Symbicort Turbuhaler

Budesonide, formoterol.

Each delivered dose (the dose that leaves the mouthpiece) contains: budesonide 80, 160, or 320 micrograms/inhalation and formoterol fumarate dihydrate 4.5, 4.5, or 9 micrograms/inhalation, respectively.
80/4.5 mcg: Each metered dose contains: budesonide 100 micrograms/inhalation and formoterol fumarate dihydrate 6 micrograms/inhalation.
Excipient with known effect: Lactose monohydrate 810 micrograms per delivered dose.
160/4.5 mcg: Excipient with known effect: Lactose monohydrate.
320/9 mcg: Each metered dose contains: budesonide 400 micrograms/inhalation and formoterol fumarate dihydrate 12 micrograms/inhalation.
Excipient with known effect: Lactose monohydrate 491 micrograms per delivered dose.
Excipients/Inactive Ingredients: Lactose monohydrate (which contains milk proteins).

Pharmacology: Pharmacodynamics: Mechanism of action: Symbicort Turbuhaler 160/4.5 μg/dose contains budesonide and formoterol, which have different modes of action and show additive effects in terms of reduction of asthma and COPD exacerbations. The specific properties of budesonide and formoterol allow the combination to be used either as an anti-inflammatory reliever or as maintenance treatment for asthma, and for symptomatic treatment of patients with moderate to severe COPD.
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.)

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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 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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Study 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.)

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The 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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Study 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).

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This 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.)

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When 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.)

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In 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.)

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When 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.

Asthma: 80/4.5 mcg: Symbicort Turbuhaler 80/4.5 μg/dose is indicated in adults, adolescents, and children aged 6 years and older.
Symbicort Turbuhaler 80/4.5 μg/dose is indicated in the regular treatment of asthma where use of a combination (inhaled corticosteroid and long-acting β₂ adrenoceptor agonist) is appropriate: patients not adequately controlled with inhaled corticosteroids and "as needed" inhaled short-acting β₂ adrenoceptor agonists; or patients already adequately controlled on both inhaled corticosteroids and long-acting β₂ adrenoceptor agonists.
Note: Symbicort (80 micrograms/4.5 micrograms/inhalation) is not appropriate in patients with severe asthma.
160/4.5 mcg: Symbicort Turbuhaler is indicated in adults and adolescents (12 years and older), for the treatment of asthma, to achieve overall asthma control, including the relief of symptoms and the reduction of the risk of exacerbations (see Dosage & Administration).
320/9 mcg: Symbicort Turbuhaler 320/9 μg/dose is indicated in adults, and adolescents aged 12-17 years, for the regular treatment of asthma where use of a combination (inhaled corticosteroid and long-acting β₂ adrenoceptor agonist) is appropriate: patients not adequately controlled with inhaled corticosteroids and "as needed" inhaled short-acting β₂ adrenoceptor agonists; or patients already adequately controlled on both inhaled corticosteroids and long-acting β₂ adrenoceptor agonists.
Chronic Obstructive Pulmonary Disease (COPD): 160/4.5 mcg: Symbicort is indicated for the symptomatic treatment of moderate to severe COPD (FEV₁ ≤50% predicted normal) in adults with frequent symptoms despite long-acting bronchodilator use, and/or a history of recurrent exacerbations. Symbicort is not indicated for the initiation of bronchodilator therapy in COPD.
320/9 mcg: Symbicort Turbuhaler 320/9 μg/dose is indicated in adults, aged 18 years and older, for the symptomatic treatment of patients with COPD with forced expiratory volume in 1 second (FEV₁) <70% predicted normal (post-bronchodilator) and an exacerbation history despite regular bronchodilator therapy (see also Precautions).

