Budesonide/Formoterol

The use of combination budesonide/formoterol dry powder inhaler (Symbicort® Turbuhaler®) for both daily maintenance therapy and as-needed relief of breakthrough symptoms using a single inhaler is a new approach to asthma management that is indicated in patients with persistent asthma not adequately controlled by conventional regimens using reliever therapy with a short-acting β₂-adrenoceptor agonist alone. The administration of additional corticosteroid with each reliever inhalation in response to symptoms is expected to provide improved control of airway inflammation.

Budesonide/formoterol maintenance and reliever therapy reduced the risk of severe asthma exacerbations compared with conventional regimens using a short-acting β₂-adrenoceptor agonist alone as reliever therapy in the majority of trials, while providing similar or better daily asthma control than higher fixed maintenance doses of budesonide or inhaled corticosteroid/long-acting β₂-adrenoceptor agonist combination therapy in patients with generally moderate to severe, uncontrolled, persistent asthma. The strategy offers the convenience of a single inhaler and simplifies treatment by providing immediate additional anti-inflammatory medication in response to asthma symptoms and immediate step-down when symptoms abate. The improved efficacy, with respect to exacerbation prevention, observed with budesonide/formoterol maintenance and reliever therapy in all double-blind comparative trials was achieved with a lower mean daily dose of inhaled corticosteroid or with fewer daily inhalations of reliever medication. Budesonide/formoterol maintenance and reliever therapy was well tolerated with an incidence of adverse events similar to that with conventional regimens. Therefore, it offers a new approach to therapy in patients with uncontrolled, persistent asthma; providing improved efficacy with a lower overall drug load.

The fixed combination budesonide/formoterol Turbuhaler® delivers the same amounts of budesonide and formoterol per inhalation (80μg/4.5μg or 160μg/ 4.5μg) as the corresponding single-agent inhalers at the same nominal dose. There do not appear to be any pharmacokinetic interactions between budesonide and formoterol when administered in combination.

Budesonide is a corticosteroid with high affinity for the glucocorticoid receptor and a high ratio of topical to systemic activity. It displays anti-inflammatory activity ≈1000-fold greater than cortisol. It dose-dependently protects against bronchial hyperresponsiveness to a variety of agents, attenuates the early and late asthmatic responses to inhaled allergen and reduces other signs of airway inflammation. Budesonide is moderately lipophilic and forms reversible conjugates with intracellular fatty acids, which prolongs its retention within the airways. A mean of 27–44% of the dose delivered by Turbuhaler® is deposited in the lungs. The mean systemic bioavailability of inhaled budesonide was calculated to be 38% of the metered dose. Budesonide is rapidly absorbed after inhalation, undergoes extensive metabolism in the liver, mainly by cytochrome P450 3A4, and is eliminated, almost exclusively as metabolites, in the urine with an elimination half-life (t1/2β) of 2–4 hours. p ]Formoterol is a potent, long-acting, selective β₂-adrenoceptor agonist that displays full agonist activity. It has a rapid onset of bronchodilator action (1–3 minutes) that is maintained for ≥12 hours. The mean lung deposition of formoterol after administration by Turbuhaler® is 28–49% of the delivered dose. The systemic bioavailability of inhaled formoterol is ≈61% of the delivered dose. It is extensively metabolised in the liver and eliminated in the urine with a t1/2β of ≈17 hours. Only 8–13% of the delivered dose is eliminated in the urine as unchanged drug.

Inhaled budesonide/formoterol maintenance (160μg/9μg or 320μg/9μg daily) and reliever therapy was superior to maintenance therapy with a 2- to 4-fold higher dosage of budesonide (320μg or 640μg daily) plus terbutaline reliever with respect to the primary endpoints of time to first severe exacerbation or change from baseline in morning peak expiratory flow in three randomised, double-blind trials of 6–12 months’ duration. The risk of experiencing a severe exacerbation was reduced by 39–54% with budesonide/formoterol maintenance and reliever therapy compared with the conventional therapy in these trials.

Budesonide/formoterol maintenance (160μg/9μg or 320μg/9μg daily) and reliever therapy was likewise superior to the same dosage of budesonide/ formoterol maintenance therapy combined with terbutaline or formoterol single-agent reliever therapy for the primary endpoint of time to first severe exacerbation in two randomised, double-blind, 12-month trials. Budesonide/formoterol maintenance and reliever therapy reduced the risk of a severe exacerbation by 45% compared with terbutaline reliever in both trials and by 27% compared with formoterol reliever in one trial.

In a randomised, double-blind, 6-month trial, budesonide/formoterol maintenance (320μg/9μg daily) and reliever therapy was shown to be superior to a 2-fold higher dosage of budesonide/formoterol (640μg/18μg daily) maintenance therapy combined with terbutaline reliever according to the primary endpoint of time to first severe exacerbation, reducing the risk of a severe exacerbation by 26%.

Budesonide/formoterol maintenance (320μg/9μg daily) and reliever therapy also significantly prolonged the time to first severe exacerbation compared with salmeterol/fluticasone propionate 50μg/250μg twice daily maintenance therapy plus terbutaline reliever in the aforementioned trial; budesonide/formoterol maintenance and reliever therapy reduced the risk of a severe exacerbation by 33% compared with salmeterol/fluticasone propionate. However, in another 6-month, randomised, double-blind trial, budesonide/formoterol maintenance (640μg/18μg daily) and reliever therapy displayed similar efficacy to high-dosage salmeterol/ fluticasone propionate 50μg/500μg twice daily maintenance plus terbutaline reliever for the primary endpoint of time to first severe exacerbation.

In a nonblind study in which the maintenance therapy dosages were titrated throughout treatment, budesonide/formoterol maintenance and reliever therapy was superior to salmeterol/fluticasone propionate maintenance plus salbutamol (albuterol) reliever with respect to time to first severe exacerbation and was associated with a 25% lower risk of a severe exacerbation.

In all studies, including two nonblind, real-life comparisons with conventional regimens, budesonide/formoterol maintenance and reliever therapy was consistently associated with either a reduction in daily inhaled corticosteroid dose (descriptive statistics only in some studies) or a significant reduction in the mean number of reliever inhalations per day during treatment, or both. It was also associated with greater improvements in measures of daily asthma control and lung function, and less use of oral corticosteroids than conventional regimens in most double-blind trials.

In each of four cost-effectiveness analyses using clinical and resource utilisation data from one of three randomised, controlled trials and costs from a variety of countries, budesonide/formoterol maintenance and reliever therapy was consistently dominant (greater efficacy at lower cost) over both salmeterol/fluticasone propionate maintenance therapy plus salbutamol or terbutaline reliever and budesonide/formoterol maintenance plus terbutaline reliever from the societal perspective (direct plus indirect costs). When only direct healthcare costs were considered, budesonide/formoterol maintenance and reliever therapy was either dominant over the alternative treatments or delivered the increased efficacy at a relatively small incremental cost.

Budesonide/formoterol maintenance and reliever therapy was well tolerated in randomised, controlled clinical trials. The incidence, type and severity of adverse events were similar to those with the comparator conventional regimens. The most common adverse events were respiratory tract infection, pharyngitis, rhinitis, bronchitis, sinusitis and headache. The incidences of the pharmacologically predictable adverse events of tremor, palpitations, tachycardia, candidiasis, dysphonia and hoarseness were low (≤2%). The incidence of serious adverse events considered related to treatment was ≤0.3%, while treatment discontinuations as a result of asthma were generally numerically lower with budesonide/formoterol maintenance and reliever therapy than with the comparator conventional regimens.