Symbicort Turbuhaler Mechanism of Action

Pharmacotherapeutic group: Adrenergics and other drugs for obstructive airway diseases. ATC code: R03AK07.
Pharmacology: Pharmacodynamics: Mechanisms of action and pharmacodynamic effects: 80 mcg/4.5 mcg & 160 mcg/4.5 mcg: Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) contains formoterol and budesonide, which have different modes of action and show additive effects in terms of reduction of asthma exacerbations. The specific properties of budesonide and formoterol allow the combination to be used both as maintenance and reliever therapy, and as maintenance treatment of asthma.
320 mcg/9 mcg: Budesonide/Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) contains formoterol and budesonide, which have different modes of action and show additive effects in terms of reduction of asthma and COPD exacerbations. The respective mechanisms of action of both drugs are discussed as follows.
Budesonide: Budesonide is a glucocorticosteroid which when inhaled has a rapid (within hours) and dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer asthma exacerbations. Inhaled budesonide has less severe adverse effects than systemic corticosteroids. The exact mechanism responsible for the anti-inflammatory effect of glucocorticosteroids is unknown.
Formoterol: Formoterol is a selective beta₂-adrenergic agonist that when inhaled 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. The duration of effect is at least 12 hours after a single dose.
Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER): 80 mcg/4.5 mcg: Clinical Efficacy for Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) maintenance and reliever therapy in asthma.
A total of 12076 asthma patients were included in 5 double-blind clinical studies (4447 were randomised to Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) maintenance and reliever therapy) for 6 or 12 months. Patients were required to be symptomatic despite daily use of inhaled glucocorticosteroids. Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) maintenance and reliever therapy provided statistically significant and clinically meaningful reductions in severe exacerbations by prolonging time to first event and reducing the event rate (Table 1), as compared with all comparator treatments, including Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) at a higher maintenance dose (in Study 735). Symptom control, lung function and reliever use were similar compared with a higher maintenance dose of Budesonide + Formoterol fumarate dihydrate (SYMBICORT), and all three parameters were improved compared with Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) at the same maintenance dose or budesonide at a 2 to 4 times higher maintenance dose. (See Table 1.)

Click on icon to see table/diagram/image

In Study 735, Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) maintenance and reliever therapy significantly prolonged the time to the first exacerbation (see Figure 1) compared to the other treatment groups. The rate of exacerbations was reduced by 28% compared to twice the maintenance dose of Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) with terbutaline as reliever. Lung function, symptom control, and reliever use were similar in all treatment groups. (See Figures 1 and 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In Study 734, Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) maintenance and reliever therapy prolonged the time to the first exacerbation compared to Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) at the same maintenance dose with either formoterol or terbutaline as reliever (see Figure 2). The rate of exacerbations was reduced by 33% and 48%, respectively. Symptoms and reliever use were reduced and lung function improved, compared with both comparator treatments.
In Studies 673, 668 and 667, Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) maintenance and reliever therapy prolonged the time to the first exacerbation compared to Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) at the same maintenance dose with terbutaline as reliever and compared to a 2- to 4-fold higher maintenance dose of budesonide with terbutaline as reliever. Across the 3 studies, the rate of exacerbations was reduced by 45-76%. Symptoms and reliever use were reduced and lung function improved compared with all other treatments. For children (118 randomised to Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) maintenance and reliever therapy in study 673), the exacerbation rate was reduced by 70-79%.
In the 5 long-term studies, patients (adults and adolescents) receiving Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) maintenance and reliever therapy was allowed 12 inhalations per day (maintenance and as needed) without being reassessed. On average, no reliever inhalation was used on 57% of treatment days and 0-2 reliever inhalations on 87% of treatment days. There was no sign of development of tolerance over time.
In 2 studies with patients seeking medical attention due to acute asthma symptoms, Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) provided rapid and effective relief of bronchoconstriction similar to salbutamol and formoterol.
Clinical Efficacy in asthma for Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) maintenance therapy: Clinical studies have shown that the addition of formoterol to budesonide improved asthma symptoms and lung function, and reduced exacerbations. The effect on lung function of Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER), given as a maintenance dose only, was equal to that of budesonide and formoterol in separate inhalers in adults and exceeded that of budesonide alone in adults and children. All treatment arms used a short acting beta₂ -agonist as needed. There was no sign of attenuation of the anti-asthmatic effect over time.
