Symbicort Turbuhaler

Budesonide, formoterol.

Symbicort 80/4.5 mcg turbuhaler: Each delivered dose (the dose that leaves the mouthpiece) contains budesonide 80 micrograms/inhalation and formoterol fumarate dihydrate 4.5 micrograms/inhalation.
Symbicort Turbuhaler 80/4.5 micrograms/inhalation delivers the same amount of budesonide and formoterol as the corresponding Turbuhaler monoproducts, i.e. budesonide 100 micrograms/inhalation (metered dose) and formoterol 6 micrograms/inhalation (metered dose) alternatively labelled as 4.5 micrograms/inhalation (delivered dose).
Symbicort 160/4.5 mcg turbuhaler: Each delivered dose (the dose that leaves the mouthpiece) contains budesonide 160 micrograms/inhalation and formoterol fumarate dihydrate 4.5 micrograms/inhalation.
Symbicort Turbuhaler 160/4.5 micrograms/inhalation delivers the same amount of budesonide and formoterol as the corresponding Turbuhaler monoproducts, i.e. budesonide 200 micrograms/inhalation (metered dose) and formoterol 6 micrograms/inhalation (metered dose) alternatively labelled as 160 micrograms/inhalation and 4.5 micrograms/inhalation (delivered dose).
Symbicort Forte 320/9 mcg turbuhaler: Each delivered dose (the dose that leaves the mouthpiece) contains budesonide 320 micrograms/inhalation and formoterol fumarate dihydrate 9 micrograms/inhalation.
Symbicort Turbuhaler delivers the same amount of budesonide and formoterol as the corresponding Turbuhaler monoproducts, i.e. budesonide 400 micrograms/inhalation (metered dose) and formoterol 12 micrograms/inhalation (metered dose) alternatively labeled as 320 micrograms/inhalation and 9 micrograms/inhalation (delivered dose).
Excipients/Inactive Ingredients: Symbicort 80/4.5 mcg turbuhaler: Lactose monohydrate (which contains milk proteins) 810 micrograms per dose.
Symbicort 160/4.5 mcg turbuhaler: Lactose monohydrate (which contains milk proteins) 730 micrograms per dose.
Symbicort Forte 320/9 mcg turbuhaler: Lactose monohydrate (which contains milk proteins) 491 micrograms per dose.