Route of administration: For inhalation use.
General Information: If patients take Symbicort Turbuhaler as an anti-inflammatory reliever (either alone or in combination with maintenance therapy) physicians should discuss allergen exposure and exercise patterns with the patients and take these into consideration when recommending the dose frequency for asthma treatment.
If patients take Symbicort Turbuhaler as a maintenance therapy, they should be instructed that Symbicort Turbuhaler must be used even when asymptomatic for optimal benefit.
Special patient populations: Renal impairment: There are no data available for use of Symbicort Turbuhaler in patients with renal impairment.
Hepatic impairment: There are no data available for use of Symbicort Turbuhaler in patients with hepatic impairment. As budesonide and formoterol are primarily eliminated via hepatic metabolism an increased systemic availability can be expected in patients with severe liver disease.
Use in the elderly: There are no special dosing requirements for elderly patients.
Use in paediatric patients: Symbicort Turbuhaler is not recommended for children below 12 years of age.
Posology: Asthma: 80/4.5 mcg: Symbicort Turbuhaler 80/4.5 μg/dose is not intended for the initial management of asthma.
The dosage of the components of Symbicort Turbuhaler 80/4.5 μg/dose is individual and should be adjusted to the severity of the disease. This should be considered not only when treatment with combination products is initiated but also when the maintenance dose is adjusted. If an individual patient should require a combination of doses other than those available in the combination inhaler, appropriate doses of β₂ adrenoceptor agonists and/or corticosteroids by individual inhalers should be prescribed.
The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Patients should be regularly reassessed by their prescriber/health care provider so that the dosage of Symbicort Turbuhaler 80/4.5 μg/dose remains optimal. When long-term control of symptoms is maintained with the lowest recommended dosage, then the next step could include a test of inhaled corticosteroid alone.
For Symbicort Turbuhaler 80/4.5 μg/dose there are two treatment approaches: A. Symbicort maintenance therapy: Symbicort Turbuhaler 80/4.5 μg/dose is taken as regular maintenance treatment with a separate rapid-acting bronchodilator as rescue; B. Symbicort maintenance and reliever therapy: Symbicort Turbuhaler 80/4.5 μg/dose is taken as regular maintenance treatment and as needed in response to symptoms.
A. Symbicort maintenance therapy: Patients should be advised to have their separate rapid-acting bronchodilator available for rescue use at all times.
Recommended doses: Adults (18 years and older): 1-2 inhalations twice daily. Some patients may require up to a maximum of 4 inhalations twice daily.
Adolescents (12-17 years): 1-2 inhalations twice daily.
Children (6 years and older): 2 inhalations twice daily.
In usual practice when control of symptoms is achieved with the twice daily regimen, titration to the lowest effective dose could include Symbicort Turbuhaler 80/4.5 μg/dose given once daily, when in the opinion of the prescriber, a long-acting bronchodilator in combination with an inhaled corticosteroid would be required to maintain control.
Increasing use of a separate rapid acting bronchodilator indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy.
Children under 6 years: As only limited data are available, Symbicort Turbuhaler 80/4.5 μg/dose is not recommended for children younger than 6 years.
B. Symbicort maintenance and reliever therapy: Patients take a daily maintenance dose of Symbicort Turbuhaler 80/4.5 μg/dose and in addition take Symbicort Turbuhaler 80/4.5 μg/dose as needed in response to symptoms. Patients should be advised to always have Symbicort Turbuhaler 80/4.5 μg/dose available for rescue use.
Symbicort maintenance and reliever therapy should especially be considered for patients with: inadequate asthma control and in frequent need of reliever medication; asthma exacerbations in the past requiring medical intervention.
Close monitoring for dose-related adverse effects is needed in patients who frequently take high numbers of Symbicort Turbuhaler 80/4.5 μg/dose as-needed inhalations.
Recommended doses: Adults and adolescents (12 years and older): The recommended maintenance dose is 2 inhalations per day, given either as one inhalation in the morning and evening or as 2 inhalations in either the morning or evening. Patients should take 1 additional inhalation as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. Not more than 6 inhalations should be taken on any single occasion.
A total daily dose of more than 8 inhalations is not normally needed; however, a total daily dose of up to 12 inhalations could be used for a limited period. Patients using more than 8 inhalations daily should be strongly recommended to seek medical advice. They should be reassessed and their maintenance therapy should be reconsidered.
Children under 12 years: Symbicort maintenance and reliever therapy is not recommended for children.
160/4.5 mcg: Symbicort Turbuhaler can be used according to different treatment approaches: A. Symbicort anti-inflammatory reliever therapy (patients with mild disease); B. Symbicort anti-inflammatory reliever plus maintenance therapy; C. Symbicort maintenance therapy (fixed dose).
Symbicort anti-inflammatory reliever therapy (patients with mild disease): Symbicort Turbuhaler 160/4.5 μg/dose is taken as needed for the relief of asthma symptoms when they occur, and as a preventative treatment of symptoms in those circumstances recognised by the patient to precipitate an asthma attack. Patients should be advised to always have Symbicort Turbuhaler 160/4.5 μg/dose available for relief of symptoms.
Adults and adolescents (12 years and older): Patients should take 1 inhalation of Symbicort Turbuhaler 160/4.5 μg/dose as needed in response to symptoms. If symptoms persist after a few minutes, 1 additional inhalation should be taken. No more than 6 inhalations should be taken on any single occasion.
