Symbicort Mechanism of Action

Pharmacotherapuetic group: Adrenergics and other drugs for obstructive airway diseases. ATC-code: R03AK07.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Turbuhaler: SYMBICORT 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 (80/4.5 mcg/dose) or anti-inflammatory reliever plus maintenance therapy (160/4.5 mcg/dose), and as maintenance treatment of asthma.
Rapihaler: Symbicort contains formoterol and budesonide, which have different modes of action and show additive effects in terms of reduction of asthma; and COPD exacerbations (160/4.5 mcg/dose). The specific properties of budesonide and formoterol allow the combination to be used as maintenance treatment of asthma.
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.
Turbuhaler: SYMBICORT Turbuhaler: Asthma: Clinical efficacy in asthma for SYMBICORT maintenance therapy: Clinical studies 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 beta₂-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 beta₂-agonist as needed. Lung function was improved and the treatment was well tolerated compared to the corresponding dose of budesonide Turbuhaler.
Clinical efficacy for SYMBICORT maintenance and reliever therapy in asthma: A total of 12076 asthma patients were included in 5 double-blind clinical studies (4447 were randomised to SYMBICORT maintenance and reliever therapy) for 6 or 12 months. Patients were required to be symptomatic despite daily use of inhaled glucocorticosteroids. SYMBICORT 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 SYMBICORT at a higher maintenance dose (in Study 735). Symptom control, lung function and reliever use were similar compared with a higher maintenance dose of SYMBICORT, and all three parameters were improved compared with SYMBICORT at the same maintenance dose or budesonide at a 2 to 4 times higher maintenance dose. (See Table 1.)


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In Study 735, SYMBICORT 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 SYMBICORT with terbutaline as reliever. Lung function, symptom control, and reliever use were similar in all treatment groups. (See Figure 1.)


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In Study 734, SYMBICORT maintenance and reliever therapy (Turbuhaler 80/4.5 mcg/dose) or anti-inflammatory reliever plus maintenance therapy (Turbuhaler 160/4.5 mcg/dose) prolonged the time to the first exacerbation compared to Symbicort at the same maintenance dose with either formoterol or terbutaline as reliever (see Figure 1). The rate of exacerbation 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, SYMBICORT maintenance and reliever therapy (Turbuhaler 80/4.5 mcg/dose) or anti-inflammatory reliever plus maintenance therapy (Turbuhaler 160/4.5 mcg/dose) prolonged the time to the first exacerbation compared to Symbicort 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 randomized to SYMBICORT maintenance and reliever therapy in study 673), the exacerbation rate was reduced by 70-79%.
In the 5 long-term studies, patients receiving SYMBICORT maintenance and reliever therapy used, on average, no reliever inhalations 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, SYMBICORT provided rapid and effective relief of bronchoconstriction similar to salbutamol and formoterol.
Turbuhaler 160/4.5 mcg/dose: Clinical efficacy in asthma for SYMBICORT anti-inflammatory reliever therapy (patients with Mild Disease): 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 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, Symbicort 160/4.5 micrograms used as needed in response to symptoms (anti-inflammatory reliever therapy) 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 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 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 Symbicort 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 Symbicort 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 Symbicort 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 Symbicort 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 Symbicort anti-inflammatory reliever therapy compared to patients on as-needed short-acting β₂ 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 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 Symbicort 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 Symbicort may be considered an alternative treatment option for patients with mild asthma who are eligible for inhaled corticosteroid treatment. (See Table 2.)


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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 Symbicort (Symbicort anti-inflammatory reliever therapy) over the 1 year treatment period (see Figure 2), 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 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 Figure 2 and Figure 3).


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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 severe COPD was evaluated. Median FEV1 at inclusion in the trials was 36% of 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 FEV1, SYMBICORT was not superior to treatment with formoterol alone.
Rapihaler: Clinical Trial: Asthma: Therapeutic equivalence between Symbicort Rapihaler and Symbicort Turbuhaler was demonstrated in three clinical efficacy and safety studies in adults and adolescents with asthma. They included two randomised, double-blind, active controlled, parallel-group studies, Studies 681 (12 weeks duration) and 003 (6 weeks duration); and one randomised, open-label, parallel group, long-term (12 months) study, Study 715.