Pharmacotherapeutic group: Adrenergics and other drugs for obstructive airway diseases. ATC code: R03AK07.
Pharmacology: Pharmacodynamics: Mechanisms of action and pharmacodynamic effects: Symbicort Turbuhaler 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 (for 160/4.5 mcg only). The mechanisms of action of the two substances, respectively are discussed as follows.
Budesonide: Budesonide given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma with less adverse effects than when corticosteroids are administered systemically. The exact mechanism responsible for this anti-inflammatory effect is unknown.
Formoterol: Formoterol is a selective β₂ adrenoceptor agonist that produces relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect sets in rapidly, within 1-3 minutes after inhalation, and has a duration of 12 hours after a single dose.
80/4.5 mcg: Symbicort maintenance and reliever therapy: In studies of 6-12 months duration in patients from 4 years of age, as-needed use of Symbicort Turbuhaler, as an addition to a maintenance dose, was compared to treatment with the same maintenance dose of Symbicort or a 2-4 fold higher dose of budesonide, both with terbutaline as needed. Improved asthma control was seen from the first days of treatment, and the improvement was greater than that seen in the comparator treatments. Patients took, on average, 1 as-needed Symbicort inhalation per day and achieved statistically and clinically significant reductions in severe exacerbations and improvements in lung function and symptoms. These improvements were achieved with lower inhaled and oral steroid load than in the comparator treatments. There was no sign of attenuation of the anti-asthmatic effect over time.
A short-term study in patients experiencing an acute asthma attack has shown no difference in lung function improvements during the first three hours between treatment with Symbicort Turbuhaler and salbutamol pMDI + spacer.
Symbicort maintenance therapy: Clinical studies have shown that the addition of formoterol to budesonide improved asthma symptoms and lung function, and reduced exacerbations. The effect on lung function of Symbicort, given as a maintenance dose only, was equal to that of budesonide and formoterol in separate inhalers in adults and exceeded that of budesonide alone in adults and children. All treatment arms used a short acting β₂ adrenoceptor agonist as needed. There was no sign of attenuation of the anti-asthmatic effect over time.
In a 12 week paediatric study, 85 children aged 6-11 years were treated with Symbicort (2 inhalations of 80/4.5 micrograms/inhalation twice daily), which improved lung function and was well tolerated.
160/4.5 mcg: 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 mcg used as needed in response to symptoms) to budesonide Turbuhaler 200 mcg (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 and 160/4.5 mcg) 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: Symbicort anti-inflammatory reliever plus maintenance therapy: Symbicort Turbuhaler 160/4.5 mcg, 1 inhalation twice daily plus additional inhalations as needed.
Symbicort Turbuhaler 160/4.5 mcg, 1 inhalation twice daily with formoterol Turbuhaler as needed.
Symbicort Turbuhaler 160/4.5 mcg, 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 Turbuhaler contribute to improved asthma control achieved through the as-needed dosing of Symbicort Turbuhaler 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: Symbicort anti-inflammatory reliever plus maintenance therapy: Symbicort Turbuhaler 160/4.5 mcg, 1 inhalation twice daily plus additional inhalation as needed.
Fluticasone/salmeterol Inhaler 125/25, 2 inhalations twice daily with terbutaline Turbuhaler as needed.
Symbicort Forte Turbuhaler 320/9 mcg, 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 fluticasone/salmeterol 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 fluticasone/salmeterol 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 fluticasone/salmeterol plus salbutamol 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 fluticasone/salmeterol 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.
Exercise-induced and allergen-induced bronchoconstriction: The use of Symbicort Turbuhaler 160/4.5 mcg in relation to exercise-induced and allergen-induced bronchoconstriction has been studied in three clinical trials for patients with mild/intermittent asthma.
Study D5890L00032 was a 6-week, 3-arm study in 66 adults and adolescents with mild asthma and episodic exercise-induced bronchoconstriction, in which the primary variable was change in maximum decrease in post-exercise FEV₁ calculated before and after 6 weeks of treatment. This study demonstrated that Symbicort Turbuhaler 160/4.5 mcg, taken as 1 inhalation before exercise plus additional inhalations as needed in response to symptoms, improved asthma control by reducing exercise-induced bronchoconstriction to the same order of magnitude as regular maintenance treatment with budesonide 400 mcg plus terbutaline 0.5 mg as needed, despite a substantially lower steroid dose. Both treatments were superior to terbutaline as needed when taken alone.
Study AF-039-0001 was a 6-month, 2-arm study in 92 adults and adolescents with mild intermittent asthma who used SABA for symptom relief, in which the primary variable of efficacy was the change in level of fractional exhaled nitric oxide (FENO) in the two treatment groups over the duration of the study. This study demonstrated that the budesonide component in Symbicort Turbuhaler 160/4.5 mcg taken before exercise and as needed, reduced airway inflammation and improved airway function, and showed the beneficial effect of the budesonide component when taken as needed together with formoterol (for symptom relief) as Symbicort Turbuhaler 160/4.5 mcg.
Study D5890L00007 was a 3-arm, placebo-controlled, cross-over study in 15 adult patients with mild allergic asthma, in which the primary efficacy variable was change in PD20 (the provocative dose causing a 20% fall in FEV₁) methacholine (MCh) during each treatment period. This study showed that when administered 30 minutes after a low-dose allergen challenge, Symbicort Turbuhaler 160/4.5 mcg abolished allergen-induced components of asthma deterioration whilst improving baseline pulmonary function, whereas, formoterol 6 ug alone inhibited the rise in symptoms but did not protect against allergen-induced airway inflammation. This study indicated that deteriorating asthma, provoked by low-dose allergen, is managed more effectively with Symbicort Turbuhaler 160/4.5 mcg than with formoterol.