A total daily dose of more than 8 inhalations is normally not needed, however a total daily dose of up to 12 inhalations can be used temporarily. If the patient experiences a 3-day period of deteriorating symptoms after taking additional as needed inhalations, the patient should be reassessed for alternative explanations of persisting symptoms.
Symbicort anti-inflammatory reliever plus maintenance therapy: When maintenance treatment with a combination of inhaled corticosteroid (ICS) and long acting β₂ agonist (LABA) is required, patients take Symbicort anti-inflammatory reliever therapy and in addition take a daily maintenance dose of Symbicort Turbuhaler. The as-needed inhalations provide both rapid relief of symptoms and improved overall asthma control. Patients should be advised to have Symbicort Turbuhaler available for relief of symptoms at all times.
Adults and adolescents (12 years and older): Patients should take 1 inhalation of Symbicort Turbuhaler 160/4.5 μg/dose as needed in response to symptoms to control asthma. If symptoms persist after a few minutes, 1 additional inhalation should be taken. No more than 6 inhalations should be taken on any single occasion.
Patients also take the recommended maintenance dose of Symbicort Turbuhaler 160/4.5 μg/dose, which is 2 inhalations per day, given as either 1 inhalation in the morning and evening or as 2 inhalations in either the morning or evening. For some patients, a maintenance dose of Symbicort Turbuhaler 160/4.5 μg/dose 2 inhalations twice daily may be appropriate. The maintenance dose should be titrated to the lowest dose at which effective control of asthma is maintained.
A total daily dose of more than 8 inhalations is normally not needed, however a total daily dose of up to 12 inhalations can be used temporarily. If the patient experiences a 3-day period of deteriorating symptoms after taking the appropriate maintenance therapy and additional as needed inhalations, the patient should be reassessed for alternative explanations of persisting symptoms.
Symbicort maintenance therapy (fixed dose): When maintenance treatment with a combination of ICS and LABA is required, Symbicort Turbuhaler is taken as a fixed daily dose treatment, with a separate short-acting bronchodilator for relief of symptoms. Patients should be advised to have their separate short-acting bronchodilator available for relief of symptoms at all times.
Increasing use of short-acting bronchodilators indicates a worsening of the underlying condition and warrants reassessment of the asthma therapy. The dosage of Symbicort Turbuhaler should be individualised according to disease severity. When control of asthma has been achieved, the maintenance dose should be titrated to the lowest dose at which effective asthma control is maintained.
Adults and adolescents (12 years and older): 1 or 2 inhalations of Symbicort Turbuhaler 160/4.5 μg/dose twice daily. The maximum recommended daily maintenance dose is 4 inhalations.
320/9 mcg: Symbicort Turbuhaler 320/9 μg/dose is not intended for the initial management of asthma. The dosage of the components of Symbicort Turbuhaler 320/9 μg/dose is individual and should be adjusted to the severity of the disease. This should be considered not only when treatment with combination products is initiated but also when the maintenance dose is adjusted. If an individual patient should require a combination of doses other than those available in the combination inhaler, appropriate doses of β₂ adrenoceptor agonists and/or corticosteroids by individual inhalers should be prescribed.
Recommended doses: Adults (18 years and older): 1 inhalation twice daily. Some patients may require up to a maximum of 2 inhalations twice daily.
Adolescents (12-17 years): 1 inhalation twice daily.
Patients should be regularly reassessed by their prescriber/health care provider, so that the dosage of Symbicort Turbuhaler 320/9 μg/dose remains optimal. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. When long-term control of symptoms is maintained with the lowest recommended dosage, then the next step could include a test of inhaled corticosteroid alone.
In usual practice when control of symptoms is achieved with the twice daily regimen, titration to the lowest effective dose could include Symbicort Turbuhaler 320/9 μg/dose given once daily, when in the opinion of the prescriber, a long-acting bronchodilator would be required to maintain control.
Increasing use of a separate rapid-acting bronchodilator indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy.
Children (6 years and older): A lower strength of Symbicort Turbuhaler is available for children aged from 6 to 11 years.
Children under 6 years: As only limited data are available, Symbicort Turbuhaler is not recommended to be used in children who are younger than 6 years.
Symbicort 320 microgrmas/9 micrograms/inhalation should be used as Symbicort maintenance therapy only. Lower strengths are available for the Symbicort maintenance and reliever therapy regimen (160 micrograms/4.5 micrograms/inhalation and 80 micrograms/4.5 micrograms/inhalation).
COPD: 160/4.5 mcg: Adults: 2 inhalations of Symbicort Turbuhaler 160/4.5 μg/dose twice daily. The maximum recommended daily dose is 4 inhalations.
320/9 mcg: Recommended doses: Adults: 1 inhalation twice daily.
Instruction for correct use of Symbicort Turbuhaler: Turbuhaler is inspiratory flow-driven which means that, when the patient inhales through the mouthpiece, the substance will follow the inspired air into the airways.
NOTE: It is important to instruct the patient to: Check the expiry date; Carefully read the instructions for use in the patient information leaflet that are provided with each pack of Symbicort Turbuhaler; Breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is delivered to the lungs; Never to breathe out through the mouthpiece; Replace the cover of Symbicort Turbuhaler after use; Rinse their mouth out with water after inhaling the maintenance dose to minimise the risk of oropharyngeal thrush.
The patient may not taste or feel any medication when using Symbicort Turbuhaler due to the small amount of drug delivered.

