Symbicort

Symbicort

budesonide + formoterol

Manufacturer:

AstraZeneca

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Budesonide, formoterol.
Description
Turbuhaler: 80/4.5 μg/dose: 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).
160/4.5 μg/dose: Each delivered dose (the dose that leaves the mouthpiece) contains: budesonide 160 micrograms/inhalation, 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 mcg/inhalation (metered dose) and formoterol 6 micrograms/inhalation (metered dose) alternatively labelled as 4.5 micrograms/inhalation (delivered dose).
320/9 μg/dose: Each delivered dose (the dose that leaves the mouthpiece) contains: budesonide 320 micrograms/inhalation and formoterol fumarate dihydrate 9 micrograms/inhalation.
Symbicort Turbuhaler 320/9 micrograms/inhalation 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 labelled as 9 micrograms/inhalation (delivered dose).
Rapihaler: Each single actuation delivers budesonide 80 or 160 micrograms and formoterol fumarate dihydrate 2.25 or 4.5 micrograms. Each dose is administered as 2 actuations.
Formoterol fumarate dihydrate is hereafter referred to as "formoterol."
Excipients/Inactive Ingredients: Turbuhaler: Lactose monohydrate 810 micrograms per dose (80/4.5 μg/dose); 730 micrograms per dose (160/4.5 μg/dose); 491 micrograms per dose (320/9 μg/dose).
Rapihaler: Apaflurane (HFA 227); Povidone K25; Macrogol (polyethylene glycol) 1000.
Action
Pharmacotherapeutic group: Adrenergics and other drugs for obstructive airway diseases. ATC code: R03AK07.
Pharmacology: Pharmacodynamics: Mechanisms of action and pharmacodynamic effects: Symbicort contains budesonide and formoterol, which have different modes of action and show additive effects in terms of reduction of asthma; and COPD exacerbations (Rapihaler). The specific properties of budesonide and formoterol allow the combination to be used either as an anti-inflammatory reliever therapy or as maintenance treatment of asthma (Turbohaler 160/4.5 μg and Rapihaler). The mechanisms of action of the two substances, respectively are discussed as follows: Budesonide: The exact mechanism responsible for this anti-inflammatory effect is unknown.
Turbuhaler: 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.
Rapihaler: Budesonide is a glucocorticosteroid which when inhaled has a rapid (within hours) and dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer asthma exacerbations. Inhaled budesonide has less severe adverse effects than systemic corticosteroids.
Formoterol: Formoterol is a selective β2-adrenergic agonist that when inhaled results in rapid and long-acting (Rapihaler) relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect is dose-dependant, with an onset of effect within 1-3 minutes after inhalation. The duration of effect is at least 12 hours after a single dose.
Turbuhaler 80/4.5 μg/dose: Clinical efficacy for Symbicort maintenance and reliever therapy in asthma: A total of 12076 asthma patients were included in 5 double-blind efficacy and safety studies (4447 were randomised to Symbicort maintenance and reliever therapy) for 6 or 12 months. Patients were required to be symptomatic despite use of inhaled glucocorticosteroids.
Symbicort maintenance and reliever therapy provided statistically significant and clinically meaningful reductions in severe exacerbations for all comparisons in all 5 studies. This included a comparison with Symbicort at a higher maintenance dose with terbutaline as reliever (study 735) and Symbicort at the same maintenance dose with either formoterol or terbutaline as reliever (study 734) (Table 1). In Study 735, lung function, symptom control, and reliever use were similar in all treatment groups. In Study 734, symptoms and reliever use were reduced and lung function improved, compared with both comparator treatments. In the 5 studies combined, patients receiving Symbicort maintenance and reliever therapy used, on average, no reliever inhalations on 57% of treatment days. There was no sign of development of tolerance over time. (See Table 1.)