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 and 160/4.5 presentations) while the 320/9 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 mcg: In one study, the maximum recommended maintenance dose of Symbicort Turbuhaler 160/4.5 mcg (2 inhalations twice daily) was compared to corresponding doses of the free combination (budesonide Turbuhaler 200 mcg + formoterol Turbuhaler 6 mcg, two inhalations twice daily) and budesonide Turbuhaler 200 mcg (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 mcg is a more effective treatment than budesonide, at corresponding budesonide doses.
320/9 mcg: Asthma: In clinical trials in adults, the additional of formoterol to budesonide improved asthma symptoms and lung function, and reduced exacerbations.
In two 12-week studies the effect on lung function of Symbicort Turbuhaler was equal to that of the free combination of budesonide and formoterol, and exceeded that of budesonide alone. There was no sign of attenuation of the anti-asthmatic effect over time. No clinical studies have been performed with Symbicort Forte Turbuhaler. Corresponding doses delivered with the lower strengths of Symbicort Turbuhaler are efficacious and well tolerated.
In a 12-week paediatric study 85 children aged 6-11 years were treated with Symbicort (2 inhalations of 80/4.5 micrograms/inhalation twice daily), which improved lung function and was well tolerated.
160/4.5 mcg and 320/9 mcg: COPD: In two 12-month studies, the effect on lung function and the rate of exacerbation (defined as courses of oral steroids and/or course of antibiotics and/or hospitalisations) in patients with moderate to severe COPD was evaluated. The inclusion criteria for both studies was pre-bronchodilator FEV₁ <50% predicted normal. Median post-bronchodilator FEV₁ at inclusion in the trials was 42% predicted normal.
The mean number of exacerbations per year (as defined previously) was significantly reduced with Symbicort as compared with treatment with formoterol alone or placebo (mean rate 1.4 compared with 1.8-1.9 in the placebo/formoterol group). The mean number of days on oral corticosteroids/patient during the 12 months was slightly reduced in the Symbicort group (7-8 days/patient/year compared with 11-12 and 9-12 days in the placebo and formoterol groups, respectively). For changes in lung-function parameters, such as FEV₁, Symbicort was not superior to treatment with formoterol alone.
Pharmacokinetics: Absorption: Symbicort Turbuhaler and the corresponding monoproducts have been shown to be bioequivalent with regard to systemic exposure of budesonide and formoterol. In spite of this, a small increase in cortisol suppression was seen after administration of Symbicort compared to the monoproducts. The difference is considered not to have an impact on clinical safety.
There was no evidence of pharmacokinetic interactions between budesonide and formoterol.
Pharmacokinetic parameters for the respective substances were comparable after the administration of budesonide and formoterol as monoproducts or as Symbicort Turbuhaler. For budesonide, AUC was slightly higher, rate of absorption more rapid and maximal plasma concentration higher after administration of the fixed combination. For formoterol, maximal plasma concentration was similar after administration of the fixed combination. Inhaled budesonide is rapidly absorbed and the maximum plasma concentration is reached within 30 minutes after inhalation. In studies, mean lung deposition of budesonide after inhalation via Turbuhaler ranged from 32 to 44% of the delivered dose. The systemic bioavailability is approximately 49% of the delivered dose.
In children aged 6-16 years, lung deposition fall in the same range as in adults for the same given dose, the resulting plasma concentrations were not determined (for 80/4.5 mcg only).
Inhaled formoterol is rapidly absorbed and the maximum plasma concentration is reached within 10 minutes after inhalation. In studies the mean lung deposition of formoterol after inhalation via Turbuhaler ranged from 28-49% of the delivered dose. The systemic bioavailability is about 61% of the delivered dose.
Distribution and metabolism: Plasma protein binding is approximately 50% for formoterol and 90% for budesonide. Volume of distribution is about 4 L/kg for formoterol and 3 L/kg for budesonide. Formoterol is inactivated via conjugation reactions (active O-demethylated and deformylated metabolites are formed, but they are seen mainly as inactivated conjugates). Budesonide undergoes an extensive degree (approx. 90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6-beta-hydroxy-budesonide and 16-alfa-hydroxy-prednisolone, is less than 1% of that of budesonide. There are no indications of any metabolic interactions or any displacement reactions between formoterol and budesonide.
Elimination: The major part of a dose of formoterol is transformed by liver metabolism followed by renal elimination. After inhalation, 8-13% of the delivered dose of formoterol is excreted unmetabolised in the urine. Formoterol has a high systemic clearance (approximately 1.4 L/min) and the terminal elimination half-life averages 17 hours.
Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites of budesonide are eliminated in urine as such or in conjugated form. Only negligible amounts of unchanged budesonide have been detected in the urine.
Budesonide has a high systemic clearance (approximately 1.2 L/min) and the plasma elimination half-life after i.v. dosing averages 4 hours.
The pharmacokinetics of formoterol in children have not been studied (for 80/4.5 mcg only). The pharmacokinetics of budesonide or formoterol in patients with renal failure is unknown. The exposure of budesonide and formoterol may be increased in patients with liver disease.
Toxicology: Preclinical safety data: The toxicity observed in animal studies with budesonide and formoterol, given in combination or separately, were effects associated with exaggerated pharmacological activity.
In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant in humans at the recommended doses. Animal reproduction studies with formoterol have shown a somewhat reduced fertility in male rats at high systemic exposure and implantation losses as well as decreased early postnatal survival and birth weight at considerably higher systemic exposure than those reached during clinical use. However, these animal experimental results do not seem to be relevant in humans.