160 mcg/4.5 mcg: Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER): Clinical Efficacy for Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) as an anti-inflammatory reliever: anti-inflammatory reliever therapy (therapy A) and anti-inflammatory reliever plus maintenance therapy (therapy B) in asthma (see Dosage & Administration): Overall, 20140 asthma patients were included in 7 double-blind clinical studies, of which 7831 were randomised to a therapy which included Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) as an anti-inflammatory reliever, both with a maintenance (therapy B) and without a maintenance dosing (therapy A).
A total of 8064 asthma patients with mild asthma were included in 2 double-blind efficacy and safety studies (SYGMA 1 and SYGMA 2 studies), of which 3384 patients were randomised to Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever therapy (therapy A) for 12 months. Patients were required to be uncontrolled on only short-acting inhaled bronchodilator as needed or controlled on a low dose of inhaled corticosteroids or LTRA (leukotriene receptor agonist) plus short-acting inhaled bronchodilator as needed.
In the SYGMA 2 study, Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) 160/4.5 micrograms used as needed in response to symptoms (anti-inflammatory reliever therapy - therapy A) was comparable to a maintenance dose of budesonide (1 inhalation of 200 micrograms/inhalation twice daily) given with as-needed short-acting β₂ agonist in terms of the rate of severe exacerbations (Table 2). Protection against severe exacerbation was achieved with a 75% reduction in median inhaled steroid load and without requiring adherence to maintenance inhaled corticosteroids treatment. The SYGMA 1 study showed that Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever therapy provided statistically significant and clinically meaningful reduction in the rate of annual severe exacerbation by 64% compared with as-needed use of a short-acting β₂ agonist (Table 2). Reduction in the annual rate of moderate to severe exacerbations was consistent (60%) with that observed for severe exacerbations ([RR] 0.40, 95% CI 0.32 to 0.49, p-value <0.001).
In the SYGMA 1 study, as-needed use of Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) 160/4.5 micrograms provided superior daily asthma symptom control compared to as-needed short-acting β₂ agonist (OR 1.14, 95% CI 1.00 to 1.30, p-value 0.046), showing a mean percentage of weeks with well-controlled asthma of 34.4% and 31.1%, respectively. Asthma symptom control was inferior for Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) as needed compared to a maintenance dose of budesonide (1 inhalation of 200 micrograms/inhalation twice daily) given with as-needed short-acting β₂ agonist (OR 0.64, 2-sided 95% CI 0.57 to 0.73, lower limit of the CI ≥0.8 for non-inferiority), showing a mean percentage of well-controlled asthma weeks of 34.4% and 44.4%, respectively. Improvements in asthma control (as defined by ACQ5) in patients using Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever therapy were superior to improvements in patients using a short-acting β₂ agonist as needed (-0.15, 95% CI -0.20 to -0.11, p-value <0.001). Improvements in asthma control were lower for Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) as needed compared to a maintenance dose of budesonide (1 inhalation of 200 micrograms/inhalation twice daily) given with a short-acting β₂ agonist to be used as needed (SYGMA 1: 0.15, 95% CI 0.10 to 0.20; SYGMA 2: 0.11, 95% CI 0.07 to 0.15, both p-value <0.001). For both comparisons, mean differences in treatments' effect upon ACQ5 are not clinically meaningful (as assessed by a difference of greater than or equal to 0.5). These results were observed in a clinical study setting with considerably higher adherence to budesonide maintenance dosing than expected in real life.
In the SYGMA studies, increases in lung function compared to baseline (mean pre-bronchodilator FEV1) were statistically significantly larger for patients on Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever therapy compared to patients on as-needed short-acting β₂ agonist treatment. Statistically significantly smaller increases were observed for Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) as needed compared to a maintenance dose of budesonide (1 inhalation of 200 micrograms/inhalation twice daily) given with a short-acting β₂ agonist to be used as needed. For both comparisons, mean differences in treatments' effect were small (approximately 30 to 55 mL, equating to approximately 2% of the baseline mean).