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In 2 other studies with patients seeking medical attention due to acute asthma symptoms, Symbicort provided rapid and effective relief of bronchoconstriction similar to salbutamol and formoterol.
Turbuhaler 80/4.5 and 160/4.5 μg/dose: Clinical Efficacy in asthma for Symbicort maintenance therapy [therapy C (160/4.5 μg/dose)]: Clinical studies in adults have shown that the addition of formoterol to budesonide improved asthma symptoms and lung function, and reduced exacerbations. In two 12-week studies the effect on lung function of Symbicort was equal to that of the free combination of budesonide and formoterol, and exceeded that of budesonide alone. All treatment arms used a short-acting beta2-agonist as needed. There was no sign of attenuation of the anti-asthmatic effect over time.
In a 12-week paediatric study 85 children aged 6-11 years were treated with a maintenance dose of Symbicort (2 inhalations of 80/4.5 micrograms/inhalation twice daily), and a short-acting beta2-agonist as needed. Lung function was improved and the treatment was well tolerated compared to the corresponding dose of budesonide Turbuhaler.
Turbuhaler 160/4.5 μg/dose: Clinical Efficacy for Symbicort as an anti-inflammatory reliever: anti-inflammatory reliever therapy (therapy A) and anti-inflammatory reliever plus maintenance therapy (therapy B) in asthma (see Dosage & Administration): Overall, 20140 asthma patients were included in 7 double-blind clinical studies, of which 7831 were randomised to a therapy which included Symbicort as an anti-inflammatory reliever, both with a maintenance (therapy B) and without a maintenance dosing (therapy A).
A total of 8064 asthma patients with mild asthma were included in 2 double-blind efficacy and safety studies (SYGMA 1 and SYGMA 2 studies), of which 3384 patients were randomised to Symbicort anti-inflammatory reliever therapy (therapy A) for 12 months. Patients were required to be uncontrolled on only short-acting inhaled bronchodilator as needed or controlled on a low dose of inhaled corticosteroids or LTRA (leukotriene receptor antagonist) plus short-acting inhaled bronchodilator as needed.
In the SYGMA 2 study, Symbicort160/4.5 micrograms used as needed in response to symptoms (anti-inflammatory reliever therapy - therapy A) was comparable to a maintenance dose of budesonide (1 inhalation of 200 micrograms/inhalation twice daily) given with as-needed short-acting β2 agonist in terms of the rate of severe exacerbations (Table 2). Protection against severe exacerbation was achieved with a 75% reduction in median inhaled steroid load and without requiring adherence to maintenance inhaled corticosteroids treatment. The SYGMA 1 study showed that Symbicort anti-inflammatory reliever therapy provided statistically significant and clinically meaningful reduction in the rate of annual severe exacerbation by 64% compared with as-needed use of a short-acting β2 agonist (Table 2). Reduction in the annual rate of moderate to severe exacerbations was consistent (60%) with that observed for severe exacerbations ([RR] 0.40, 95% CI 0.32 to 0.49, p-value <0.001).
In the SYGMA 1 study, as-needed use of Symbicort 160/4.5 micrograms provided superior daily asthma symptom control compared to as-needed short-acting β2 agonist (OR 1.14, 95% CI 1.00 to 1.30, p-value 0.046), showing a mean percentage of weeks with well-controlled asthma of 34.4% and 31.1%, respectively. Asthma symptom control was inferior for Symbicort as needed compared to a maintenance dose of budesonide (1 inhalation of 200 micrograms/inhalation twice daily) given with as-needed short-acting β2 agonist (OR 0.64, 2-sided 95% CI 0.57 to 0.73, lower limit of the CI ≥ 0.8 for non-inferiority), showing a mean percentage of well-controlled asthma weeks of 34.4% and 44.4%, respectively. Improvements in asthma control (as defined by ACQ5) in patients using Symbicort anti-inflammatory reliever therapy were superior to improvements in patients using a short-acting β2 agonist as needed (-0.15, 95% CI -0.20 to -0.11, p-value <0.001). Improvements in asthma control were lower for Symbicort as needed compared to a maintenance dose of budesonide (1 inhalation of 200 micrograms/inhalation twice daily) given with a short-acting β2 agonist to be used as needed (SYGMA 1: 0.15, 95% CI 0.10 to 0.20; SYGMA 2: 0.11, 95% CI 0.07 to 0.15, both p-value <0.001). For both comparisons, mean differences in treatments' effect upon ACQ5 are not clinically meaningful (as assessed by a difference of greater than or equal to 0.5). These results were observed in a clinical study setting with considerably higher adherence to budesonide maintenance dosing than expected in real life.
In the SYGMA studies, increases in lung function compared to baseline (mean pre-bronchodilator FEV1) were statistically significantly larger for patients on Symbicort anti-inflammatory reliever therapy compared to patients on as-needed short-acting β2 agonist treatment. Statistically significantly smaller increases were observed for Symbicort as needed compared to a maintenance dose of budesonide (1 inhalation of 200 micrograms/inhalation twice daily) given with a short-acting β2 agonist to be used as needed. For both comparisons, mean differences in treatments' effect were small (approximately 30 to 55 mL, equating to approximately 2% of the baseline mean).
Overall, the results of the SYGMA studies show that Symbicort anti-inflammatory reliever therapy is a more effective treatment than a short-acting β2 agonist as needed in patients with mild asthma. In addition, these studies suggest that the as-needed use of Symbicort may be considered an alternative treatment option for patients with mild asthma who are eligible for inhaled corticosteroid treatment.
In a separate clinical programme, a total of 12076 asthma patients were included in 5 double-blind efficacy and safety studies (4447 were randomised to Symbicort anti-inflammatory reliever plus maintenance therapy - therapy B) for 6 or 12 months. Patients were required to be symptomatic despite use of inhaled glucocorticosteroids.
Symbicort anti-inflammatory reliever plus maintenance therapy provided statistically significant and clinically meaningful reductions in severe exacerbations for all comparisons in all 5 studies. This included a comparison with Symbicort at a higher maintenance dose with terbutaline as reliever (study 735) and Symbicort at the same maintenance dose with either formoterol or terbutaline as reliever (study 734) (Table 2). In Study 735, lung function, symptom control, and reliever use were similar in all treatment groups. In Study 734, symptoms and reliever use were reduced and lung function improved, compared with both comparator treatments. In the 5 studies combined, patients receiving Symbicort anti-inflammatory reliever plus maintenance therapy used, on average, no reliever inhalations on 57% of treatment days. There was no sign of development of tolerance over time. (See Table 2.)

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Analysis of time to first severe exacerbation in the SYGMA 1 study showed that the likelihood of experiencing a severe exacerbation was statistically significantly higher for the as-needed use of a short-acting β2 agonist compared to the as-needed use of Symbicort (Symbicort anti-inflammatory reliever therapy - therapy A) over the 1 year treatment period (see Figure 1), with a risk reduction of 56% ([HR] 0.44, 95% CI: 0.33-0.58, p-value <0.001). There were no differences in the probability of experiencing a severe exacerbation between Symbicort anti-inflammatory reliever therapy (therapy A) and a therapy including a maintenance dose of budesonide (1 inhalation of 200 micrograms/inhalation twice daily) and a short-acting β2 agonist used as needed (see Figures 1 and 2).

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Click on icon to see table/diagram/image