Asthma: 80/4.5 mcg and 320/9 mcg: Symbicort is indicated in the 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 Turbuhaler 80/4.5 micrograms/inhalation is not appropriate in patients with severe asthma.
160/4.5 mcg: Symbicort Turbuhaler 160/4.5 mcg 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).
Chronic Obstructive Pulmonary Disease (COPD): 160/4.5 mcg and 320/9 mcg: Symptomatic treatment of patients with COPD with FEV₁ <70% predicted normal (post-bronchodilator) and an exacerbation history despite regular bronchodilator therapy (see also Precautions).

80/4.5 mcg and 320/9 mcg: Asthma: Symbicort is not intended for the initial management of asthma. The dosage of the components of Symbicort 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.
80/4.5 mcg: For Symbicort there are two treatment approaches: Symbicort maintenance and reliever therapy: Patients take a daily maintenance dose of Symbicort and additional take Symbicort as needed in response to symptoms. Patients should be advised to always have Symbicort available for rescue use.
A. Symbicort maintenance therapy: Symbicort is taken as regular maintenance treatment with separate rapid-acting bronchodilator as rescue.
B. Symbicort maintenance and reliever therapy: Symbicort 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): 1-2 inhalations twice daily.
Patients should be regularly reassessed by a doctor, so that the dosage of Symbicort remains optimal. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. When 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 given once daily.
Increasing use of a separate rapid-acting bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy.
Children under 6 years: Symbicort is not recommended for children under 6 Years of age.
B. Symbicort maintenance and reliever therapy: Patients take a daily maintenance dose of Symbicort and in additional take Symbicort as needed in response to symptoms. Patients should be advised to always have Symbicort available for rescue use.
Recommended doses: Adults and adolescents (12 years and older): The recommended maintenance dose is 2 inhalations per day, given either as 1 inhalation in the morning and evening or 2 inhalations in either the morning or evening. Patients should take 1 additional inhalations as needed in response to symptoms. If symptoms persist after a few minutes, an additional 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 (6 years and older): The usual maintenance dose is 1 inhalations once daily. Some patients may require a maintenance dose of 1 inhalations twice daily. Patients should take additional inhalations as needed in response to symptoms. A total daily dose of up to 8 inhalations may be used temporarily.
Children under 6 years: Symbicort is not recommended for children under 6 years of age.
160/4.5 mcg: Asthma: Symbicort 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).
A. Symbicort anti-inflammatory reliever therapy (patients with mild disease): Symbicort Turbuhaler 160/4.5 mcg is taken as needed for the relief of asthma symptoms when they occur, and as a preventive 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 mcg available for relief of symptoms.
Preventive use of Symbicort Turbuhaler 160/4.5 mcg for allergen- or exercise-induced bronchoconstriction (AIB/EIB) should be discussed between physician and patient; the recommended dose frequency should take into consideration both allergen exposure and exercise patterns.
Recommended doses: Adults and adolescents (12 years and older): Patients should take 1 inhalation of Symbicort Turbuhaler 160/4.5 mcg 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 normally not needed, however a total daily dose of up to 12 inhalations can be used temporarily. If the patient experiences a three-day period of deteriorating symptoms after taking additional as needed inhalations, the patient should be reassessed for alternative explanations of persisting symptoms.
B. 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, patient 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.
Preventative use of Symbicort Turbuhaler 160/4.5 mcg for AIB/EIB should be discussed between physician and patient; the recommended dose frequency should take into consideration both allergen exposure and exercise patterns.
Recommended doses: Adults and adolescents (12 years and older): Patients should take 1 inhalation of Symbicort Turbuhaler 160/4.5 mcg as needed in response to symptoms to control asthma. If symptoms persist after a few minutes, another inhalation should be taken. Not more than 6 inhalations should be taken on any single occasion.
Patients also take the recommended maintenance dose of Symbicort Turbuhaler 160/4.5 mcg, which is two inhalations per day, given as either one inhalation in the morning and evening or as two inhalations in either the morning or evening. For some patients, a maintenance dose of Symbicort Turbuhaler 160/4.5 mcg two 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 three-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.
Children (6 years and older): A lower strength is available for children 6-11 years.
C. 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 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.
Recommended doses: Adults and adolescents (12 years and older): 1-2 inhalations of Symbicort Turbuhaler 160/4.5 mcg twice daily. The maximum recommended daily maintenance dose is 4 inhalations (2 inhalations twice daily corresponding to 800 mcg metered dose (640 mcg delivered dose) budesonide/24 mcg metered dose (18 mcg delivered dose) formoterol).
COPD: Adults: 2 inhalations twice daily.
320/9 mcg: 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 a doctor, so that the dosage of Symbicort remains optimal. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. When 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 Forte Turbuhaler given once daily, when in the opinion of the prescriber, a long acting bronchodilator would be required to maintain control.
Children (6 years and older): A lower strength (80/4.5 μg/inhalation) is available for children 6-11 years. Symbicort Forte Turbuhaler is not recommended for children under 12 years old.
COPD: Adults: 1 inhalation twice daily.
General Information: 160/4.5 mcg: 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 to take the maintenance dose of Symbicort Turbuhaler even when asymptomatic for optimal benefit.
Special patient groups: There are no special dosing requirements for elderly patients.
There are no data available for use of Symbicort Turbuhaler in patients with hepatic or renal impairment. As budesonide and formoterol are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver cirrhosis.
Instructions 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.
To carefully read the instructions for use/handling at the end of this monograph.
To 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.
To replace the cover of the Symbicort Turbuhaler after use.
To rinse the 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 dispensed.

