintenance, and SABA as needed.¹⁷

Prescribers need to be aware and educate patients that different management regimens (ie Step 2 and Step 3) are now available for the same medicine (budesonide + formoterol FDC), as this may cause confusion.

For patients already diagnosed with and receiving treatment for asthma, the Australian Asthma Handbook guidelines recommends regular review, including reviewing the patient’s written asthma action plan every year or when there is a significant change to their treatment or asthma status. A review should lead to a discussion with the patient about whether the medicines are appropriate for their current treatment and their level of recent asthma symptom control. This may lead to consideration of changing medicines.¹⁴

With any consideration of choice of treatment, cost may also be an issue for patients. Even with the new PBS listing, a SABA costs less than budesonide + formoterol FDC.^1,3

SABAs are also more easily available for patients. The PBAC noted that the proportion of people currently only purchasing SABA over the counter, who would end up presenting to a GP for review because of the availability of budesonide + formoterol FDC as needed on the PBS, may depend on asthma counselling in pharmacies.² Advice on what this counselling should involve will have to wait until the release of the updated Australian Asthma Handbook guidelines.

Ensure all patients with asthma have an individualised written asthma action plan that is appropriate for their treatment regimen, asthma severity, culture, language, literacy level, and ability to self-manage.¹⁴

Try to ensure the patient is able to use the correct device (inhaler) technique before starting treatment with budesonide + formoterol FDC and review the technique at each clinical visit.¹

Explain to the patient that the devices Spiromax for DuoResp and Turbuhaler and Rapihaler for Symbicort differ in design and technique of use, and that some patients may find one easier to use than the others. In addition, point out that the differences may cause confusion if brand substitution between Symbicort Turbuhaler and DuoResp Spiromax occurs at the pharmacy.¹⁹

During the COVID-19 pandemic, it may be difficult to try out inhalers before filling out a prescription, if a new sample or dummy inhaler isn’t available for each patient. It may be helpful once a device has been chosen, for the prescriber to add a note to the pharmacist to check technique when the inhaler is dispensed.

Advise patients:

• to carry a budesonide + formoterol FDC inhaler with them at all times⁴
• they do not need to rinse mouth out with water to prevent oral candidiasis (thrush) when taking budesonide + formoterol occasionally as reliever (unlike for maintenance therapy).²⁰

Asthma Australia has resources and information, in particular about the new PBS listing.

NPS MedicineWise has information for patients about asthma, asthma medicines and inhaler devices.

If preferred, patients can also get information over the phone by calling NPS MedicineWise’s Medicines Line at 1300 MEDICINE (1300 633 424).

• Australian Prescriber: The cost of asthma medicines
• National Asthma Council Australia: Australian Asthma Handbook 2019 – Stepped approach to adjusting asthma medication in adolescents and young adults
• GINA: Global Strategy for Asthma Management and Prevention (2020 update)
• NPS MedicineWise: Inhaler technique: a device-specific checklist