80/4.5 mcg and 320/9 mcg: An overdose of formoterol would likely lead to effects that are typical for β₂ adrenoceptor agonists: tremor, headache, palpitations. Symptoms reported from isolated cases are tachycardia, hyperglycaemia, hypokalaemia, prolonged QTc-interval, arrhythmia, nausea and vomiting. Supportive and symptomatic treatment may be indicated. A dose of 90 micrograms administered during three hours in patients with acute bronchial obstruction raised no safety concerns.
Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical problem. When used chronically in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression, may appear.
If Symbicort Turbuhaler 80/4.5 or 320/9 μg/dose therapy has to be withdrawn due to overdose of the formoterol component of the drug, provision of appropriate inhaled corticosteroid therapy must be considered.
160/4.5 mcg: An overdose of formoterol may lead to effects that are typical for β₂-adrenergic agonists: tremor, headache, palpitations, and tachycardia. Monitoring of serum potassium concentrations may be warranted. Hypotension, metabolic acidosis, hypokalaemia and hyperglycaemia may also occur. Supportive and symptomatic treatment may be indicated. β-blockers should be used with care because of the possibility of inducing bronchospasm in sensitive individuals. A metered dose of 120μg administered during three hours in patients with acute bronchial obstruction raised no safety concerns.
Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical problem. However, the plasma cortisol level will decrease, and number and percentage of circulating neutrophils will increase. The number and percentage of lymphocytes and eosinophils will decrease concurrently. When used chronically in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression, may appear.
Withdrawing Symbicort Turbuhaler or decreasing the dose of budesonide will abolish these effects, although the normalisation of the HPA-axis may be a slow process.