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 therapy has to be withdrawn due to overdose of the formoterol component of the drug, provision of appropriate inhaled corticosteroid therapy must be considered.

Hypersensitivity (allergy) to budesonide, formoterol or lactose (which contains small amounts of milk proteins).

It is recommended that the dose is tapered when the treatment is discontinued and should not be stopped abruptly.
If patients find the treatment ineffective, or exceed the highest recommended dose of Symbicort Turbuhaler or current dose of the fixed combination (for 320/9 mcg only), medical attention must be sought. Increasing use of rescue bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy. 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 or addition of systemic anti-inflammatory therapy, e.g. a course of oral corticosteroids, or antibiotic treatment if an infection is present.
There are no data available on the use of Symbicort Forte Turbuhaler in the treatment of an acute asthma attack. Patients should be advised to have their rapid acting bronchodilator available at all times (for 320/9 mcg only.)
Patients should be reminded to take Symbicort Turbuhaler/Symbicort Forte Turbuhaler daily as prescribed even when asymptomatic.
Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Symbicort Turbuhaler. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Symbicort Turbuhaler should be used (see Dosage & Administration).
Patients should not be initiated on Symbicort Turbuhaler during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.
Serious asthma-related adverse events and exacerbations may occur during treatment with Symbicort Turbuhaler. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation with Symbicort Turbuhaler.
There are no clinical study data on Symbicort Turbuhaler and Symbicort Forte Turbuhaler available in COPD patients with a pre-bronchodilator FEV₁>50% predicted normal and with a post-bronchodilator FEV₁<70% predicted normal (see Pharmacology: Pharmacodynamics under Actions).
As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. Symbicort Turbuhaler/Symbicort Forte Turbuhaler should then be discontinued; treatment should be re-assessed and alternative therapy instituted if necessary.
Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma.
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of inhaled corticosteroid. The benefits of the corticosteroid therapy and the possible risks of growth suppression must be carefully weighed. In addition consideration should be given to referring the patient to a paediatric respiratory specialist.
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.
Potential effects on bone density should be considered particularly in patients on high doses for prolonged periods that have coexisting risk factors for osteoporosis (for 160/4.5 mcg and 320/9 mcg only). Long-term studies with inhaled budesonide in children at mean daily dose of 400 micrograms (metered dose) or in adults at daily doses of 800 micrograms (metered dose) have not shown any significant effects on bone mineral density. No information regarding the effect of Symbicort at higher doses is available.
If growth is slowed, and to minimise the risk of possible systemic effects, it is important that therapy is reviewed and the dose of inhaled corticosteroid is adjusted to the lowest dose at which effective control is maintained.
If there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy, care should be taken when transferring patients to Symbicort Turbuhaler/Symbicort Forte Turbuhaler therapy.
The benefits of inhaled budesonide therapy would normally minimise the need for oral steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time. Patients who have required high dose emergency corticosteroid therapy in the past or prolonged treatment with high doses of inhaled corticosteroids, may also be at risk. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.
To minimise the risk of oropharyngeal candida infection the patient should be instructed to rinse the mouth with water after each dosing occasion.
Symbicort Turbuhaler/Symbicort Forte Turbuhaler should be administered with caution in patients with thyrotoxicosis, phaeochromocytoma, diabetes mellitus, untreated hypokalaemia, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heart failure.
Caution should be observed when treating patients with prolongation of the QTc-interval. Formoterol itself may induce prolongation of the QTc-interval.
The need for, and dose of inhaled corticosteroids should be re-evaluated in patients with active or quiescent pulmonary tuberculosis, fungal and viral infections in the airways.
Potentially serious hypokalaemia may result from high doses of β₂ adrenoceptor agonists. Concomitant treatment of β₂ adrenoceptor agonist with drugs which can induce hypokalaemia or potentiate a hypokalemic effect, e.g. xanthine-derivatives, steroids and diuretics, may add to a possible hypokalaemic effect of the β₂ adrenoceptor agonist. Particular caution is recommended in unstable asthma with variable use of rescue bronchodilators, in acute severe asthma as the associated risk may be augmented by hypoxia and in other conditions when the likelihood for hypokalaemia adverse effects is increased. It is recommended that serum potassium levels are monitored during these circumstances.
As for all β₂ adrenoceptor agonists, additional blood glucose controls should be considered in diabetic patients.
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.
Symbicort Turbuhaler/Symbicort Forte Turbuhaler contains lactose (<1 mg/inhalation). This amount does not normally cause problems in lactose intolerant people. The excipient lactose contains small amounts of milk proteins, which may cause allergic reactions.
160/4.5 mcg: 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 is 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.
160/4.5 mcg and 320/9 mcg: Pneumonia in patients with COPD: An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.
There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products.
Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.
Risk factors for pneumonia in patient with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.
Effects on ability to drive and use machines: Symbicort Turbuhaler/Symbicort Forte Turbuhaler has no or negligible influence on the ability to drive and use machines.