In Study 735, Symbicort anti-inflammatory reliever plus maintenance therapy (therapy B) significantly prolonged the time to the first exacerbation (see Figure 3) compared to the other treatment groups. The rate of exacerbations was reduced by 28% compared to twice the maintenance dose of Symbicort with terbutaline as reliever. Lung function, symptom control, and reliever use were similar in all treatment groups. (See Figures 3 and 4.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In Study 734, Symbicort anti-inflammatory reliever plus maintenance therapy (therapy B) prolonged the time to the first exacerbation compared to Symbicort at the same maintenance dose with either formoterol or terbutaline as reliever (see Figure 4). The rate of exacerbations was reduced by 33% and 48%, respectively. Symptoms and reliever use were reduced and lung function improved, compared with both comparator treatments.
In 2 separate studies with patients seeking medical attention due to acute asthma symptoms, Symbicort provided rapid and effective relief of bronchoconstriction similar to salbutamol and formoterol.
Turbuhaler 160/4.5 and 320/9 μg/dose: 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.
Turbuhaler 320/9 μg/dose: Asthma: Clinical studies in adults have shown that the addition of formoterol to budesonide improved asthma symptoms and lung function, and reduced exacerbations.
In two 12-week studies, the effect on lung function of Symbicort was equal to that of the free combination of budesonide and formoterol, and exceeded that of budesonide alone. All treatment arms used a short-acting β2-agonist as needed. There was no sign of attenuation of the anti-asthmatic effect over time.
In a 12-week paediatric study, 85 children aged 6-11 years were treated with a maintenance dose of Symbicort (2 inhalations of 80/4.5 micrograms/inhalation twice daily), and a short-acting β2-agonist as needed. Lung function was improved, and the treatment was well tolerated compared to the corresponding dose of budesonide Turbuhaler.
Rapihaler: Clinical efficacy in asthma: Therapeutic equivalence between Symbicort Rapihaler and Symbicort Turbuhaler was demonstrated in three clinical efficacy and safety studies, including asthmatic patients from 6 to 79 years of age and one long-term safety study in adolescents and adults with asthma. The safety profile of Symbicort Rapihaler has been shown to be as safe and well tolerated as Symbicort Turbuhaler. As a result of demonstrating therapeutic equivalence, the clinical efficacy for Symbicort Rapihaler in asthma described as follows is based on studies conducted with Symbicort Turbuhaler.
It has been shown in a separate study that Symbicort Rapihaler can be used safely with a named spacer device in children.
Clinical efficacy in COPD: In one 12-month study and one 6-month study in patients with COPD, Symbicort Rapihaler 160/4.5 was superior to placebo, budesonide and formoterol for post-dose FEV1 and predose FEV1. In the 12-month study, Symbicort Rapihaler was also superior to placebo and formoterol for both the number of, and the time to first severe COPD exacerbation (a worsening of COPD requiring oral steroid use of hospitalization.) Thus, the contribution of both budesonide and formoterol to the effect of Symbicort Rapihaler was demonstrated. Symbicort Rapihaler 160/4.5 also significantly reduced breathlessness, daily rescue medication use, night-time awakenings and improved health-related quality of life compared with placebo in both studies. Serial FEV1 measures over 12 hours were obtained in subsets of patients in both studies. The median time to onset of bronchodilation (>15% improvement in FEV1) was seen within 5 minutes at the end of treatment in patients receiving Symbicort Rapihaler 160/4.5. Maximal improvement in FEV1 occurred at approximately 2 hours post-dose and post-dose bronchodilator effect was generally maintained over 12 hours. The treatment was well tolerated.
Pharmacokinetics: Absorption: Turbuhaler: Symbicort Turbuhaler and the corresponding monoproducts have been shown to be bioequivalent with regard to systemic exposure of budesonide and formoterol, respectively. In spite of this, a small increase in cortisol suppression was seen after administration of Symbicort compared to the monoproducts. The difference is considered not to have an impact on clinical safety.
There was no evidence of pharmacokinetic interactions between budesonide and formoterol.
Pharmacokinetic parameters for the respective substances were comparable after the administration of budesonide and formoterol as monoproducts or as Symbicort Turbuhaler. For budesonide, AUC was slightly higher, rate of absorption more rapid and maximal plasma concentration higher after administration of the fixed combination. For formoterol, maximal plasma concentration was similar after administration of the fixed combination. Inhaled budesonide is rapidly absorbed and the maximum plasma concentration is reached within 30 minutes after inhalation. In studies, mean lung deposition of budesonide after inhalation via Turbuhaler ranged from 32 to 44% of the delivered dose. The systemic bioavailability is approximately 49% of the delivered dose.
In children 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. (Turbuhaler 80/4.5 mcg).
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.
The systemic bioavailability of budesonide and formoterol was comparable for the two treatments Symbicort Rapihaler and Symbicort Turbuhaler.
Rapihaler: There was no evidence of pharmacokinetic interactions between budesonide and formoterol when given together.
In studies where Symbicort Rapihaler was administered to healthy subjects and patients with moderate asthma, peak plasma concentrations for budesonide occurred approximately 30 minutes and for formoterol 10 minutes after dosing. Peak plasma concentrations were 30-40% higher in healthy subjects compared to asthma patients. However, the total systemic exposure was comparable to that in asthma patients.
In repeat dose studies plasma concentrations of budesonide and formoterol generally increased in proportion to dose.
Collectively, in pharmacokinetic studies conducted in adults with asthma, systemic exposure to budesonide and formoterol administered via Symbicort Rapihaler was lower than when given via the monoproducts Pulmicort Turbuhaler and Oxis Turbuhaler. Collectively, the pharmacokinetic data from clinical efficacy and safety studies indicate that Symbicort Rapihaler delivers a comparable amount of budesonide to the systemic circulation, and thus the lung, as do budesonide pMDI and Pulmicort Turbuhaler. The results of the systemic exposure for formoterol were generally similar when administered via Symbicort Rapihaler and Oxis Turbuhaler.