Hypersensitivity to budesonide, formoterol or lactose.

This medicine should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinue, if possible, once asthma control is achieved.
This medicine should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications.
Treatment of asthma or COPD should be in accordance with physician recommendations or current national treatment guidelines.
Patients with asthma should have a personal asthma action plan designed in association with their healthcare professional. This plan should incorporate a stepwise treatment regime which can be instituted if the patient's asthma improves or deteriorates.
Patients should be advised to have their reliever available at all times, either Symbicort Turbuhaler (for asthma patients on Symbicort anti-inflammatory reliever therapy and Symbicort anti-inflammatory reliever plus maintenance therapy) or a separate short-acting bronchodilator (for other asthma patients using Symbicort Turbuhaler as fixed dose maintenance therapy only and for COPD patients).
Sudden and progressive deterioration in control of asthma or COPD is potentially life threatening and the patient should undergo urgent medical assessment. In this situation, consideration should be given to the need for increased therapy with corticosteroids (eg a course of oral corticosteroids), or antibiotic treatment if a bacterial infection is present. For treatment of severe exacerbations, a combination product of ICS and LABA alone is not sufficient. Patients should be advised to seek medical attention if they find the treatment ineffective or they have exceeded the prescribed dose of Symbicort Turbuhaler.
It is recommended that the maintenance dose be tapered when long-term treatment is discontinued, and the dosing should not be stopped abruptly. Complete withdrawal of ICS should not be considered unless it is temporarily required to confirm the diagnosis of asthma.
Oral corticosteroid usage: Symbicort should not be used to initiate treatment with inhaled steroids in patients being transferred from oral steroids. Care should be taken when commencing Symbicort treatment, particularly if there is any reason to suspect that adrenal function is impaired from previous systemic steroid therapy.
Potential systemic effects of ICS: ICS are designed to direct glucocorticoid delivery to the lungs in order to reduce overall systemic glucocorticoid exposure and side effects. However, in higher than recommended doses, ICS may have adverse effects; possible systemic effects of ICS include depression of the HPA axis, reduction of bone density, cataract and glaucoma, and retardation of growth rate in children and adolescents. In steroid-dependent patients, prior systemic steroid usage may be a contributing factor, but such effects may occur amongst patients who use only ICS regularly.
HPA axis suppression and adrenal insufficiency: Dose-dependent HPA axis suppression (as indicated by 24 hour urinary and/or plasma cortisol AUC) has been observed with inhaled budesonide, although the physiological circadian rhythms of plasma cortisol were preserved. This indicates that the HPA axis suppression represents a physiological adaption in response to inhaled budesonide, not necessarily adrenal insufficiency. The lowest dose that results in clinically relevant adrenal insufficiency has not been established. Very rare cases of clinically relevant adrenal dysfunction have been reported in patients using inhaled budesonide at recommended doses.
Clinically important disturbances of the HPA axis and/or adrenal insufficiency induced by severe stress (eg trauma, surgery, infection in particular gastroenteritis or other conditions associated with severe electrolyte loss) may be related to inhaled budesonide in specific patient populations. These are patients with prolonged treatment at the highest recommended dose of Symbicort Turbuhaler and patients administered concomitant CYP3A4-inhibitors (see Interactions). Monitoring for signs of adrenal dysfunction is advisable in these patient groups. For these patients additional systemic glucocorticosteroid treatment should be considered during periods of stress, a severe asthma attack or elective surgery.
Bone density: Whilst corticosteroids may have an effect on bone mass at high doses, long term follow up (3-6 years) studies of budesonide treatment in adults at recommended doses, have not demonstrated a negative effect on bone mass compared to placebo, including one study conducted in patients with a high risk of osteoporosis. The lowest dose that does effect bone mass has not been established.
Bone mineral density measurements in children should be interpreted with caution as an increase in bone area in growing children may reflect an increase in bone volume. In three large medium to long term (12 months-6 years) studies in children (5-16 years), no effects on bone mineral density were observed after treatment with budesonide (189-1322 μg/day) compared to nedocromil, placebo or age matched controls. However, in a randomised 18-month paediatric study (n=176; 5-10 years), bone mineral density was significantly decreased by 0.11 g/cm² (p=0.023) in the group treated with inhaled budesonide via Turbuhaler compared with the group treated with inhaled disodium cromoglycate. The dose of budesonide was 400 μg twice-daily for 1 month, 200 μg twice-daily for 5 months and 100 μg twice-daily for 12 months and the dose of disodium cromoglycate 10 mg three times daily. The clinical significance of this result remains uncertain.
Growth: Limited data from long-term studies suggest that most children and adolescents treated with inhaled budesonide will ultimately achieve their adult target height. However, an initial small but transient reduction in growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment.
Rare individuals may be exceptionally sensitive to ICS. Height measurements should be performed to identify patients with increased sensitivity. The potential growth effects of prolonged treatment should be weighed against the clinical benefit. To minimise the systemic effects of ICS, each patient should be titrated to his/her lowest dose at which effective control of symptoms is maintained (see Dosage & Administration).
Visual disturbance: Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
Infections/tuberculosis: Signs of existing infection may be masked by the use of high doses of glucocorticosteroids and new infections may appear during their use. Special care is needed in patients with active or quiescent pulmonary tuberculosis or fungal, bacterial or viral infections of the respiratory system.
Sensitivity to sympathomimetic amines: In patients with increased susceptibility to sympathomimetic amines (eg inadequately controlled hyperthyroidism), formoterol should be used with caution.
Cardiovascular disorders: β₂-agonists have an arrhythmogenic potential that must be considered before commencing treatment for bronchospasm.
The effects of formoterol in acute as well as chronic toxicity studies were seen mainly on the cardiovascular system and consisted of hyperaemia, tachycardia, arrhythmias and myocardial lesions. These are known pharmacological manifestations seen after administration of high doses of β₂-adrenoceptor agonists.
Patients with pre-existing cardiovascular conditions may be at greater risk of developing adverse cardiovascular effects following administration of β₂-adrenoreceptor agonists. Caution is advised when formoterol is administered to patients with severe cardiovascular disorders such as ischaemic heart disease, tachyarrhythmias or severe heart failure.
Hypokalaemia: High doses of β₂-agonists can lower serum potassium by inducing a redistribution of potassium from the extracellular to the intracellular compartment, via stimulation of Na+/K+-ATPase in muscle cells.
Potentially serious hypokalaemia may result. Particular caution is advised in acute exacerbation as the associated risk may be augmented by hypoxia. The hypokalaemic effect may be potentiated by concomitant treatments (see Interactions). Patients receiving digoxin are particularly sensitive to hypokalaemia. Serum potassium levels should therefore be monitored in such situations.
Diabetes: Due to the blood-glucose increasing effects of β₂-stimulants extra blood glucose controls are initially recommended when diabetic patients are commenced on formoterol.
Pneumonia: Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap.
Pneumonia has been reported following the administration of inhaled corticosteroids. (See Adverse Reactions.)
Lactose: Symbicort Turbuhaler contains lactose (<1 mg/inhalation) which may contain milk protein residue. This amount does not normally cause problems in lactose intolerant people.
Use in hepatic impairment: The effect of decreased liver function on the pharmacokinetics of formoterol and budesonide are not known. As budesonide and formoterol are primarily eliminated via hepatic metabolism an increased exposure can be expected in patients with severe liver disease.
Use in renal impairment: The effect of decreased kidney function on the pharmacokinetics of formoterol and budesonide are not known.
Effects on laboratory tests: No data available.
Effects on Ability to Drive and Use Machines: Driving or using machinery should be undertaken with caution until the effect of Symbicort Turbuhaler on the individual is established. Symbicort Turbuhaler does not generally affect the ability to drive or use machinery.
Use in the elderly: See Pharmacology: Pharmacodynamics: Clinical trials under Actions.
Use in children: 160/4.5 mcg and 320/9 mcg: Symbicort Turbuhaler is not recommended for children below 12 years of age.

