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The combination of budesonide/formoterol contains the LABA, formoterol, and the ICS, budesonide. These have different modes of action and show additive effects in terms of reduction of asthma exacerbations. The specific properties of these two components allow the budesonide/formoterol combination to be used as a maintenance treatment for asthma, or as both maintenance and reliever therapy.

The difference between the single combination inhaler and a SABA as relievers is the simultaneous administration of an ICS, which may play a key role in reducing exacerbations. There have been studies that have shown that single reliever therapy along with the combination inhaler as rescue therapy was similar to using the same fixed-dose combination therapy with formoterol alone as rescue therapy in terms of the number of additional puffs needed to control symptoms; also, the combination inhaler was significantly better than using formoterol alone as reliever in reducing exacerbations, thereby providing strong support for the idea that the "as required" additional use of an ICS plays a critical role in reducing asthma exacerbations and improving asthma control.

When inhaled, budesonide exerts a dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer asthma exacerbations. Budesonide is retained in the airway tissue to a greater extent than other ICS and also has the unique property of undergoing esterification, thus increasing its retention and thereby prolonging its duration of action. There is also increasing evidence that ICS have a relatively rapid suppressive effect on inflammation.

Inhaled formoterol, a selective LABA bronchodilator, results in rapid and long-acting relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect is dose-dependent, with an onset of effect within 1-3 minutes. Studies performed in both stable and acute severe asthma cases confirm that formoterol works as fast as salbutamol or terbutaline and faster than salmeterol (Figure 4).

Single doses of budesonide/formoterol protect against late-phase bronchial hyper-responsiveness provoked by allergens; this bronchoprotective/airway stabilizing effect was not seen with budesonide and formoterol monotherapies.

In a study conducted in a subgroup of patients to examine the changes in induced sputum eosinophil count in patients receiving SMART (160/4.5 mcg b.i.d.) compared with the conventional best practice, it was concluded that budesonide/formoterol maintenance and reliever therapy achieved similar control of eosinophilic inflammation compared with conventional best practice, despite a lower mean ICS dose (Figure 8).

This treatment approach should be considered in any patient who requires combination treatment with an ICS/LABA, especially those patients who are prepared to use a reliever in response to relevant symptoms.

Large-scale, randomized, blind clinical studies in patients with asthma, aged 12 years or older, have highlighted the benefits of the budesonide/formoterol maintenance and reliever therapy. These studies have consistently shown significant improvements in the time to first exacerbation and reductions in the rate of severe exacerbations (defined as events requiring oral corticosteroids for 3 days or hospitalization/emergency room treatment) with budesonide/ formoterol maintenance and reliever therapy as well as reductions in the total number of oral steroid days relative to all comparator therapies (Figure 9 a and b).

The mean number of days requiring high reliever medication has been shown to be lower with SMART compared to traditional therapies using SABAs (Figure 10).

Randomized clinical studies have demonstrated that, compared with conventional therapies, SMART has a favourable tolerability profile and similar side effects; most adverse events are mild to moderate and no new or unexpected adverse events have been reported.

The incidence, frequency and profile of adverse effects were similar to comparator therapies, and discontinuations because of adverse effects were lower or equivalent. The most commonly reported adverse events were as follows:

A recent study analysed safety data from a trial database (N= 14,346) comprising six randomized clinical trials where budesonide/formoterol was used as maintenance and reliever therapy for at least 6 months and it concluded that budesonide/formoterol maintenance and reliever therapy was well-tolerated and not associated with increased risk of death or cardiac-related serious adverse events or discontinuation, compared with fixed-dose alternatives. Furthermore, asthma-related serious adverse events and discontinuations were significantly reduced.

A possible concern is that the use of SMART may deliver a higher overall ICS dose, resulting in ICS-related side effects. However, SMART has been shown to achieve similar efficacy to conventional therapies using a similar or even lower overall ICS load.

Budesonide/formoterol maintenance and reliever therapy is recommended by the Global Initiative for Asthma Management (GINA) guidelines for the treatment of patients with moderate-to-severe disease that is uncontrolled with ICS.

Additionally, the country-specific guidelines such as those of the Canadian Thoracic Society (CTS) also recommend that "formoterol should only be used as a reliever in individuals on regular ICS therapy in adults and children 12 years of age and over, preferably in the same inhaler device (i.e. combination budesonide/formoterol preparation), instead of two separate inhalers".

Also, the British Thoracic Society guidelines state that "in selected adult patients at step 2 and 3 who are poorly controlled, the use of SMART as rescue medication instead of a SABA, in addition to its regular use as controller therapy, has been shown to be an effective treatment regimen".

Accordingly, budesonide/formoterol maintenance and reliever therapy has been approved in more than 90 countries, including those of the European Union.

Two strengths of budesonide/formoterol SMART are approved for use only in adults, aged 18 years and over - 100/6 mcg and 200/6 mcg per inhalation allowing for personalization, dependent on clinician advice and patient response.

Maintenance doses of 1 inhalation twice daily or 2 inhalations once daily have been studied in moderate-to-severe asthma and both regimens have been shown to be highly effective. A maintenance dose of 2 inhalations twice daily is an option in patients with more severe asthma.

Patients should additionally take 1 inhalation, as needed, in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. Not more than 6 additional inhalations should be taken on any single occasion.

A total daily dose of more than 8 inhalations is not normally needed; however, a total daily dose of up of 12 inhalations could be used for a limited period. Patients using more than 8 inhalations daily should be strongly recommended to seek medical advice. They should be reassessed and their maintenance therapy should be reconsidered.

A single inhaler as maintenance and reliever therapy is not recommended in children and adolescents since it has not yet been approved for use in this age group. However, in a large randomized, controlled trial with 341 children (aged 4 to 11 years) [budesonide/formoterol 80/4.5 mcg o.d. maintenance plus relief], it was concluded that the SMART regimen reduced exacerbation rates compared with both the fixed-dose combination and higher fixed dose alone in children with asthma.

Regarding safety, the same study observed that patients receiving the SMART regimen grew significantly more than patients in the fixed-dose budesonide group, thus making the SMART regimen an effective and well-tolerated treatment approach that may greatly simplify paediatric asthma management in the future.

During pregnancy and lactation, budesonide/formoterol should only be used after special consideration, particularly during the first 3 months and shortly before delivery. One study reported that in asthmatic women, maintenance treatment with budesonide (200 or 400 mcg b.i.d.) results in negligible systemic exposure of breastfed infants.

Reliever inhalations of budesonide/formoterol should be taken in response to asthma symptoms but are not intended for regular prophylactic use, e.g. before exercise.

Dosage is individual and should be adjusted according to disease severity. When control has been achieved, the dose should be titrated to the lowest effective dose, which could include once-daily use.

Due to its unique properties, the budesonide/formoterol combination is currently the only ICS/LABA combination that is approved to be used as maintenance and relief in one inhaler. This is because both budesonide and formoterol show a clear dose response (i.e. higher doses have a greater effect).

This approach is not possible with a combination product containing the LABA, salmeterol (such as salmeterol/fluticasone), due to the lack of dose response and slower onset of action for salmeterol.

Theoretically, all formoterol-containing ICS/LABA combinations can be considered for a SMART regimen and a number of other combinations using formoterol and other ICS are in development. However, there have been no trials conducted to demonstrate their effectiveness and safety if used as SMART.

Two strengths of budesonide/formoterol SMART are approved for use only in adults, aged 18 years and over-100/6 mcg and 200/6 mcg per inhalation allowing for personalization, dependent on clinician advice and patient response.