For Symbicort or the concomitant treatment with formoterol and budesonide, no clinical data on exposed pregnancies are available. Data from an embryo-fetal development study in the rat, showed no evidence of any additional effect from the combination.
There are no adequate data from use of formoterol in pregnant women. In animal studies formoterol has caused adverse effects in reproduction studies at very high systemic exposure levels.
Data in more than 17000 exposed pregnancies indicate no increased teratogenic risk associated with the use of inhaled budesonide. In animal studies glucocorticosteroids have been shown to induce malformations. This is not likely to be relevant for humans given recommended doses.
Animal studies have also identified an involvement of excess prenatal glucocorticoids in increased risks for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.
During pregnancy, Symbicort Turbuhaler/Symbicort Forte Turbuhaler should only be used when the benefits outweigh the potential risks. The lowest effective dose of budesonide needed to maintain adequate asthma control should be used.
Budesonide is excreted in breast milk. However, at therapeutic doses no effects on the nursing infant are anticipated. It is not known whether formoterol passes into human breast milk. In rats, small amounts of formoterol have been detected in maternal milk. Administration of Symbicort 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/Symbicort Forte Turbuhaler contains both budesonide and formoterol, the same pattern of undesirable effects as reported for these substances may occur. 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 adrenoceptor agonist therapy, such as tremor and palpitations. These tend to be mild and usually disappear within a few days of treatment.
In a 3-year clinical trial with budesonide in COPD, skin bruises and pneumonia occurred at a frequency of 10% and 6%, respectively, compared with 4% and 3% in the placebo group (p<0.001 and p<0.01, respectively) (for 160/4.5 mcg and 320/9 mcg only).
Adverse reactions, which have been associated with budesonide or formoterol, are given as follows. (See Table 10.)