Overall, the results of the SYGMA studies show that Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever therapy is a more effective treatment than a short-acting β₂ agonist as needed in patients with mild asthma. In addition, these studies suggest that the as-needed use of Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) may be considered an alternative treatment option for patients with mild asthma who are eligible for inhaled corticosteroid treatment.
In a separate clinical programme, a total of 12076 asthma patients were included in 5 double-blind clinical studies (4447 were randomised to Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy - therapy B) for 6 or 12 months. Patients were required to be symptomatic despite daily use of inhaled glucocorticosteroids. Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy provided statistically significant and clinically meaningful reductions in severe exacerbations by prolonging time to first event and reducing the event rate (Table 2), as compared with all comparator treatments, including Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) at a higher maintenance dose (in Study 735). Symptom control, lung function and reliever use were similar compared with a higher maintenance dose of Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER), and all three parameters were improved compared with Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) at the same maintenance dose or budesonide at a 2 to 4 times higher maintenance dose. (See Table 2.)

Click on icon to see table/diagram/image

Analysis of time to first severe exacerbation in the SYGMA 1 study showed that the likelihood of experiencing a severe exacerbation was statistically significantly higher for the as-needed use of a short-acting β₂ agonist compared to the as-needed use of Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever therapy - therapy A) over the 1 year treatment period (see Figure 3), with a risk reduction of 56% ([HR] 0.44, 95% CI: 0.33-0.58, p-value <0.001). There were no differences in the probability of experiencing a severe exacerbation between Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever therapy (therapy A) and a therapy including a maintenance dose of budesonide (1 inhalation of 200 micrograms/inhalation twice daily) and a short-acting β₂ agonist used as needed (see Figures 3 and 4).

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In Study 735, Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy (therapy B) significantly prolonged the time to the first exacerbation (see Figure 5) compared to the other treatment groups. The rate of exacerbations was reduced by 28% compared to twice the maintenance dose of Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) with terbutaline as reliever. Lung function, symptom control, and reliever use were similar in all treatment groups. (See Figures 5 and 6.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In Study 734, Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy (therapy B) prolonged the time to the first exacerbation compared to Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) at the same maintenance dose with either formoterol or terbutaline as reliever (see Figure 6). The rate of exacerbations was reduced by 33% and 48%, respectively. Symptoms and reliever use were reduced and lung function improved, compared with both comparator treatments.
In Studies 673, 668 and 667, Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy (therapy B) prolonged the time to the first exacerbation compared to Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) at the same maintenance dose with terbutaline as reliever and compared to a 2- to 4-fold higher maintenance dose of budesonide with terbutaline as reliever. Across the 3 studies, the rate of exacerbations was reduced by 45-76%. Symptoms and reliever use were reduced and lung function improved compared with all other treatments. For children (118 randomised to Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy (therapy B) in study 673), the exacerbation rate was reduced by 70-79%.
In the 5 long-term studies, patients (adults and adolescents) receiving Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy (therapy B) was allowed 12 inhalations per day (maintenance and as needed) without being reassessed. On average, no reliever inhalation was used on 57% of treatment days and 0-2 reliever inhalations on 87% of treatment days. There was no sign of development of tolerance over time.
In 2 separate studies with patients seeking medical attention due to acute asthma symptoms, Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) provided rapid and effective relief of bronchoconstriction similar to salbutamol and formoterol.
Clinical Efficacy in asthma for Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) maintenance therapy (therapy C): Clinical studies have shown that the addition of formoterol to budesonide improved asthma symptoms and lung function, and reduced exacerbations. The effect on lung function of Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER), given as a maintenance dose only, was equal to that of budesonide and formoterol in separate inhalers in adults and exceeded that of budesonide alone in adults and children. All treatment arms used a short-acting β₂-agonist as needed. There was no sign of attenuation of the anti-asthmatic effect over time.
Clinical Efficacy in Chronic Obstructive Pulmonary disease COPD: In two 12-month studies in patients with COPD, Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) was superior to placebo, formoterol and budesonide regarding lung function and showed a significant reduction in the exacerbation rate compared with placebo and formoterol. Thus, the contribution of both budesonide and formoterol to the effect of Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) was demonstrated. Budesonide + Formoterol fumarate (SYMBICORT TURBUHALER) was also superior to placebo regarding symptoms and quality of life. The treatment was well tolerated.