Effects on fertility: There are no animal studies on the effect of the budesonide/formoterol combination on fertility.
Long-term treatment of female mice and rats with formoterol fumarate causes ovarian stimulation, the development of ovarian cysts and hyperplasia of granulosa/theca cells as a result of the β-agonist properties of the compound. A study by another company showed no effect on fertility of female rats dosed orally with formoterol fumarate at 60 mg/kg/day for two weeks. This finding was repeated in an AstraZeneca study where no effect was seen on the fertility of female rats dosed orally with formoterol fumarate at 15 mg/kg/day for two weeks.
Testicular atrophy was observed in mice given formoterol fumarate in the diet at 0.2 to 50 mg/kg/day for two years, but no effect on male fertility was observed in rats dosed orally at 60 mg/kg/day for nine weeks, in studies undertaken by another company.
Use in pregnancy: Category B3. For Symbicort Turbuhaler or the concomitant treatment with budesonide and formoterol, no clinical data on exposed pregnancies are available. Animal studies with respect to the reproductive toxicity of the combination have not been performed.
Symbicort Turbuhaler should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Only after special consideration should Symbicort Turbuhaler be used during the first 3 months and shortly before delivery.
Because β-agonists, including formoterol, may potentially interfere with uterine contractility, due to a relaxant effect on uterine smooth muscle, Symbicort Turbuhaler should be used during labour only if the potential benefit justifies the potential risk.
Budesonide: Results from a large prospective epidemiological study and from worldwide post marketing experience indicate no adverse effects of inhaled budesonide during pregnancy on the health of the fetus or newborn child.
If treatment with glucocorticosteroids during pregnancy is unavoidable, ICS such as budesonide should be considered due to their lower systemic effect. The lowest effective dose of budesonide to maintain asthma control should be used.
Formoterol: No teratogenic effects were observed in rats receiving formoterol fumarate at doses up to 60 mg/kg/day orally or 1.2 mg/kg/day by inhalation. Fetal cardiovascular malformations were observed in one study in which pregnant rabbits were dosed orally at 125 or 500 mg/kg/day during the period of organogenesis, but similar results were not obtained in another study at the same dose range. In a third study, an increased incidence of subcapsular hepatic cysts was observed in fetuses from rabbits dosed orally at 60 mg/kg/day. Decreased birth weight and increased perinatal/postnatal mortality were observed when formoterol fumarate was given to rats at oral doses of 0.2 mg/kg/day or greater during late gestation.
Use in lactation: Budesonide is excreted in breast milk. However, due to the relatively low doses used via the inhalational route the amount of drug present in the breast milk, if any, is likely to be low.
It is not known whether formoterol is excreted in human milk. In reproductive studies in rats, formoterol was excreted into breast milk. There are no well-controlled human studies of the use of Symbicort Turbuhaler in nursing mothers. Administration of Symbicort Turbuhaler to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

