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Budesonide: Budesonide is a non-halogenated glucocorticosteroid structurally related to 16α hydroxyprednisolone with a high local anti-inflammatory effect. Budesonide has shown antianaphylactic and anti-inflammatory effects in provocation studies in animals and humans, manifested as decreased bronchial obstruction in the immediate as well as the late phase of an allergic reaction. Budesonide has also been shown to decrease airway reactivity to both direct (histamine, methacholine) and indirect (exercise) challenge in hyperreactive patients. Budesonide, when inhaled, has a rapid (within hours) and dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer 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 potent selective β2-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.
Clinical trials: 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 160/4.5 μg/dose used as needed in response to symptoms) to budesonide Turbuhaler 160 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 1). 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 1). 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. (See Table 1.)
Click on icon to see table/diagram/imageAnalysis 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 plus maintenance therapy: The safety and efficacy of Symbicort in the Symbicort anti-inflammatory reliever plus maintenance therapy regimen have been investigated in six clinical trials using two dose strengths (80/4.5 μg/dose and 160/4.5 μg/dose) of Symbicort Turbuhaler in patients with asthma. A total of 14219 patients (1134 elderly, 11144 adults, 1595 adolescents and 345 children) were randomised into the studies, of which 5514 were treated with Symbicort anti-inflammatory reliever plus maintenance therapy. Of the overall patient population 7% were smokers. In comparison with the usual patient proportions seen in practice, smokers and the elderly were under-represented in the trials. However, the results for these subgroups were generally consistent with the results for the whole study population. Patients with COPD were excluded.
The studies showed that Symbicort anti-inflammatory reliever plus maintenance therapy was significantly superior compared with fixed dose combination products or higher doses of ICS with a separate short acting or long acting β-agonist used as reliever (see Table 2 and Table 3). In the 5 double-blind long-term studies, patients receiving Symbicort anti-inflammatory reliever plus maintenance therapy used no reliever inhalations on 57% of treatment days and 0-2 reliever inhalations on 87% of treatment days. (See Tables 2 and 3.)
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Click on icon to see table/diagram/imageStudy 734 (SMILE): A 12-month randomised, double-blind, parallel-group, trial in 3394 adult and adolescent patients aged 12 to 89 years with moderate to severe asthma. The study comprised of the following three arms: 1) Symbicort anti-inflammatory reliever plus maintenance therapy - Symbicort Turbuhaler 160/4.5 μg/dose, 1 inhalation twice daily plus additional inhalations as needed; 2) Symbicort Turbuhaler 160/4.5 μg/dose, 1 inhalation twice daily with formoterol Turbuhaler as needed; 3) Symbicort Turbuhaler 160/4.5 μg/dose, 1 inhalation twice daily with terbutaline Turbuhaler as needed.
The primary efficacy variable, time to first severe exacerbation, was significantly increased with Symbicort anti-inflammatory reliever plus maintenance therapy compared with Symbicort plus formoterol and Symbicort plus terbutaline (see Table 2).
Use of oral steroids due to exacerbations was lower in the Symbicort anti-inflammatory reliever plus maintenance therapy group (1204 days total vs 2063 and 2755 days in the Symbicort plus formoterol and Symbicort plus terbutaline groups, respectively).
The majority of secondary variables supported the superiority of Symbicort anti-inflammatory reliever plus maintenance therapy over both comparators (see Table 4). The average daily as-needed use in the Symbicort anti-inflammatory reliever plus maintenance therapy group was 1.02 inhalations/day and the frequency of high as-needed use was lower for Symbicort anti-inflammatory reliever plus maintenance therapy compared to both comparators. (See Table 4.)
Click on icon to see table/diagram/imageThe study specifically demonstrates that both the budesonide and the formoterol components of Symbicort contribute to improved asthma control achieved through the as-needed dosing of Symbicort within the Symbicort anti-inflammatory reliever plus maintenance therapy concept.