No clinical studies have been conducted to directly compare the efficacy and safety of Symbicort Rapihaler 80/2.25 with Symbicort Turbuhaler 160/4.5.
In Study 681, Symbicort Rapihaler 160/4.5 (2 inhalations twice daily) was compared with the corresponding dose of budesonide pressurised metered dose inhaler (pMDI) (200 μg; 2 inhalations twice daily), or Symbicort Turbuhaler (160/4.5; 2 inhalations twice daily) in adults and adolescents (≥12 years) with moderate to severe asthma [eg mean forced expiratory volume during the first second (FEV₁) ≥50% and ≤90% of predicted normal (PN) and FEV₁ reversibility ≥12%]. Symbicort Rapihaler was shown to significantly improve morning peak expiratory flow rate (primary efficacy variable), other lung function parameters, symptom scores and use of rescue medication compared to budesonide and was equivalent to Symbicort Turbuhaler (see Table 3).


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Study 003 was a 6-week study with similar design to Study 681. In this study, Symbicort Rapihaler 40/2.25 (2 inhalations twice daily) was compared primarily (as regular therapy) with the corresponding dose of budesonide Turbuhaler 100 μg (1 inhalation twice daily), or and secondarily with Symbicort Turbuhaler 80/4.5 (1 inhalation twice daily) in adults and adolescents (≥12 years) with asthma (mean FEV₁ 74% PN and FEV₁ reversibility 24%). The primary efficacy variable was the change in morning peak expiratory flow (mPEF) from baseline (mean of the 10 last days of the run-in period) to the treatment period (mean of the 6-week treatment period). The primary objective was to demonstrate that Symbicort Rapihaler 40/2.25 was more efficacious than budesonide Turbuhaler 100 μg. The adjusted mean mPEF increased by 12.2 L/min with Symbicort Rapihaler 40/2.25, 4.15 L/min with budesonide Turbuhaler, and 13.1 L/min with Symbicort Turbuhaler 80/4.5. The results showed that the mean change from baseline in mPEF was greater with Symbicort Rapihaler 40/2.25 than with budesonide Turbuhaler, and that the mean difference was statistically significant (mean difference of 8.07 L/min [95% CI: 3.26 to 12.9], p=0.001). The secondary objective was to demonstrate therapeutic equivalence of Symbicort Rapihaler 40/2.25 and Symbicort Turbuhaler 80/4.5. The results supported equivalence of the two Symbicort formulations as regular treatment in both the ITT and per-protocol analyses. There was no statistically significant difference between the two Symbicort formulations for any outcome variable in this study.
Study 715 investigated primarily the safety of Symbicort Rapihaler 160/4.5 (2 inhalations twice daily) during 12 months. The reference treatment was the corresponding dose of Symbicort Turbuhaler 160/4.5 and in a population consisting of adults and adolescents (≥12 years) with moderate to severe asthma (eg mean FEV₁ of ≥50% of PN and FEV₁ reversibility ≥12%). The study was of an open-label design.
There was no statistically significant difference between Symbicort Rapihaler and Symbicort Turbuhaler regarding FEV₁ and FVC (forced vital capacity). The percentage of patients experiencing one or more severe asthma exacerbations did not differ between the two Symbicort groups: 11% in the Symbicort Rapihaler group and 13% in the Symbicort Turbuhaler group. The maximum number of severe exacerbations per patient was 6 in the Symbicort Rapihaler group and 4 in the Symbicort Turbuhaler group. There was no statistical significant difference in time to first severe asthma exacerbation between the two treatment groups.
Rapihaler 160/4.5 mcg/dose: Clinical Trial in COPD: The efficacy and safety of Symbicort in the treatment of patients with moderate to severe COPD (pre-bronchodilator FEV₁ ≥50% predicted normal) has been evaluated in four randomised, double-blind, placebo and active controlled, parallel-group, multi-centre clinical studies. Two 12-month studies were performed with the dry powder inhaler Symbicort Turbuhaler (studies 629 and 670), and one 12-month and one 6-month study were performed with the pressurised metered dose inhaler (pMDI) Symbicort Rapihaler (studies 001 and 002, respectively).