Since Symbicort Turbuhaler contains both budesonide and formoterol, the same adverse effects as reported for these substances may be expected. No increased incidence of adverse reactions has been seen following concurrent administration of the two compounds. The most common drug related adverse reactions are pharmacologically predictable side-effects of β₂-agonist therapy, such as tremor and palpitations. These tend to be mild and usually disappear within a few days of commencing treatment.
If oropharyngeal candidiasis develops, it may be treated with appropriate anti-fungal therapy whilst still continuing with Symbicort Turbuhaler therapy. The incidence of candidiasis can generally be held to a minimum by having patients rinse their mouth out with water after inhaling their maintenance dose.
Adverse reactions, which have been associated with budesonide, formoterol and Symbicort, are given in Table 12. (See Table 12.)

Click on icon to see table/diagram/image

As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases.
Treatment with β-sympathomimetics may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.
Pneumonia: The following table provides the incidence of pneumonia observed in the four pivotal phase III COPD studies (see Pharmacology: Pharmacodynamics: Clinical trials under Actions) for the Symbicort (as Turbuhaler or Rapihaler 200/6) and comparative placebo arms. (See Table 13.)

Click on icon to see table/diagram/image

In these placebo-controlled studies, the incidence of pneumonia was low.
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 μg/dose as needed in a mild asthma population.
Reporting suspected adverse effects: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are recommended to report any suspected adverse reactions to AstraZeneca.

Pharmacokinetic interactions: The metabolism of budesonide is primarily mediated by the enzyme CYP3A4. Potent CYP3A4 inhibitors may therefore increase systemic exposure to budesonide. This is of limited clinical importance for short-term (1-2 weeks) treatment with potent CYP3A4 inhibitors but should be taken into consideration during long-term treatment.
If a patient requires long-term concomitant treatment with Symbicort and a potent CYP3A4 inhibitor, the benefit should be weighed against the increased risk of systemic corticosteroid side effects, patients should be monitored for corticosteroid side effects and/or a reduction of the ICS dose could be considered.
Pharmacodynamic interactions: Neither budesonide nor formoterol have been observed to interact with any other drug used in the treatment of asthma or COPD.
β-receptor blocking agents: β-receptor blocking agents, especially those that are non-selective, may partially or totally inhibit the effect of β₂-agonists. These drugs may also increase airway resistance, therefore the use of these drugs in asthma patients is not recommended.
Other sympathomimetic agents: Other β-adrenergic stimulants or sympathomimetic amines such as ephedrine should not be given concomitantly with formoterol, since the effects will be cumulative. Patients who have already received large doses of sympathomimetic amines should not be given formoterol.
Xanthine derivatives, mineralocorticosteroids and diuretics: Hypokalaemia may result from β₂-agonist therapy and may be potentiated by concomitant treatment with xanthine derivatives, mineralocorticosteroids, and diuretics (see Hypokalaemia under Precautions).
Monoamine oxidase inhibitors, tricyclic antidepressants, quinidine, disopyramide, procainamide, phenothiazines and antihistamines: The adverse cardiovascular effects of formoterol may be exacerbated by concurrent administration of drugs associated with QT interval prolongation and increased risk of ventricular arrhythmia. For this reason, caution is advised when formoterol is administered to patients already taking monoamine oxidase inhibitors, tricyclic antidepressants, quinidine, disopyramide, procainamide, phenothiazines or antihistamines associated with QT interval prolongation (eg terfenadine, astemizole).