Distribution and Metabolism: Plasma protein binding is approximately 50% for formoterol and 90% for budesonide. Volume of distribution is about 4 L/kg for formoterol and 3 L/kg for budesonide. Formoterol is inactivated via conjugation reactions (active O-demethylated and deformylated metabolites are formed, but they are seen mainly as inactivated conjugates). Budesonide undergoes an extensive degree (approximately 90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6 beta-hydroxy-budesonide and 16-alfa-hydroxy-prednisolone, is less than 1% of that of budesonide. There are no indications of any metabolic interactions or any displacement reactions between formoterol and budesonide.
Elimination: The major part of a dose of formoterol is transformed by liver metabolism followed by renal elimination. After inhalation, 8% to 13% of the delivered dose of formoterol is excreted unmetabolised in the urine. Formoterol has a high systemic clearance (approximately 1.4 L/min) and the terminal elimination half-life averages 17 hours.
Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites of budesonide are eliminated in urine as such or in conjugated form. Only negligible amounts of unchanged budesonide have been detected in the urine. Budesonide has a high systemic clearance (approximately 1.2 L/min) and the plasma elimination half-life after i.v. dosing averages 4 hours.
The pharmacokinetics of formoterol in children have not been studied (turbuhaler 80/4.5 mcg).
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.
Rapihaler: Budesonide has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance, which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. The pharmacokinetics of formoterol in children has not been studied.
The pharmacokinetics of budesonide or formoterol in elderly and 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 (Turbuhaler).
The toxicity observed in animal studies with budesonide and formoterol was similar whether budesonide or formoterol were given in combination or separately. The effects were associated with pharmacological actions and dose dependent (Rapihaler).
In animal reproduction studies, glucocorticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant in humans at the recommended doses (see Use in Pregnancy & Lactation). Animal reproduction studies with formoterol have shown a somewhat reduced fertility in male rats at high systemic exposure and implantation losses as well as decreased early postnatal survival and birth weight at considerably higher systemic exposures than those reached during clinical use. However, these animal experimental results do not seem to be relevant to humans.
Rapihaler: Symbicort Rapihaler contains the excipients povidone (polyvinylpyrrolidone) K25, macrogol (polyethylene glycol) 1000 and the pressurised liquid propellant apaflurane (HFA 227). The safe use of apaflurane has been fully evaluated in preclinical studies. Povidones have a history of safe use in man for many years, which supports the view that povidones are essentially biologically inert. Macrogols are recognized as safe excipients in pharmaceuticals, food and cosmetic products. Furthermore, toxicity studies carried out using Symbicort Rapihaler have shown no evidence of any local or systemic toxicity or irritation attributable to the excipients.
Indications/Uses
Asthma: Turbuhaler 80/4.5 and 320/9 μg/dose: Symbicort is indicated in the regular treatment of asthma where use of a combination (inhaled corticosteroid and long-acting beta2-agonist) is appropriate: patients not adequately controlled with inhaled corticosteroids and "as needed" inhaled short acting beta2-agonists or; patients already adequately controlled on both inhaled corticosteroids and long acting beta2-agonists.
Turbuhaler 160/4.5 μg/dose and Rapihaler: Symbicort is indicated in the treatment of asthma to achieve overall asthma control, including the prevention and relief of symptoms as well as the reduction of the risk of exacerbations.
Symbicort is indicated for treatment of asthma, where the use of inhaled corticosteroids is appropriate.
Note: Symbicort Turbuhaler 80/4.5 micrograms/inhalation is not appropriate in patients with severe asthma.
Chronic Obstructive Pulmonary Disease (COPD): Turbuhaler 160/4.5 and 320/9 μg/dose: Symptomatic treatment of patients with COPD with FEV1 <70% predicted normal (post-bronchodilator) and a history of repeated exacerbations, despite regular long-acting bronchodilator therapy (see Precautions).
Rapihaler: Symbicort Rapihaler is indicated in the regular treatment of patients with severe COPD (FEV1 <50% predicted normal), with frequent symptoms and a history of exacerbations despite regular bronchodilator therapy.
Dosage/Direction for Use
Turbuhaler 80/4.5 and 320/9 μg/dose: Asthma: Symbicort is not intended for the initial management of asthma. The dosage of the components of Symbicort is individualized 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-agonists and/or corticosteroids by individual inhalers should be prescribed.
Turbuhaler 80/4.5 μg/dose: For Symbicort has 2 alternative therapies: Symbicort maintenance and reliever therapy: Symbicort is taken as both regular maintenance treatment, and also as needed in response to symptoms. The as needed inhalations provide both rapid relief and improved asthma control. Patients should be advised to have Symbicort available for rescue use at all times. A separate inhaler for rescue use is not necessary. Clinical studies have demonstrated that Symbicort maintenance and reliever therapy provides clinically meaningful reductions in severe exacerbations while maintaining symptom control, compared to Symbicort maintenance therapy with a separate rapid-acting bronchodilator (see Pharmacology: Pharmacodynamics under Actions).
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 the 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 re-assessed and their maintenance therapy should be reconsidered.
Children under 12 years: Symbicort maintenance and reliever therapy is not recommended for children under 12 years.
Symbicort maintenance therapy: Symbicort taken as regular maintenance treatment with a separate rapid-acting bronchodilator as rescue. 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.
Patients should be regularly reassessed by a doctor, so that the dosage of Symbicort Turbuhaler 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, when in the opinion of the prescriber, a long acting bronchodilator would be required to maintain control.
Children under 6 years: Symbicort Turbuhaler is not recommended for children under 6 years of age.
Turbuhaler 80/4.5 nd 160/4.5 μg/dose: Special patient groups: There is no need to adjust the dose in 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.
Turbuhaler 160/4.5 mcg: The dosage of Symbicort Turbuhaler should be individualised according to disease severity.
Asthma: Symbicort can be used according to different treatment approaches: Symbicort anti-inflammatory reliever therapy.
Symbicort anti-inflammatory reliever plus maintenance therapy.
As an alternative, Symbicort can be used in a fixed dose therapy: Symbicort maintenance therapy.
