Pharmacotherapeutic group: Adrenergics and other drugs for obstructive airway diseases.
ATC code: R03AK07.
Pharmacology: Pharmacodynamics: Mechanisms of action and pharmacodynamic effects: Symbicort contains budesonide and formoterol, which have different modes of action and show additive effects in terms of reduction of asthma; and COPD exacerbations (Rapihaler). The specific properties of budesonide and formoterol allow the combination to be used both as reliever therapy and as maintenance therapy. The mechanisms of action of the two substances, respectively 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 β
2-adrenergic agonist that when inhaled results in a 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 after inhalation. The duration of effect is at least 12 hours after a single dose.
Turbuhaler: Clinical Efficacy for Symbicort 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 Symbicort 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 Symbicort 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 antagonist) plus short-acting inhaled bronchodilator as needed.
In the SYGMA 2 study, 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 β
2 agonist in terms of the rate of severe exacerbations (Table 1). Protection against severe exacerbation was achieved with a 75% reduction in median inhaled steroid load. The SYGMA 1 study showed that Symbicort 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 β
2 agonist (Table 1). 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 Symbicort Turbuhaler 160/4.5 micrograms provided superior daily asthma symptom control compared to as-needed short-acting β
2 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 Symbicort as needed compared to a maintenance dose of budesonide (1 inhalation of 200 micrograms/inhalation twice daily) given with as needed short-acting β
2 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 Symbicort anti-inflammatory reliever therapy were superior to improvements in patients using a short-acting β
2 agonist as needed (-0.15, 95% CI -0.20 to -0.11, p-value < 0.001). Improvements in asthma control were lower for Symbicort as needed compared to a maintenance dose of budesonide (1 inhalation of 200 micrograms/inhalation twice daily) given with a short-acting β
2 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 FEV
1) were statistically significantly larger for patients on Symbicort anti-inflammatory reliever therapy compared to patients on as-needed short-acting β
2 agonist treatment. Statistically significantly smaller increases were observed for Symbicort as needed compared to a maintenance dose of budesonide (1 inhalation of 200 micrograms/inhalation twice daily) given with a short-acting β
2 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 Symbicort anti-inflammatory reliever therapy is a more effective treatment than a short-acting β
2 agonist as needed in patients with mild asthma. In addition, these studies suggest that the as-needed use of Symbicort 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 efficacy and safety studies (4447 were randomised to Symbicort anti-inflammatory reliever plus maintenance therapy - therapy B) for 6 or 12 months. Patients were required to be symptomatic despite use of inhaled glucocorticosteroids.
Symbicort anti-inflammatory reliever plus maintenance therapy provided statistically significant and clinically meaningful reductions in severe exacerbations for all comparisons in all 5 studies. This included a comparison with Symbicort at a higher maintenance dose with terbutaline as reliever (study 735) and Symbicort at the same maintenance dose with either formoterol or terbutaline as reliever (study 734) (Table 1). In Study 735, lung function, symptom control, and reliever use were similar in all treatment groups. In Study 734, symptoms and reliever use were reduced and lung function improved, compared with both comparator treatments. In the 5 studies combined, patients receiving Symbicort anti-inflammatory reliever plus maintenance therapy used, on average, no reliever inhalations on 57% of treatment days. There was no sign of development of tolerance over time. (See Table 1.)
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 β
2 agonist compared to the as-needed use of Symbicort (Symbicort anti-inflammatory reliever therapy - therapy A) over the 1 year treatment period (see Figure 1), 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 Symbicort 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 β
2 agonist used as needed (see Figures 1 and 2).
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
In Study 735, Symbicort anti-inflammatory reliever plus maintenance therapy (therapy B) significantly prolonged the time to the first severe exacerbation (see Figure 3) compared to the other treatment groups. The rate of severe exacerbations was reduced by 28% compared to twice the maintenance dose of Symbicort with terbutaline as reliever. Lung function, symptom control, and reliever use were similar in all treatment groups. (See Figures 3 and 4.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
In Study 734, Symbicort anti-inflammatory reliever plus maintenance therapy (therapy B) prolonged the time to the first severe exacerbation compared to Symbicort at the same maintenance dose with either formoterol or terbutaline as reliever (see Figure 4). The rate of severe exacerbations was reduced by 33% and 48%, respectively. Symptoms and reliever use were reduced and lung function improved, compared with both comparator treatments.