320 mcg/9 mcg: Clinical Efficacy in asthma for Budesonide/Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) maintenance therapy: Clinical studies have shown that the addition of formoterol to budesonide improved asthma symptoms and lung function, and reduced exacerbations. The effect on lung function of Budesonide/Formoterol fumarate dihydrate (SYMBICORT TURBUHALER), given as a maintenance dose only, was equal to that of budesonide and formoterol in separate inhalers in adults and exceeded that of budesonide alone in adults and children. All treatment arms used a short acting beta₂-agonist as needed. There was no sign of attenuation of the anti-asthmatic effect over time.
Clinical Efficacy in Chronic Obstructive Pulmonary disease COPD: In two 12-month studies in patients with COPD, Budesonide/Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) was superior to placebo, formoterol and budesonide regarding lung function and showed a significant reduction in the exacerbation rate compared with placebo and formoterol. Thus, the contribution of both budesonide and formoterol to the effect of Budesonide/Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) was demonstrated. Budesonide/Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) was also superior to placebo regarding symptoms and quality of life. The treatment was well tolerated.
Pharmacokinetics: Absorption: Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) and the corresponding monoproducts (Budecort TURBUHALER and Oxis TURBUHALER, respectively) have been shown to be bioequivalent with regard to systemic exposure of budesonide and formoterol, respectively.
There was no evidence of pharmacokinetic interactions between budesonide and formoterol.
Pharmacokinetic parameters for the respective substances were comparable after the administration of budesonide and formoterol as monoproducts or as Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER).
Inhaled budesonide is rapidly absorbed and the maximum plasma concentration is reached within 30 minutes after inhalation.
In studies, mean lung deposition of budesonide after inhalation via Budecort Turbuhaler ranged from 32% to 44% of the delivered dose. The systemic bioavailability is approximately 49% of the delivered dose.
Inhaled formoterol is rapidly absorbed and the maximum plasma concentration is reached within 10 minutes after inhalation. In studies, the mean lung deposition of formoterol after inhalation via Oxis Turbuhaler ranged from 28% to 49% of the delivered dose. The systemic availability is about 61% of the delivered dose.
80 mcg/4.5 mcg & 160 mcg/4.5 mcg: In children, the plasma concentration and lung deposition fall in the same range as in adults.
Distribution and metabolism: Plasma protein binding is approximately 50% for formoterol and 90% for budesonide. Volume of distribution is about 4 L/kg for formoterol and 3 L/kg for budesonide. Formoterol is inactivated via conjugation reactions (active O-demethylated and deformylated metabolites are formed, but they are seen mainly as inactivated conjugates). Budesonide undergoes an extensive degree (approximately 90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxy-budesonide and 16α-hydroxy-prednisolone, is less than 1% of that of budesonide. There are no indications of any metabolic interactions or any displacement reactions between formoterol and budesonide.
Elimination: The major part of a dose of formoterol is eliminated by metabolism in the liver followed by renal excretion. After inhalation, 8% to 13% of the delivered dose of formoterol is excreted unmetabolised in the urine. Formoterol has a high systemic clearance (approximately 1.4 L/min) and the terminal elimination half-life averages 17 hours.
Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites of budesonide are excreted in urine as such or in conjugated form. Only negligible amounts of unchanged budesonide have been detected in the urine. Budesonide has a high systemic clearance (approximately 1.2 L/min) and the plasma elimination half-life after IV dosing averages 4 hours.
Budesonide has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance, which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. The pharmacokinetics of formoterol in children has not been studied.
The pharmacokinetics of budesonide and formoterol in elderly and patients with renal failure is unknown. The exposure of budesonide and formoterol may be increased in patients with liver disease.
Toxicology: Preclinical safety data: The toxicity observed in animal studies with budesonide and formoterol was similar whether budesonide or formoterol were given in combination or separately. The effects were associated with pharmacological actions and dose dependent.
In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant in humans at the recommended doses (see Use in Pregnancy & Lactation). Animal reproduction studies with formoterol have shown a somewhat reduced fertility in male rats at high systemic exposure and implantation losses as well as decreased early postnatal survival and birth weight at considerably higher systemic exposures than those reached during clinical use. However, these animal experimental results do not seem to be relevant to man.