Special Precautions for Disposal: Any unused medicine or waste material should be disposed of by taking to the local pharmacy.
Incompatibilities: Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

Do not store above 30°C. Keep the container tightly closed, in order to protect form moisture.

Preparing your new Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler: Before using your new Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler for the first time, you need to prepare it for use as follows: Unscrew the cover and lift it off. You may hear a rattling sound.
Hold your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler upright with the red grip at the bottom.
Turn the red grip as far as it will go in one direction. Then turn it as far as it will go in the other direction (it does not matter which way you turn it first). You should hear a click sound.
Do this again, turning the red grip in both directions.
Your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler is now ready for use.
How to take an inhalation: Every time you need to take an inhalation, follow the instructions as follows.
1. Unscrew the cover and lift it off. You may hear a rattling sound.
2. Hold your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler upright with the red grip at the bottom.
3. Do not hold the mouthpiece when you load your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler. To load your Symbicort Turbuhaler Inhaler with a dose, turn the red grip as far as it will go in one direction.
Then turn it as far as it will go in the other direction (it does not matter which way you turn it first). You should hear a click sound. Your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler is now loaded and ready to use. Only load your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler when you need to use it.
4. Hold your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler away from your mouth. Breathe out gently (as far as is comfortable). Do not breathe out through your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler.
5. Place the mouthpiece gently between your teeth. Close your lips. Breathe in as deeply and as hard as you can through your mouth. Do not chew or bite on the mouthpiece.
6. Remove your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler from your mouth. Then breathe out gently. The amount of medicine that is inhaled is very small. This means you may not be able to taste it after inhalation. If you have followed the instructions, you can still be confident that you have inhaled the dose and the medicine is now in your lungs.
7. If you are to take a second inhalation, repeat steps 2 to 6.
8. Replace the cover tightly after use.
9. Rinse your mouth with water after your daily morning and/or evening doses, and spit it out.
Do not try to remove or twist the mouthpiece. It is fixed to your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler and must not be taken off. Do not use your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler if it has been damaged or if the mouthpiece has come apart from your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler.
As with all inhalers, caregivers should ensure that children prescribed Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose use correct inhalation technique, as described previously.
Cleaning your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler: Wipe the outside of the mouthpiece once a week with a dry tissue. Do not use water or liquids.
When to start using a new inhaler: The dose indicator tells you how many doses (inhalations) are left in your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler, starting with 60 doses when it is full.
The dose indicator is marked in intervals of 10 doses. Therefore, it does not show every dose.
When you first see a red mark at the edge of the indicator window, there are approximately 20 doses left. For the last 10 doses, the background of the dose indicator is red. When the '0' on the red background has reached the middle of the window, you must start using your new Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler.
Note: The grip will still twist and 'click' even when your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler is empty.
The sound that you hear as you shake your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler is produced by a drying agent and not the medicine. Therefore, the sound does not tell you how much medicine is left in your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler.
If you load your Symbicort Turbuhaler 80/4.5, 160/4.5, or 320/9 μg/dose Inhaler more than once by mistake before taking your dose, you will still only receive one dose. However, the dose indicator will register all the loaded doses.

Antiasthmatic & COPD Preparations

R03AK07 - formoterol and budesonide ; Belongs to the class of adrenergics in combination with corticosteroids or other drugs, excluding anticholinergics. Used in the treatment of obstructive airway diseases.

P₁S₁S₃