Studies 629 and 670: In both studies, Symbicort Turbuhaler 160/4.5 was compared with placebo and the corresponding mono-products (budesonide Turbuhaler 200 μg and eformoterol Turbuhaler 6 μg), all taken as two inhalations twice daily. A total of 812 and 1022 patients with moderate to severe COPD were randomised, of which 208 and 254 were treated with Symbicort Turbuhaler. Patients in both studies had a mean age of 64 years and FEV₁ of 0.99 L or 36% of predicted normal at baseline.
Studies 001 and 002: The study plans were similar. Both studies used Symbicort Rapihaler.
For Study 001, after a screening visit (visit 1), subjects entered a two weeks run-in period after which they were randomly assigned (visit 2) to one of the four following treatments: 1. Symbicort Rapihaler 160/4.5, fixed combination of 200 μg budesonide and 6 μg eformoterol per actuation, administered as 2 actuations twice daily; 2. Symbicort Rapihaler 80/4.5, fixed combination of 100 μg budesonide and 6 μg eformoterol per actuation, administered as 2 actuations twice daily; 3. Eformoterol Turbuhaler, 6 μg per inhalation, administered as 2 actuations twice daily; 4. Placebo.
Study 002 had two additional treatment groups: 5. Budesonide pMDI 200 μg per actuation, administered as 2 actuations twice daily; 6. Free combination of budesonide pMDI 200 μg per actuation plus eformoterol Turbuhaler 6 μg per actuation, administered as 2 actuations of each twice daily.
A total of 1964 (Study 001) and 1704 (Study 002) patients with moderate to severe COPD were randomised, of which 494 and 277 were treated with Symbicort Rapihaler 160/4.5. The study populations had a mean age of 63 years and mean FEV₁ of 1.04-1.05 L or 34% of predicted normal at baseline.
Study 629: In Study 629, efficacy was evaluated over 12 months using the co-primary endpoints of post-dose FEV₁ and number of severe COPD exacerbations (defined as intake of a course of oral steroids and/or antibiotics and/or hospitalisation due to respiratory symptoms): Symbicort Turbuhaler significantly improved mean FEV₁ compared with placebo and budesonide by 15% (p<0.001) and 9% (p<0.001) respectively.
Symbicort Turbuhaler significantly reduced the number of severe exacerbations compared with placebo and eformoterol by 24% (p=0.035) and 23% (p=0.043) respectively. The number needed to treat (NNT) to prevent one severe COPD exacerbation in a year for Symbicort Turbuhaler compared with eformoterol was 2.4.
Study 670: In Study 670, efficacy was evaluated over 12 months using the co-primary endpoints of post dose-FEV₁ and time to first severe COPD exacerbation (defined as intake of a course of oral steroids and/or antibiotics and/or hospitalisation due to respiratory symptoms): Symbicort Turbuhaler significantly improved mean FEV₁ compared with placebo, budesonide and eformoterol by 14% (p<0.001), 11% (p<0.001), and 5% (p=0.002) respectively.
Symbicort Turbuhaler significantly prolonged the time to first severe COPD exacerbation compared to all comparator treatments. The instantaneous risk of experiencing a severe COPD exacerbation compared to placebo, budesonide and eformoterol was reduced by 29% (p=0.006), 23% (p=0.033), and 30% (p=0.003) respectively.
Symbicort Turbuhaler also significantly reduced the number of severe COPD exacerbations compared to placebo and eformoterol by 24% (p=0.029) and 26% (p=0.015) respectively. The NNT to prevent one COPD exacerbation in a year compared to eformoterol was 2.1.
Study 001: In Study 001, efficacy was evaluated over 12 months using the co-primary efficacy variables of change from baseline in average pre-dose and 1-hour post-dose FEV₁ over the treatment period.
Primary endpoints: Symbicort Rapihaler 80/4.5 produced a significantly greater change in post-dose FEV₁ compared to placebo (LS mean = 0.16 L; p<0.001); however the change in pre-dose FEV₁ was not significantly different to eformoterol 6 μg (LS mean = 0.02 L; p=0.161).
Symbicort Rapihaler 160/4.5 significantly improved 1-hour pre-dose FEV₁ compared with eformoterol and placebo by 0.04 L (p=0.008) and 0.09 L (p<0.001) respectively.
Symbicort Rapihaler 160/4.5 significantly improved post-dose FEV₁ over the treatment period compared with eformoterol and placebo by 0.03 L (p=0.023) and 0.18 L (p<0.001) respectively.