Study 735 (COMPASS): A 6-month randomised, double-blind, parallel-group trial in 3335 adult and adolescent patients aged 11 to 83 years. The study compared the following three arms: 1) Symbicort anti-inflammatory reliever plus maintenance therapy - Symbicort Turbuhaler 160/4.5 μg/dose, 1 inhalation twice daily plus additional inhalation as needed; 2) Seretide Inhaler 125/25, 2 inhalations twice daily with terbutaline Turbuhaler as needed; 3) Symbicort Turbuhaler 320/9 μg/dose, 1 inhalation twice daily with terbutaline Turbuhaler as needed.
The primary efficacy variable, time to first severe exacerbation, was significantly increased with Symbicort anti-inflammatory reliever plus maintenance therapy compared with both Seretide plus terbutaline and Symbicort at a higher maintenance dose plus terbutaline (see Table 2).
Use of oral steroids due to exacerbations was lower in the Symbicort anti-inflammatory reliever plus maintenance therapy group compared to Seretide plus terbutaline and Symbicort plus terbutaline (619 days total use vs. 1132 and 1044 days, respectively).
Results for secondary variables, including lung function, mean use of as-needed medication and symptom variables, were not significantly different between Symbicort anti-inflammatory reliever plus maintenance therapy and the other two groups. The average daily as-needed use in the Symbicort anti-inflammatory reliever plus maintenance therapy group was 1.02 inhalations/day.
Since the mean daily dose in the Symbicort anti-inflammatory reliever plus maintenance therapy group remained lower than in the Symbicort plus terbutaline group, the study specifically confirms the benefit of as-needed administration of part of the Symbicort dose.
Study 673 (STAY), Study 668 (STEP) and Study 667 (STEAM): In Studies 673, 668 and 667, Symbicort anti-inflammatory reliever plus maintenance therapy 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 (see Table 2). Symptoms and reliever use were reduced and lung function improved compared with all other treatments (see Table 5, Table 6 and Table 7).
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Click on icon to see table/diagram/imageStudy 691 (COSMOS): A 12-month, randomised, open, parallel group trial that compared the effectiveness of Symbicort anti-inflammatory reliever plus maintenance therapy with Seretide plus Ventolin in steroid-treated adult and adolescent patients (N=2143) aged 12 to 84 years with asthma. Randomised treatment started with a 4-week period during which the maintenance doses were fixed, followed by 11 months where the maintenance dose was adjusted to the lowest dose required for symptom control (see Table 8).
Click on icon to see table/diagram/imageThis study showed that Symbicort anti-inflammatory reliever plus maintenance therapy treatment is more effective than adjustable therapy with Seretide plus Ventolin in controlling asthma in adults and adolescents. Symbicort anti-inflammatory reliever plus maintenance therapy increased the time to first severe asthma exacerbations, reduced the total number of severe asthma exacerbations (see Table 2 and Table 3), reduced use of oral steroids for severe asthma exacerbations, and reduced use of as needed medications as compared with Seretide at a similar daily ICS dose.
Safety in the combined studies: Symbicort anti-inflammatory reliever plus maintenance therapy treatment has a safety profile that is similar to budesonide and Symbicort maintenance therapy with a decrease in asthma-related adverse events.
Symbicort maintenance therapy: The efficacy and safety of Symbicort Turbuhaler for maintenance therapy has been evaluated in seven randomised, double-blind, double-dummy, active controlled, parallel group studies. All treatment arms in these studies used a SABA for relief of symptoms. Six studies were conducted for 12 weeks (80/4.5 μg/dose and 160/4.5 μg/dose presentations) while the 320/9 μg/dose presentation study was conducted for 24 weeks (12 weeks efficacy and additional 12 weeks safety). Efficacy and safety data were collected for 3340 mild to moderate/severe asthmatic patients (2411 adults, 128 adolescents, 801 children aged 4 to 11 years old); 1704 were treated with Symbicort Turbuhaler.