In 2 other studies with patients seeking medical attention due to acute asthma symptoms, Symbicort provided rapid and effective relief of bronchoconstriction similar to salbutamol and formoterol.
Clinical Efficacy in asthma for Symbicort maintenance therapy (therapy C): Clinical studies with Symbicort Turbuhaler in adults, have shown that the addition of formoterol to budesonide improved asthma symptoms and lung function, and reduced exacerbations. In two 12-week studies, the effect on lung function of Symbicort was equal to that of the free combination of budesonide and formoterol, and exceeded that of budesonide alone. All treatment arms used a short-acting β
2 agonist as needed. There was no sign of attenuation of the anti-asthmatic effect over time.
In a 12-week paediatric study, 85 children aged 6-11 years were treated with a maintenance dose of Symbicort (2 inhalations of 80/4.5 micrograms/inhalation twice daily), and a short-acting β
2 agonist as needed. Lung function was improved and the treatment was well tolerated compared to the corresponding dose of budesonide Turbuhaler.
Clinical Efficacy in Chronic Obstructive Pulmonary Disease (COPD): In two 12-month studies, the effect on lung function and the rate of exacerbation (defined as courses of oral steroids and/or course of antibiotics and/or hospitalisations) in patients with moderate to severe COPD was evaluated. The inclusion criteria for both studies was pre-bronchodilator FEV
1 <50% predicted normal. Median post-bronchodilator FEV
1 at inclusion in the trials was 42% predicted normal. The mean number of exacerbations per year (as defined previously) was significantly reduced with Symbicort as compared with treatment with formoterol alone or placebo (mean rate 1.4 compared with 1.8-1.9 in the placebo/formoterol group). The mean number of days on oral corticosteroids/patient during the 12 months was slightly reduced in the Symbicort group (7-8 days/patient/year compared with 11-12 and 9-12 days in the placebo and formoterol groups, respectively). For changes in lung-function parameters, such as FEV
1, Symbicort was not superior to treatment with formoterol alone.
Rapihaler: Clinical efficacy in asthma: Therapeutic equivalence between Symbicort Rapihaler and Symbicort Turbuhaler was demonstrated in three clinical efficacy and safety studies, including asthmatic patients from 6 to 79 years of age and one long-term safety study in adolescents and adults with asthma. The safety profile of Symbicort Rapihaler has been shown to be as safe and well tolerated as Symbicort Turbuhaler. As a result of demonstrating therapeutic equivalence, the clinical efficacy for Symbicort Rapihaler in asthma described as follows is based on studies conducted with Symbicort Turbuhaler.
It has been shown in a separate study that Symbicort Rapihaler can be used safely with a named spacer device in children.
Clinical efficacy in Chronic Obstructive Pulmonary Disease (COPD): In one 12-month study and one 6-month study in patients with COPD, Symbicort Rapihaler 160/4.5 was superior to placebo, budesonide and formoterol for post-dose FEV1 and predose FEV1. In the 12-month study, Symbicort Rapihaler was also superior to placebo and formoterol for both the number of, and the time to first severe COPD exacerbation (a worsening of COPD requiring oral steroid use of hospitalization.) Thus, the contribution of both budesonide and formoterol to the effect of Symbicort Rapihaler was demonstrated. Symbicort Rapihaler 160/4.5 also significantly reduced breathlessness, daily rescue medication use, night-time awakenings and improved health-related quality of life compared with placebo in both studies. Serial FEV1 measures over 12 hours were obtained in subsets of patients in both studies. The median time to onset of bronchodilation (>15% improvement in FEV1) was seen within 5 minutes at the end of treatment in patients receiving Symbicort Rapihaler 160/4.5. Maximal improvement in FEV1 occurred at approximately 2 hours post-dose and post-dose bronchodilator effect was generally maintained over 12 hours. The treatment was well tolerated.