Symbicort anti-inflammatory reliever therapy (patients with mild disease): Symbicort is taken as needed for the relief of asthma symptoms when they occur, and to prevent allergen- or exercise- induced bronchoconstriction (or to prevent symptoms in those circumstances recognised by the patient to precipitate an asthma attack). The formoterol component in Symbicort Turbuhaler provides fast onset of effect (within 1-3 minutes) with long-acting (at least 12 hours after a single dose) bronchodilation in reversible airways obstruction. Patients should be advised to always have Symbicort available for relief of symptoms.
Clinical studies have demonstrated that Symbicort anti-inflammatory reliever therapy provides significant reductions in severe exacerbations and was statistically superior on daily asthma symptom control compared to a short-acting β2 agonist therapy alone (see Pharmacology: Pharmacodynamics under Actions). Asthma symptom control was inferior for Symbicort as needed compared to a maintenance dose of corticosteroid given with as needed short-acting β2 agonist.
Recommended doses: Physicians should discuss allergen exposure and exercise patterns with the patients and take these into consideration when recommending the dose frequency.
Adults and adolescents (12 years and older): Patients should take 1 inhalation as needed in response to symptoms and for the prevention of allergen- or exercise-induced bronchoconstriction to control asthma. 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. Patients using more than 8 inhalations daily should be reassessed for alternative explanations of persisting symptoms.
Children under 12 years: Efficacy and safety of Symbicort anti-inflammatory reliever therapy in children under 12 years have not been studied.
Symbicort anti-inflammatory reliever plus maintenance therapy: When maintenance treatment with a combination of inhaled corticosteroid and long-acting β2 agonist is required, Symbicort is taken as anti-inflammatory reliever therapy and in addition, patients take a daily maintenance dose of Symbicort. The as needed inhalations provide both rapid relief of symptoms and improved overall asthma control. Patients should be advised to have Symbicort available for relief of symptoms at all times. A separate inhaler for relief of symptoms is not necessary.
Clinical studies have demonstrated that Symbicort anti-inflammatory reliever plus maintenance therapy provides clinically meaningful reductions in severe exacerbations while maintaining symptom control, compared to Symbicort maintenance therapy with a separate short-acting bronchodilator (see Pharmacology: Pharmacodynamics under Actions).
Recommended doses: Physicians should discuss allergen exposure and exercise patterns with the patients and take these into consideration when recommending the dose frequency.
Adults and adolescents (12 years and older): Patients should take 1 inhalation as needed in response to symptoms and for the prevention of allergen- or exercise-induced bronchoconstriction to control asthma. 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. Patients also take the recommended maintenance dose, which is 2 inhalations per day, given either as one inhalation in the morning and evening or as 2 inhalations in either the morning or the evening. For some patients, a maintenance dose of 2 inhalations twice daily may be appropriate.
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 anti-inflammatory reliever plus maintenance therapy is not recommended for children under 12 years.
Symbicort maintenance therapy (fixed dose): When maintenance treatment with a combination of inhaled corticosteroid and long-acting β2 agonist is required, Symbicort 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.
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. During worsening of asthma, the dose may temporarily be increased to a maximum of 4 inhalations twice daily.
Children (6 years and older): A lower strength is available for children 6-11 years.
COPD: Adults: 2 inhalations twice daily.
General information: If patients take Symbicort as a maintenance therapy, they should be instructed to take the maintenance dose of Symbicort Turbuhaler even when asymptomatic for optimal benefit.
Turbuhaler 320/9 mcg/dose: Recommended Dose: 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 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 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 is available for children 6-11 years.
Symbicort 320/9 micrograms/inhalation should be used as Symbicort maintenance therapy only. Lower strengths are available for the Symbicort maintenance and reliever therapy regimen.
COPD: Recommended doses: Adults: 1 inhalation twice daily.
General information: Special patient groups: There are no special dosing requirements for elderly patients. There are no data available for use of Symbicort 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.
Turbuhaler: Instructions for correct use of 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 carefully read the instructions for use/handling written 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 prescribed dose to minimise the risk of oropharyngeal thrush. If oropharyngeal thrush occurs, patients should also rinse their mouth with water after the as-needed inhalations.
The patient may not taste or feel any medication when using Turbuhaler due to the small amount of drug dispensed.
Rapihaler: Asthma: Asthma The dosage of the components of Symbicort Rapihaler 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-agonists and/or corticosteroids by individual inhalers should be prescribed.
Symbicort can be used according to different treatment approaches: Symbicort anti-inflammatory reliever therapy.
Symbicort anti-inflammatory reliever plus maintenance therapy.
As an alternative, Symbicort can be used in a fixed dose therapy: Symbicort maintenance therapy.
Symbicort anti-inflammatory reliever therapy (patients with mild disease): Symbicort is taken as needed for the relief of asthma symptoms when they occur, and to prevent allergen- or exercise- induced bronchoconstriction (or to prevent symptoms in those circumstances recognised by the patient to precipitate an asthma attack). The formoterol component in Symbicort pMDI provides fast onset of effect (within 1-3 minutes) with long-acting (at least 12 hours after a single dose) bronchodilation in reversible airways obstruction. Patients should be advised to always have Symbicort available for relief of symptoms.
Clinical studies have demonstrated that Symbicort anti-inflammatory reliever therapy provides significant reductions in severe exacerbations and was statistically superior on daily asthma symptom control compared to a short-acting β2 agonist therapy alone, and comparable to budesonide maintenance therapy given with as-needed short-acting β2 agonist in reducing severe exacerbations (see Pharmacology: Pharmacodynamics under Actions). Asthma symptom control was inferior for Symbicort as needed compared to a maintenance dose of corticosteroid given with as needed short-acting β2 agonist.
Recommended doses: Physicians should discuss allergen exposure and exercise patterns with the patients and take these into consideration when recommending the dose frequency. (See Table 3.)

