Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for obstructive airway diseases: Adrenergics, Inhalants.
ATC-code: R03AK07
Mechanisms of action and Pharmacodynamic effects
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 either as maintenance and reliever therapy, or as maintenance treatment of asthma.

Budesonide
Budesonide is a glucocorticosteroid which when inhaled has a 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 β2 adrenoceptor 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.

Clinical efficacy and safety
Asthma
Symbicort anti-inflammatory reliever therapy
A total of 8064 patients aged 12 and above with mild asthma were included in 2 double-blind efficacy and safety studies (SYGMA 1 and SYGMA 2), 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 β2 agonist (SABA) as needed or controlled on low dose ICS or leukotriene receptor agonist plus SABA as needed.
Both studies compared Symbicort anti-inflammatory reliever therapy (Symbicort Turbuhaler 200/6 used as needed in response to symptoms) to budesonide Turbuhaler 200 μg (1 inhalation twice daily) given with as needed SABA. SYGMA 1 also compared Symbicort anti-inflammatory reliever therapy to as needed SABA alone.
In SYGMA 1 and SYGMA 2, respectively, based on physician assessment before enrolment, 44.5% and 46.3% of patients were uncontrolled on SABA as needed, and 55.5% and 53.7% of patients were controlled on low dose ICS or leukotriene receptor antagonists plus SABA as needed. At baseline, patients in SYGMA 1 and SYGMA 2, respectively, had a median age of 40 and 41 years (overall range across both studies 12 to 85 years), 12.5% and 9.8% of patients were adolescents (≥12 to <18 years) and approximately 7% and 9% of patients were over 65 years of age, 87.0% and 84.3% had never smoked, 10.3% and 13.1% were former smokers, 2.7% and 2.6% were current smokers, and 19.7% and 22.0% of patients had experienced a severe exacerbation within the 12 months prior to study enrolment.
In SYGMA 2, Symbicort anti-inflammatory reliever therapy was comparable to a maintenance dose of budesonide Turbuhaler given with as-needed SABA in terms of the rate of severe exacerbations (Table 2). Protection against severe exacerbation was achieved with a 75% reduction in median ICS load and without requiring adherence to maintenance ICS treatment. SYGMA 1 showed that Symbicort anti-inflammatory reliever therapy provided a statistically significant and clinically meaningful reduction in the rate of annual severe exacerbations by 64% compared with SABA as- needed alone (Table 2). Reduction in the annual rate of moderate to severe exacerbations was consistent (60%) with that observed for severe exacerbations (Risk Ratio (RR): 0.40 (95% Confidence Interval (CI): 0.32, 0.49); p<0.001).
In SYGMA 1, Symbicort anti-inflammatory reliever therapy provided superior daily asthma symptom control compared to as-needed SABA alone (Odds Ratio (OR): 1.14 (1.00 to 1.30); p=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 anti-inflammatory reliever therapy compared to a maintenance dose of budesonide Turbuhaler given with as-needed SABA (OR: 0.64 (2-sided 95% CI 0.57, 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 Asthma Control Questionnaire (ACQ-5)) in patients using Symbicort anti-inflammatory reliever therapy were superior to improvements in patients using as needed SABA alone (estimate for difference: -0.15 (-0.20, -0.11); p<0.001). In accordance with the pre-specified hierarchical testing strategy, apart from well-controlled asthma weeks, all other efficacy results from this study were considered of nominal statistical significance. Improvements in asthma control were lower for Symbicort anti-inflammatory reliever therapy compared to a maintenance dose of budesonide Turbuhaler given with SABA as needed (SYGMA 1 estimate for difference: 0.15 (0.10, 0.20); SYGMA 2: 0.11 (0.07, 0.15); both p < 0.001). For both comparisons, mean differences in treatments’ effect upon ACQ-5 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 SABA alone. Statistically significantly smaller increases were observed for Symbicort anti-inflammatory reliever therapy compared to a maintenance dose of budesonide Turbuhaler given with SABA 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 SABA as needed in patients with mild asthma. In addition, these studies suggest that Symbicort anti-inflammatory reliever therapy may be considered an alternative treatment option for patients with mild asthma who are eligible for ICS treatment.