Click on icon to see table/diagram/image

As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases.
Systemic effects of inhaled corticosteroids may occur particularly at high doses prescribed for prolonged periods.
Treatment with β₂ adrenoceptor agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.
The excipient lactose contains small amounts of milk proteins. These may cause allergic reactions.
160/4.5 mcg: 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 mcg as needed in a mild asthma population.
_{*SYGMA 1 = Inhaled Combined Budesonide-Formoterol as Needed in Mild Asthma
**SYGMA 2 = As-Needed Budesonide-Formoterol versus Maintenance Budesonide in Mild Asthma
SYGMA = SYmbicort Given as needed in Mild Asthma}

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 inhaled corticosteroid dose could be considered.
Pharmacodynamic interactions: Beta-adrenergic blockers can weaken or inhibit the effect of formoterol. Symbicort Turbuhaler should therefore not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons.
Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), monoamine oxidase inhibitors and tricyclic anti-depressants can prolong the QTc-interval and increase the risk of ventricular arrhythmias.
In addition L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards β₂-sympathomimetics.
Concomitant treatment with monoamine oxidase inhibitors including agents with similar properties such as furazolidone and procarbazine may precipitate hypertensive reactions.
There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.
Concomitant use of other beta-adrenergic drugs can have a potentially additive effect.
Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.
Budesonide and formoterol have not been observed to interact with any other drugs used in the treatment of asthma.

Incompatibilities: Not applicable.
INSTRUCTIONS FOR USE/HANDLING: Please read the complete instructions carefully before starting to take the medication.
Turbuhaler is a multidose inhaler from which very small amounts of powder are administered. When the patient breathes in through Turbuhaler the powder is delivered to the lungs. It is therefore important that the patient inhales forcefully and deeply through the mouthpiece.
How to prepare a new inhaler for use: Before using Turbuhaler for the first time the patient needs to prepare the inhaler for use.
1. Unscrew and lift off the cover. A rattling sound is heard when unscrewing the cover.
2. Hold the inhaler upright with the red grip downwards. Do not hold the mouthpiece when turning the grip. Turn the grip as far as it will go in one direction and then back again as far as it will go. It does not matter which way the patient turns first. During this procedure the patient will hear a click. Perform the procedure twice.
The inhaler is now ready for use, and the patient should not repeat this procedure again. To take a dose, please continue according to the instructions as follows.
How to use Symbicort Turbuhaler/Symbicort Forte Turbuhaler: To administer one dose, simply follow the instructions as follows.
1. Unscrew and lift off the cover. A rattling sound is heard when unscrewing the cover.
2. Hold the inhaler upright with the red grip downwards. Do not hold the mouthpiece when turning the grip. To load the inhaler with a dose, turn the grip as far as it will go in one direction, and then back again as far as it will go. It does not matter which way the patient turns first. During this procedure the patient will hear a click.
3. Breathe out. Do not breathe out through the mouthpiece.
4. Place the mouthpiece gently between the teeth, close the lips and inhale forcefully and deeply through the mouth. Do not chew or bite on the mouthpiece.
5. Remove the inhaler from the mouth, before breathing out.
6. If more than one dose has been prescribed, repeat steps 2-5.
7. Replace the cover by screwing it back on tightly.
8. Rinse the mouth out with water. Do not swallow.
NOTE: Do not try to remove the mouthpiece since it is fixed to the inhaler. The mouthpiece can be rotated, but do not twist it unnecessarily.
As the amount of the powder dispensed is very small, the patient may not be able to taste it after inhalation. However, the patient can still be confident that he/she has inhaled the dose if the instructions were followed.
If the patient by mistake performs the loading procedure more than once before taking the dose, the patient will still only receive one dose. The dose indicator will, however, register all the loaded doses.
The sound heard if the patient shakes the inhaler is not produced by the medication but by a drying agent.
How to know when to replace the inhaler: The dose indicator tells the patient approximately how many doses are left in the inhaler, starting with either 60 or 120 when full.
The indicator is marked in intervals of 10 doses. Therefore it does not show the loading of each individual dose.
The patient should be reassured that Turbuhaler delivers the dose even if he/she may not notice a movement in the dose indicator.
For the last 10 doses, the background of the indicator is red. When the zero reaches the middle of the window, it is time to discard the inhaler.
Please note that even when the dose indicator registers zero, it is still possible to turn the grip. However, the indicator stops moving and the zero remains in the window.
Cleaning: Wipe the outside of the mouthpiece regularly (once a week) with a dry tissue. Do not use water or liquids when cleaning the mouthpiece.
Disposal: Always be sure to dispose the used Turbuhaler responsibly/in the recommended way, since some of the medicine will remain inside it. Ask the pharmacist for advice.

Store below 30°C. Keep the container tightly closed.

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.

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