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Symbicort anti-inflammatory reliever plus maintenance therapy: When maintenance treatment with a combination of inhaled corticosteroid and long-acting β2 agonist is required, Symbicort Rapihaler is taken both as an anti-inflammatory reliever and as regular maintenance treatment. The as needed inhalations provide both rapid relief of symptoms and improved asthma control. Patients should be advised to have Symbicort Rapihaler available for relief of symptoms at all times. A separate reliever inhaler is not necessary.
Clinical studies have demonstrated that Symbicort anti-inflammatory reliever plus maintenance therapy provides clinically meaningful reductions in severe exacerbations while maintaining symptom control, compared to Symbicort maintenance therapy with a separate short-acting bronchodilator (see Pharmacology: Pharmacodynamics under Actions).
Recommended doses: Physicians should discuss allergen exposure and exercise patterns with the patients and take these into consideration when recommending the strength and dose frequency. (See Table 4.)

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When control has been achieved, the dose should be titrated to the lowest dose at which effective control of symptoms is maintained.
Symbicort maintenance therapy (fixed dose): When maintenance treatment with a combination of inhaled corticosteroid and long-acting β2 agonist is required, Symbicort is taken as a fixed daily dose treatment, with a separate short-acting bronchodilator as reliever. Patients should be advised to have their separate short-acting bronchodilator available for relief of symptoms at all times. (See Table 5.)