Table 2 Overview of severe exacerbations in SYGMA 1 and 2 Study

Study               Treatment groups a                  N              Severe exacerbations b Number of            Exacerbations events              / patient-year
SYGMA 1          Symbicort Turbuhaler 200/6             1277             77                     0.07 as needed
Terbutaline Turbuhaler 0.4             1277               188                    0.20c mg as needed
Budesonide Turbuhaler 200              1282                89                    0.09d μg twice daily + terbutaline
Turbuhaler 0.4 mg as needed
SYGMA 2          Symbicort Turbuhaler 200/6             2084               217                    0.11 as needed
Budesonide Turbuhaler 200              2083               221                    0.12e μg twice daily + terbutaline
Turbuhaler 0.4 mg as needed
 a Budesonide Turbuhaler 200 μg (metered dose; Pulmicort Turbuhaler); Terbutaline Turbuhaler 0.4 mg (delivered dose; M3 version).
b Defined as hospitalisation/emergency room treatment or treatment with oral steroids due to asthma.
c Reduction in exacerbation rate is statistically significant (p<0.001) for the comparison of Symbicort Turbuhaler as needed vs terbutaline 0.4 mg as needed.
d Reduction in exacerbation rate is not statistically significantly different (p=0.279) when comparing Symbicort Turbuhaler as needed vs budesonide 200 μg twice daily + terbutaline 0.4 mg as needed in SYGMA 1.
e Symbicort Turbuhaler as needed was non-inferior to budesonide 200 μg twice daily + terbutaline 0.4 mg as needed in reducing the severe exacerbation rate in SYGMA 2. The upper limit (1.16) of the 95% CI for the rate ratio was below the pre-specified non-inferiority limit (1.20).


Analysis of time to first severe exacerbation in SYGMA 1 showed that the likelihood of experiencing a severe exacerbation was statistically significantly higher for SABA as needed use compared to Symbicort anti-inflammatory reliever therapy over the 1 year treatment period, with a risk reduction of 56% (Hazard Ratio (HR): 0.44 (0.33, 0.58); p<0.001). There were no differences in the probability of experiencing a severe exacerbation between Symbicort anti-inflammatory reliever therapy and a maintenance dose of budesonide given with SABA as needed.

Symbicort anti-inflammatory reliever therapy (SYGMA 1 and 2)
Overall, Symbicort anti-inflammatory reliever therapy is generally well tolerated, based on the frequency and nature of adverse effects. No new safety concerns were identified for the use of Symbicort Turbuhaler 160.4.5 as needed in a mild asthma population.

Clinical efficacy for budesonide/formoterol 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 budesonide/formoterol 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.

Two 12-week paediatric studies, have been performed in which 265 children aged 6-11 years were treated with a maintenance dose of budesonide/formoterol (2 inhalations of 80 micrograms/4.5 micrograms/inhalation twice daily), and a short-acting β2 adrenoceptor-agonist as needed. In both studies, Lung function was improved, and the treatment was well tolerated compared to the corresponding dose of budesonide Turbuhaler alone.

Clinical efficacy for budesonide/formoterol maintenance and reliever therapy A total of 12076 asthma patients were included in 5 double-blind efficacy and safety studies (4447 were randomised to budesonide/formoterol maintenance and reliever therapy) for 6 or 12 months.
Patients were required to be symptomatic despite use of inhaled glucocorticosteroids.
Budesonide/formoterol maintenance and reliever therapy provided statistically significant and clinically meaningful reductions in severe exacerbations for all comparisons in all 5 studies. This included a comparison with budesonide/formoterol at a higher maintenance dose with terbutaline as reliever (study 735) and budesonide/formoterol at the same maintenance dose with either formoterol or terbutaline as reliever (study 734) (Table 3). 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 budesonide/formoterol maintenance and reliever therapy used, on average, no reliever inhalations on 57% of treatment days. There was no sign of development of tolerance over time.

Table 3          Overview of severe exacerbations in clinical
Study No.       Treatment groups                      N       Severe exacerbationsa Duration
Events             Events/ Patient year
Study 735       Budesonide/formoterol 160/4.5         1103 125                0.23b 6 months        μg bd + as needed
Budesonide/formoterol 320/9 μg        1099 173                0.32 bd + terbutaline 0.4 mg as needed
Salmeterol/fluticasone 2 x 25/125     1119 208                0.38
μg bd + terbutaline 0.4 mg as needed
Study           Budesonide/formoterol 160/4.5         1107 194                0.19 b 734 12          μg bd + as needed months          Budesonide/formoterol 160/4.5 μg      1137 296                0.29 bd + formoterol 4.5 μg as needed
Budesonide/formoterol 160/4.5 μg      1138 377                0.37 bd + terbutaline 0.4 mg as needed
 a
Hospitalisation/emergency room treatment or treatment with oral steroids b
Reduction in exacerbation rate is statistically significant (P value <0.01) for both comparisons.