Pharmacokinetics: Absorption: Turbuhaler: Symbicort Turbuhaler and the corresponding monoproducts have been shown to be bioequivalent with regard to systemic exposure of budesonide and formoterol, respectively. In spite of this, a small increase in cortisol suppression was seen after administration of Symbicort compared to the monoproducts. The difference is considered not to have an impact on clinical safety.
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 Symbicort Turbuhaler. For budesonide, AUC was slightly higher, rate of absorption more rapid and maximal plasma concentration higher after administration of the fixed combination. For formoterol, maximal plasma concentration was similar after administration of the fixed combination. 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 Turbuhaler ranged from 32% to 44% of the delivered dose. The systemic bioavailability is approximately 49% of the delivered dose. In children aged 6-16 years, lung deposition fall in the same range as in adults for the same given dose, the resulting plasma concentrations were not determined.
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 Turbuhaler ranged from 28% to 49% of the delivered dose. The systemic bioavailability is about 61% of the delivered dose.
The systemic bioavailability of budesonide and formoterol was comparable for the two treatments Symbicort Rapihaler and Symbicort Turbuhaler.
Rapihaler: There was no evidence of pharmacokinetic interactions between budesonide and formoterol when given together.
In studies where Symbicort Rapihaler was administered to healthy subjects and patients with moderate asthma, peak plasma concentrations for budesonide occurred approximately 30 minutes and for formoterol 10 minutes after dosing. Peak plasma concentrations were 30-40% higher in healthy subjects compared to asthma patients. However, the total systemic exposure was comparable to that in asthma patients.
In repeat dose studies plasma concentrations of budesonide and formoterol generally increased in proportion to dose.
Collectively, in pharmacokinetic studies conducted in adults with asthma, systemic exposure to budesonide and formoterol administered via Symbicort Rapihaler was lower than when given via the monoproducts Pulmicort Turbuhaler and Oxis Turbuhaler. Collectively, the pharmacokinetic data from clinical efficacy and safety studies indicate that Symbicort Rapihaler delivers a comparable amount of budesonide to the systemic circulation, and thus the lung, as do budesonide pMDI and Pulmicort Turbuhaler. The results of the systemic exposure for formoterol were generally similar when administered via Symbicort Rapihaler and Oxis Turbuhaler.
Distribution and Biotransformation: 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, 6 β-hydroxy-budesonide and 16-α-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 transformed by liver metabolism followed by renal elimination. After inhalation of formoterol via Turbuhaler, 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 eliminated 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 i.v. dosing averages 4 hours.
Turbuhaler: The pharmacokinetics of budesonide or formoterol in children and in patients with renal failure is unknown. The exposure of budesonide and formoterol may be increased in patients with liver disease.
Rapihaler: 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 or formoterol in elderly and in patients with renal failure is unknown. The exposure of budesonide and formoterol may be increased in patients with liver disease.
Toxicology: Preclinical safety data: In animal reproduction studies, glucocorticosteroids 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.
Turbuhaler: The toxicity observed in animal studies with budesonide and formoterol, given in combination or separately, were effects associated with exaggerated pharmacological activity.
Rapihaler: 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.
Symbicort Rapihaler contains the excipients povidone (polyvinylpyrrolidone) K25, macrogol (polyethylene glycol) 1000 and the pressurised liquid propellant apaflurane (HFA 227). The safe use of apaflurane has been fully evaluated in preclinical studies. Povidones have a history of safe use in man for many years, which supports the view that povidones are essentially biologically inert. Macrogols are recognized as safe excipients in pharmaceuticals, food and cosmetic products. Furthermore, toxicity studies carried out using Symbicort Rapihaler have shown no evidence of any local or systemic toxicity or irritation attributable to the excipients.