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When control has been achieved, the dose should be titrated to the lowest dose at which effective control of symptoms is maintained.
Increasing use of a separate rapid acting bronchodilator indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy.
COPD: (See Table 6.)

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General information: If patients take Symbicort as a maintenance therapy, they should be instructed that Symbicort Rapihaler must be used even when asymptomatic for optimal benefit.
There are no special dosing requirements for elderly patients.
There are no data available for use of Symbicort 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 diseases.
Instructions for correct use of Symbicort Rapihaler: On actuation of Symbicort Rapihaler, a volume of the suspension is expelled from the canister at high velocity. When the patient inhales through the mouthpiece at the same time as actuating the inhaler, the substance will follow the inspired air into the airways.
Note: It is important to instruct the patient to: Carefully read the instructions for use/handling in the leaflet which is packed together with each inhaler.
Shake the inhaler gently prior to each use to mix its contents properly.
Prime the 80/2.25, 160/4.5 and 80/4.5 mcg/actuation inhaler by actuating it two times into the air when the inhaler is new, if it has not been used for more than one week or if it has been dropped.
Place the mouthpiece in the mouth. While breathing in slowly and deeply, press the device firmly to release the medication. Continue to breathe in and hold the breath for approximately 10 seconds or as long as is comfortable.
Shake the inhaler again and repeat.
Rinse the mouth with water after inhaling the maintenance dose to minimise the risk of oropharyngeal thrush.
Clean the mouthpiece of the inhaler regularly, at least once a week with a clean dry cloth.
Do not put the inhaler into water.
To enable patients with difficulty in coordinating inhalation with actuation to use Symbicort (such as young children or the elderly), a spacer device can be used. See Instructions for use, handling and disposal under Cautions for Usage for instructions for the correct use of Symbicort Rapihaler with a spacer device.
Overdosage
Turbuhaler: An overdose of formoterol would likely lead to effects that are typical for β2-adrenergic 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.
Rapihaler: An overdose of formoterol would likely lead to effects that are typical for β2-adrenergic agonists: tremor, headache, palpitations, and tachycardia. Hypotension, metabolic acidosis, hypokalaemia and hyperglycemia may also occur. Supportive and symptomatic treatment may be indicated. A dose of 90 micrograms administered during three hours in patients with acute bronchial obstruction and when given three times daily as a total of 54 micrograms/day for 3 days to stable asthmatics raised no safety concerns.
Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical problem. Another observation might be 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.
Contraindications
Turbuhaler: Hypersensitivity (allergy) to budesonide, formoterol or lactose (which contains small amounts of milk proteins).
Rapihaler: Hypersensitivity (allergy) to budesonide, formoterol or any of the excipients.
Special Precautions
Turbuhaler 80/4.5 and 320/9 μg/dose: 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, medical attention must be sought. Increasing use of rescue bronchodilators indicates a worsening of the underlying condition and warrants a re-assessment of the asthma therapy. Sudden and progressive deterioration in control of asthma or COPD (Turbuhaler 320/9 μg/dose) 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 such as, a course of oral corticosteroids or antibiotic treatment if an infection is present.
Patients should be advised to have their rescue inhaler available at all times, either Symbicort (for asthma patients using Symbicort as maintenance and reliever therapy) or a separate rapid-acting bronchodilator (for all patients using Symbicort as maintenance therapy only).
Patients should be reminded to take Symbicort daily as prescribed even when asymptomatic. The prophylactic use of Symbicort e.g. before exercise, has not been studied. The reliever inhalations of Symbicort should be taken in response to asthma symptoms but are not intended for regular prophylactic use, e.g. before exercise. For such use, a separate rapid-acting bronchodilator should be considered.
Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Symbicort. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Symbicort should be used (see Dosage & Administration).
Patients should not be initiated on Symbicort 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. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation with Symbicort.
There are no clinical study data on Symbicort Turbuhaler available in COPD patients with a pre-bronchodilator FEV1 >50% predicted normal and with a postbronchodilator FEV1 <70% predicted normal (see Pharmacology: Pharmacodynamics under Actions). (Turbuhaler 320/9 μg/dose)
As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. Symbicort 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.
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.
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 co-existing risk factors for osteoporosis. Long-term studies with inhaled budesonide in children at mean daily doses 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 (Turbuhaler 80/4.5 μg/dose).
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 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, particularly higher than the recommended doses, 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 or inhaling the maintenance dose.
Concomitant treatment with itraconazole, ritonavir or other potent CYP3A4 inhibitors should be avoided (see Interactions). If this is not possible, the time interval between administration of the interacting drugs should be as long as possible. In patients using potent CYP3A4 inhibitors, Symbicort 80/4.5 mcg turbuhaler and Rapihaler maintenance and reliever therapy is not recommended.
Symbicort 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 beta2-agonists. Concomitant treatment of beta2-agonists 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 beta2-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 beta2-agonists, additional blood glucose controls should be considered in diabetic patients.
Clinical studies and meta-analyses indicate that treatment of COPD with inhaled corticosteroids may lead to an increased risk of pneumonia. However, the absolute risk for budesonide is small. A meta-analysis of 11 COPD double blind trials including 10,570 patients did not demonstrate a statistically significant increased risk of pneumonia in patients treated with budesonide (with or without formoterol) compared to non-budesonide containing treatments (placebo or formoterol). The incidence rate of pneumonia reported as a serious adverse event was 1.9% per year on budesonide containing treatments and 1.5% per year on non-budesonide containing treatments. The pooled hazard ratio comparing all budesonide-containing versus non-budesonide containing treatments was 1.15 (95% CI: 0.83, 1.57). The pooled hazard ratio comparing budesonide/formoterol versus formoterol or placebo was 1.00 (95% CI: 0.69, 1.44). A causal relationship with budesonide-containing products has not been established.
Turbuhaler 160/4.5 μg/dose and Rapihaler: Dosing advice: When control has been achieved, the dose should be titrated to the lowest dose at which effective control of symptoms is maintained (Turbohaler 160/4.5 μg/dose).
If patients take Symbicort as maintenance therapy, they should be reminded to take Symbicort as prescribed even when asymptomatic.
Patients should be advised to have their rescue inhaler available at all times, either Symbicort (for asthma patients using Symbicort as anti-inflammatory reliever - therapy A or B) or a separate short-acting bronchodilator (for all patients using Symbicort as maintenance therapy only - therapy C).
To minimise the risk of oropharyngeal candida infection the patient should be instructed to rinse the mouth with water after each dosing occasion.
It is recommended that the maintenance dose is tapered when the treatment is discontinued and the dosing should not be stopped abruptly. Complete withdrawal of inhaled corticosteroids should not be considered unless it is temporarily required to confirm the diagnosis of asthma.
Deterioration of disease: Serious asthma-related adverse events and exacerbations may occur during treatment with Symbicort. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation with Symbicort.
If patients find the treatment ineffective, or exceed the current dose of the fixed combination, medical attention must be sought. 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 (Rapihaler), such as a course of oral corticosteroids, or antibiotic treatment if an infection is present. For treatment of severe exacerbations, a combination product of inhaled corticosteroid and long-acting β2 agonist alone is not sufficient.
Increasing use of rescue bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy (Rapihaler).
Paradoxical bronchospasm: As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. Symbicort should then be discontinued; treatment should be re-assessed and alternative therapy instituted if necessary.
Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway (see Adverse Reactions) (Turbohaler 160/4.5 μg/dose).
Systemic effects: 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.
More rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children) (Rapihaler).
Potential effects on bone density should be considered particularly in patients on high doses for prolonged periods that have coexisting risk factors for osteoporosis. Long-term studies with inhaled budesonide in children at mean daily doses 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.
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.
Transfer from oral therapy: 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 therapy.
Particular care is needed in patients transferring from oral steroids, since they may remain at risk of impaired adrenal function for a considerable time. Patients who have required high-dose emergency corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids, may also be at risk. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.
Interaction with other medicinal products: Concomitant treatment with itraconazole, ritonavir or other potent CYP3A4 inhibitors should be avoided (see Interactions). If this is not possible the time interval between administration of the interacting drugs should be as long as possible. In patients using potent CYP3A4 inhibitors, Symbicort anti-inflammatory reliever plus maintenance therapy is not recommended.
Caution with special diseases: Symbicort should be administered with caution in patients with severe cardiovascular disorders (including hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm, ischaemic heart disease, heart rhythm abnormalities or severe heart failure), phaeochromocytoma, diabetes mellitus, untreated hypokalaemia or thyrotoxicosis.
Caution should be observed when treating patients with prolongation of the QTc-interval. Formoterol itself may induce prolongation of the QTc-interval.
Potentially serious hypokalaemia may result from high doses of β2-agonists. Concomitant treatment of β2-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-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-agonists, additional blood glucose controls should be considered in diabetic patients.
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.
COPD population: There are no clinical study data on Symbicort 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) (Turbohaler 160/4.5 μg/dose).
Clinical studies and meta-analyses indicate that treatment of COPD with inhaled corticosteroids may lead to an increased risk of pneumonia. However, the absolute risk for budesonide is small. A meta-analysis of 11 COPD double blind trials including 10,570 patients did not demonstrate a statistically significant increased risk of pneumonia in patients treated with budesonide (with or without formoterol) compared to non-budesonide containing treatments (placebo or formoterol). The incidence rate of pneumonia reported as a serious adverse event was 1.9% per year on budesonide containing treatments and 1.5% per year on non-budesonide containing treatments. The pooled hazard ratio comparing all budesonide-containing versus non-budesonide containing treatments was 1.15 (95% CI: 0.83, 1.57). The pooled hazard ratio comparing budesonide/formoterol versus formoterol or placebo was 1.00 (95% CI: 0.69, 1.44). A causal relationship with budesonide-containing products has not been established.
Turbuhaler: Excipients: Symbicort 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.
Effects on the Ability to Drive and Use Machines: Tubuhaler: Symbicort Turbuhaler has no or negligible influence on ability to drive and use machines.
Rapihaler: Symbicort Rapihaler is not expected to adversely affect the ability to drive or use machines.
Use in Children: Turbuhaler 160/4.5 μg/dose and Rapihaler: 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.
Use In Pregnancy & Lactation
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 on approximately 2000 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 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.
Adverse Reactions
Since Symbicort contains both budesonide and formoterol, the same pattern of adverse reactions (Turbuhaler); type and intensity of undesirable effects (Rapihaler) 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 beta2-agonist therapy, such as tremor and palpitations. These tend to be mild and usually disappear within a few days of treatment.
Turbuhaler: 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).
Adverse reactions, which have been associated with budesonide or formoterol, are given as follows, listed by system organ class and frequency. Frequency is defined as: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000) and very rare (<1/10000).
Turbuhaler 80/4.5 and 320/9 μg/dose: (See Table 7.)