Serial FEV₁ measures over 12 hours were obtained in a subset of patients (N=491). The median time to onset of bronchodilation (>15% improvement in FEV₁) was seen within 5 minutes at the end of treatment time point in patients receiving Symbicort Rapihaler 160/4.5 (N=121). Maximum improvement in FEV₁ occurred at approximately 2 hours post-dose and post-dose bronchodilator effect was maintained over 12 hours.
Exacerbations (secondary variable): Symbicort Rapihaler reduced the number of severe COPD exacerbations (defined as a worsening of COPD requiring oral steroid use and/or hospitalisation) to a statistically significant degree. Overall 34.1% of subjects experienced 1159 exacerbations: Symbicort Rapihaler 160/4.5, 30.8%; Symbicort Rapihaler 80/4.5, 32.6%; placebo 37.2%. The majority of exacerbations were treated with oral glucocorticosteroids: Symbicort Rapihaler 160/4.5, 96.5% of exacerbations; Symbicort Rapihaler 80/4.5, 94.1%; placebo 97.4%. Treatment comparisons were by means of rate ratios (RR) estimates, CIs and p-values derived from a Poisson regression adjusted for treatment, country and differential treatment exposure. Symbicort Rapihaler 160/4.5 demonstrated a statistically significant reduction of 37% (p<0.001) and 25% (p=0.004) in the rate of exacerbations per subject-treatment year compared with placebo and eformoterol respectively. Symbicort Rapihaler 80/4.5 reduced the exacerbation rate by 41% compared with placebo (p<0.001).
Symbicort Rapihaler 160/4.5 significantly prolonged the time to first severe COPD exacerbation compared to placebo, reducing the instantaneous risk of experiencing a severe COPD exacerbation by 26% (p=0.009). The number needed to treat (NNT) to prevent one severe COPD exacerbation in a year for Symbicort Rapihaler compared with eformoterol was 5.4.
Study 002: In Study 002, efficacy was evaluated over 6 months using the co-primary efficacy variables of change from baseline in average pre-dose and 1-hour post-dose FEV₁ over the treatment period: Symbicort Rapihaler 80/4.5: Post-dose FEV₁ increased significantly from baseline to the average of the treatment period (LS mean [95%CI] = 0.19 [0.17, 0.22]). Symbicort Rapihaler 80/4.5 caused a significantly greater change from baseline compared to budesonide (LS mean = 0.16; p<0.001). Pre-dose FEV₁ increased significantly from baseline to the average of the treatment period, LS mean = 0.06 [0.03, 0.08]. However, the change from baseline, compared to eformoterol, for pre-dose FEV₁ was not statistically significant, LS mean = 0.02 [-0.02, 0.05; p=0.335].
Symbicort Rapihaler 160/4.5 significantly improved pre-dose FEV₁ compared with eformoterol by 0.04 L (p=0.026) and compared with placebo and budesonide by 0.08 L (p<0.001) for both comparators.
Symbicort Rapihaler 160/4.5 significantly improved 1-hour post-dose FEV₁ compared with eformoterol by 0.04 L (p=0.039) and compared with placebo and budesonide by 0.17 L (p<0.001) for both comparators.
Study 002 was not powered for showing effect on severe COPD exacerbations.
Serial FEV₁ measures over 12 hours were obtained in subsets of patients (n=618). 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 (N=101). Maximal improvement in FEV₁ occurred at approximately 2 hours post-dose and post-dose bronchodilator effect was generally maintained over 12 hours.
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 falls in the same range as in adults for the same given dose, the resulting plasma concentrations were not determined (turbuhaler 80/4.5 mcg/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 Turbuhaler ranged from 28% to 49% of the delivered dose. The systemic bioavailability is about 61% of the delivered dose.
Rapihaler: Symbicort 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.
Symbicort Turbuhaler: The systemic bioavailability of budesonide and formoterol was comparable for the two treatments Symbicort Rapihaler and Symbicort Turbuhaler.
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, 6-beta-hydroxy-budesonide and 16-alfa-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, 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.
The pharmacokinetics of formoterol in children have not been studied (Turbuhaler 80/4.5 mcg/dose).
The pharmacokinetics of budesonide or formoterol in patients with renal failure are 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.
Toxicology: Preclinical safety data: 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 exposure than those reached during clinical use. However, these animal experimental results do not seem to be relevant in humans.
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.