Symbicort Turbuhaler 160/4.5 μg/dose: In one study, the maximum recommended maintenance dose of Symbicort Turbuhaler 160/4.5 μg/dose (2 inhalations twice daily) was compared to corresponding doses of the free combination (budesonide Turbuhaler 200 μg + formoterol Turbuhaler 6 μg, two inhalations twice daily) and budesonide Turbuhaler 200 μg (2 inhalations twice daily) only in adults with moderate asthma (mean FEV1 73.8% predicted normal and reversibility 22.5%). Table 9 details the efficacy results after 12 weeks treatment. (See Table 9.)
Click on icon to see table/diagram/imageWhen administered twice daily, Symbicort Turbuhaler 160/4.5 μg/dose is a more effective treatment than budesonide, at corresponding budesonide doses.
In a study in adults with milder asthma (mean FEV1 81.7% predicted normal and reversibility 22.2%) Symbicort Turbuhaler 80/4.5 μg/dose (1 inhalation twice daily) was compared with budesonide Turbuhaler 200μg (1 inhalation twice daily). Table 10 details the efficacy results after 12 weeks treatment. (See Table 10.)
Click on icon to see table/diagram/imageIn conclusion, there was a greater improvement in lung function and asthma control with Symbicort Turbuhaler 80/4.5 μg/dose than with a doubled dose of budesonide.
Symbicort Turbuhaler 320/9 μg/dose: In a study in predominantly adult patients (<3% of patients were adolescents) with moderate to severe asthma (mean FEV1 66% predicted normal and reversibility 28%) Symbicort Turbuhaler 320/9 μg/dose (2 inhalations twice daily) was compared to corresponding doses of the free combination (formoterol Turbuhaler 12 μg + budesonide Turbuhaler 400 μg, two inhalations twice daily) and budesonide Turbuhaler 400 μg (2 inhalations twice daily) only. Table 11 details the efficacy results after 12 weeks treatment. (See Table 11.)
Click on icon to see table/diagram/imageWhen administered twice daily, Symbicort Turbuhaler 320/9 μg/dose is a more effective treatment for the majority of clinical endpoints than the corresponding budesonide dose.
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 μg/dose was compared with placebo and the corresponding mono-products (budesonide Turbuhaler 200 μg and formoterol Turbuhaler 6 μg), all taken as 2 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 200/6, fixed combination of 200 μg budesonide and 6 μg formoterol per actuation, administered as 2 actuations twice daily; 2. Symbicort Rapihaler 100/6, fixed combination of 100 μg budesonide and 6 μg formoterol per actuation, administered as 2 actuations twice daily; 3. Formoterol 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 formoterol 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 200/6. 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 formoterol 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 formoterol 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 formoterol 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 formoterol 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 formoterol by 24% (p=0.029) and 26% (p=0.015), respectively. The NNT to prevent one COPD exacerbation in a year compared to formoterol 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 100/6 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 formoterol 6 μg (LS mean = 0.02 L; p=0.161).
Symbicort Rapihaler 200/6 significantly improved 1-hour pre-dose FEV1 compared with formoterol and placebo by 0.04 L (p=0.008) and 0.09 L (p<0.001), respectively.
Symbicort Rapihaler 200/6 significantly improved post-dose FEV1 over the treatment period compared with formoterol 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 200/6 (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 200/6, 30.8%; Symbicort Rapihaler 100/6, 32.6%; placebo 37.2%. The majority of exacerbations were treated with oral glucocorticosteroids: Symbicort Rapihaler 200/6, 96.5% of exacerbations; Symbicort Rapihaler 100/6, 94.1%; placebo 97.4%. Treatment comparisons were by means of rate ratios estimates, CIs and p-values derived from a Poisson regression adjusted for treatment, country and differential treatment exposure. Symbicort Rapihaler 200/6 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 formoterol, respectively. Symbicort Rapihaler 100/6 reduced the exacerbation rate by 41% compared with placebo (p<0.001).