Comparable efficacy and safety in adolescents and adults was demonstrated in 6 double-blind studies, comprising the 5 studies mentioned above and an additional study using a higher maintenance dose of 160/4.5 micrograms, two inhalations twice daily. These assessments were based on a total of 14385 asthma patients of whom 1847 were adolescents. The number of adolescent patients taking more than 8 inhalations on at least one day as part of budesonide/formoterol maintenance and reliever therapy was limited, and such use was infrequent.

In 2 other studies with patients seeking medical attention due to acute asthma symptoms, budesonide/formoterol provided rapid and effective relief of bronchoconstriction similar to salbutamol and formoterol.

Exercise-induced and allergen-induced bronchoconstriction
The use of Symbicort Turbuhaler 160/4.5 in relation to exercise-induced and allergen-induced bronchoconstriction has been studied in three clinical trials for patients with mild / intermittent asthma.
Study D5890L00032 was a 6-week, 3-arm study in 66 adults and adolescents with mild asthma and episodic exercise-induced bronchoconstriction, in which the primary variable was change in maximum decrease in post-exercise FEV1 calculated before and after 6 weeks of treatment. This study demonstrated that Symbicort Turbuhaler 160/4.5, taken as 1 inhalation before exercise plus additional inhalations as needed in response to symptoms, improved asthma control by reducing exercise-induced bronchoconstriction to the same order of magnitude as regular maintenance treatment with budesonide 400 μg plus terbutaline 0.5 mg as needed, despite a substantially lower steroid dose. Both treatments were superior to terbutaline as needed when taken alone.

Study AF-039-0001 was a 6-month, 2-arm study in 92 adult and adolescents with mild intermittent asthma who used SABA for symptom relief, in which the primary variable of efficacy was the change in level of fractional exhaled nitric oxide (FENO) in the two treatment groups over the duration of the study. This study demonstrated that the budesonide component in Symbicort Turbuhaler 160/4.5taken before exercise and as needed, reduced airway inflammation and improved airway function, and showed the beneficial effect of the budesonide component when taken as needed together with formoterol (for symptom relief) as Symbicort Turbuhaler 160/4.5.
Study D5890L00007 was a 3-arm, placebo-controlled, cross-over study in 15 adult patients with mild allergic asthma, in which the primary efficacy variable was change in PD20 (the provocative dose causing a 20% fall in FEV1) methacholine (MCh) during each treatment period. This study showed that when administered 30 minutes after a low-dose allergen challenge, Symbicort Turbuhaler 160/4.5 abolished allergen-induced components of asthma deterioration whilst improving baseline pulmonary function, whereas, formoterol 6 ug alone inhibited the rise in symptoms but did not protect against allergen-induced airway inflammation. This study indicated that deteriorating asthma, provoked by low-dose allergen, is managed more effectively with Symbicort Turbuhaler 160/4.5 than with formoterol.

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 FEVI<50% predicted normal. Median post-bronchodilator FEVI at inclusion in the trials was 42% predicted normal.
The mean number of exacerbations per year (as defined above) was significantly reduced with budesonide/formoterol 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 budesonide/formoterol 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, budesonide/formoterol was not superior to treatment with formoterol alone.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
The fixed-dose combination of budesonide and formoterol, 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 the fixed-dose combination 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 the fixed-dose combination. 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 powder inhaler ranged from 32% to 44% of the delivered dose. The systemic bioavailability is approximately 49% of the delivered dose. In children 6-16 years of age the lung deposition falls 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 powder inhaler ranged from 28-49% of the delivered dose. The systemic bioavailability is about 61% of the delivered dose.
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-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%-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 budesonide or formoterol in patients with renal failure is unknown. The exposure of budesonide and formoterol may be increased in patients with liver disease.

Linearity/non-linearity
Systemic exposure for both budesonide and formoterol correlates in a linear fashion to administered dose.