Symbicort Rapihaler 200/6 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 NNT to prevent one severe COPD exacerbation in a year for Symbicort Rapihaler compared with formoterol 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 100/6: 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 100/6 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 formoterol, for pre-dose FEV1 was not statistically significant (LS mean = 0.02 (-0.02, 0.05; p=0.335)).
Symbicort Rapihaler 200/6 significantly improved pre-dose FEV1 compared with formoterol 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 200/6 significantly improved 1-hour post-dose FEV1 compared with formoterol 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 200/6 (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: Symbicort Turbuhaler and the corresponding monoproducts (budesonide Turbuhaler and formoterol Turbuhaler (M2 version) as per Section 2 Qualitative and quantitative composition) 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 Symbicort Turbuhaler.
Absorption: After inhalation of budesonide via Turbuhaler the mean lung deposition ranged from 26 to 34% of the metered dose. The systemic bioavailability of budesonide inhaled via Turbuhaler is approximately 40% of the metered dose.
In studies the mean lung deposition of formoterol after inhalation via Turbuhaler ranged from 21-37% of the metered dose. The total systemic bioavailability for the higher lung deposition is approximately 46%.
Distribution: Plasma protein binding of budesonide is approximately 90% with a volume of distribution of approximately 3 L/kg.
Plasma protein binding of formoterol is approximately 50% with a volume of distribution of approximately 4 L/kg.
Metabolism: Budesonide undergoes an extensive degree (approx. 90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity.
Formoterol is metabolised by conjugation to inactive glucuronides. Active O-demethylated and deformylated metabolites are formed, however plasma levels of these are low.
Excretion: Elimination of budesonide is via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites are excreted in urine as such or in conjugated form with only negligible amounts of unchanged budesonide being 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.
Elimination of formoterol is via metabolism in the liver followed by renal excretion. After inhalation of formoterol via a Turbuhaler 6-10% of the metered dose is excreted unmetabolised in the urine. Formoterol has a terminal elimination half-life of approximately 17 hours.
Special patient populations - elderly, hepatic and/or renal impairment: The pharmacokinetics of budesonide or formoterol in elderly and in patients with renal failure is unknown. The systemic availability of budesonide and formoterol may be increased in patients with liver disease.
Toxicology: Preclinical Safety Data: Genotoxicity: Individually, budesonide and formoterol were not genotoxic in a series of assays for gene mutations (except for a slight increase in reverse mutation frequency in Salmonella typhimurium at high concentrations of formoterol fumarate), chromosomal damage and DNA repair. The combination of budesonide and formoterol has not been tested in genotoxicity assays.
Carcinogenicity: The carcinogenic potential of the budesonide/formoterol combination has not been investigated in animal studies.
In formoterol carcinogenicity studies performed by AstraZeneca, there was a dose dependent increase in the incidence of uterine leiomyomas in mice dosed orally at 0.1, 0.5 and 2.5 mg/kg/day for two years, and a mesovarian leiomyoma was observed in a female rat dosed by inhalation at 0.13 mg/kg/day for two years. The effects observed are expected findings with high dose exposure to β2-agonists.
Formoterol carcinogenicity studies performed by other companies used systemic exposure levels 800 to 4800-fold higher than those expected upon clinical use of formoterol (based on an 18 μg daily dose).
Some carcinogenicity activity was observed in rats and mice. However, in view of the dose levels at which these effects were observed and the fact that formoterol is not mutagenic (except for very weak activity at high concentrations in one test system), it is concluded that the cancer risk in patients treated with formoterol fumarate is no greater than for other beta-adrenoceptor agonists.
The carcinogenic potential of budesonide has been evaluated in the mouse and rat at oral doses up to 200 and 50 μg/kg/day, respectively. In male rats dosed with 10, 25 and 50 μg budesonide/kg/day, those receiving 25 and 50 μg/kg/day showed an increased incidence of primary hepatocellular tumours. In a repeat study this effect was observed in a number of steroid groups (budesonide, prednisolone, triamcinolone acetonide) thus indicating a class effect of corticosteroids.