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Turbuhaler 160/4.5 μg/dose: (See Table 8.)

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As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases (see Precautions).
Systemic effects of inhaled corticosteroids may occur particularly at high doses prescribed for prolonged periods.
These include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract andglaucoma (see Precautions) (Turbuhaler 320/9 μg/dose).
Treatment with β2-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.
Rapihaler: Adverse reactions, which have been associated with budesonide or formoterol, are given as follows: (See Table 9.)

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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-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.
Drug Interactions
Beta-adrenergic blockers can weaken or inhibit the effect of formoterol. Symbicort should therefore not be given together with β-adrenergic blockers (including eye drops) unless there are compelling reasons.
Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants 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 eg, 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 β-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.
Turbuhaler: Ketoconazole 200 mg once daily increased plasma levels of concomitantly administered oral budesonide (single dose of 3 mg) on average 6-fold. When ketoconazole was administered 12 hrs after budesonide, the concentration was on average increased three-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected. Since data to give dosage recommendations are lacking, the combination should be avoided. If this is not possible, the time interval between administration of ketoconazole and budesonide should be as long as possible. A reduction in the dose of budesonide should also be considered. Other potent inhibitors of CYP3A4 are also likely to markedly increase plasma levels of budesonide. In patients using potent CYP3A4 inhibitors, Symbicort maintenance/anti-inflammatory reliever therapy is not recommended.
The metabolic conversion of budesonide is impeded by substances metabolized by CYP P-450 3A4 (eg, itraconazole, ritonavir). The concomitant administration of these potent inhibitors of CYP P-450 3A4 may increase plasma levels of budesonide. The concomitant use of these drugs should be avoided unless the benefit outweighs the increased risk of systemic side effects. (Turbuhaler 320/9 mcg).
Rapihaler: The metabolism of budesonide is primarily mediated by 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.
Caution For Usage
Instructions for Use/Handling: Turbuhaler: Read the complete instructions carfeully before start taking the medications.
Turbuhaler is a multidose inhaler from which very small amounts of powder are administered. When the patient breathe-in through turbuhaler, the powder is delivered in the lungs. It is therefore, important to inhale forcefully and deeply through the mouthpiece.
How to Prepare a New Inhaler for Use: Before using turbuhaler for the 1st time, prepare the inhaler for use: 1. Unscrew and lift off the cover. A rattling sound is heard when cover is unscrewed.
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 1 direction and then back again as far as it will go. It does not matter which way to turn first. During this procedure, there is a click sound. Perform the procedure twice.
The inhaler is now ready for use and the procedure should not be repeated. To take a dose, continue according to the instructions as follows.
How to use Symbicort Turbuhaler: To administer 1 dose, simply follow the following instructions.
1. Unscrew and lift off the cover. A rattling sound is heard when the cover is unscrewed.
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 1 direction and then back again as far as it will go. It does not matter which way is turn 1st. During this procedure, there is a click sound.
3. Breathe out. Do not breathe out through the mouthpiece.
4. Place the mouthpiece gently between the teeth, close 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 >1 dose has been prescribed, repeat steps 2-5.
7. Replace the cover by screwing it back on tightly.
8. Rinse 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 is 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 to inhale the dose if the instructions were followed.
If by mistake, the loading procedure must be performed more than once before taking the dose, receive only 1 dose. The dose indicator will however register all the loaded doses.
The sound heard upon shaking the inhaler is not produced by the medication but by a drying agent.
When to Replace the Inhaler: The dose indicator tells 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.
Be assured that the turbuhaler delivers the dose even if a movement in the dose indicator is not notice.
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.
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 of used turbuhaler responsibly in the recommended way since some of the medicine will remain inside it. Ask the pharmacist for advice.
Rapihaler: Patient's inhaler: Patient's inhaler will already be assembled when the patient first receive it. Please do not take the patient's inhaler apart. If it becomes loose, then place it back and continue to use it as instructed.
Preparing patient's inhaler for use: Take the inhaler out of the moisture-protective foil before the patient uses it for the first time and throw away the foil. If the inhaler is new, shake it gently and release 2 puffs if using the 80/2.25 or 160/4.5 or 80/4.5 micrograms/actuation inhaler to prepare it for use. If the inhaler has not been used for a week or more, or it has been dropped, shake it gently and release 2 puffs in the air to prepare it for use.
Taking Patient's medicine: 1. Shake the inhaler gently before each use.
2. Remove the mouthpiece cover.
3. Hold the inhaler upright in front of the mouth, using the thumb(s) at the base of the inhaler and the index finger(s) on the top. Then breathe out as far as the patient can and put the mouthpiece gently in the mouth, between the teeth, and close the lips around it.
4. Start to breathe in deeply, comfortably and slowly through the mouth, press firmly down on the inhaler to release a puff of medicine.
5. Continue to breathe in and hold the breath for approximately 10 seconds or as long as it is comfortable, take the inhaler from the mouth and the finger from the top of the inhaler.
6. Take another puff, as directed by the doctor, shake the inhaler gently then repeat steps 3 to 5.
7. Put the mouthpiece cover back to keep dust and other debris from getting into the medicine.
8. Rinse the mouth with water to remove any excess medicine.
Important Information: Cleaning Instructions: The inhaler mouthpiece will need to be cleaned regularly, at least once a week and to do this the patient will need to: 1. Remove the mouthpiece cover.
2. Wipe the inside and outside of the mouthpiece opening with a clean, dry cloth.
3. Replace the mouthpiece cover.
4. Do not put the inhaler in water.
5. Do not try to take the inhaler apart.
Reading the counter: The arrow on the counter on the top of the inhaler points to the number of puffs remaining in the inhaler. It starts with 120 puffs when it is full.
The counter will count down toward zero ("0") each time the patient releases a puff of medicine (either when preparing the inhaler for use or when taking the medicine).
When the arrow on the counter enters the yellow area, this means that there are about 20 puffs left.
It is very important that the patient should note the number of puffs remaining in the SYMBICORT inhaler by reading the counter. Discard SYMBICORT after the counter reaches zero ("0"), indicating that the patient has used the number of puffs on the product label and box. The inhaler may not feel empty and it may continue to operate, but the patient will not get the right amount of medicine if he/she keeps using it.
Instructions for use, handling and disposal: Rapihaler: See Dosage & Administration. The canister should not be broken, punctured or burnt, even when apparently empty.
The canister contains a pressurised liquid. Do not expose to temperatures above 50°C.
Instructions for the correct use of Symbicort Rapihaler with a spacer device: The use of Symbicort Rapihaler with a spacer device is recommended to enable patients with difficulty in co-ordinating inhalation with actuation, such as young children or the elderly, to derive greater therapeutic benefit.
It is important to instruct the patient to carefully read the instructions for use/handling in this monograph.
Incompatibilities: Not applicable.
Storage
Do not store above 30°C.
Turbuhaler: Keep the container tightly closed.
Rapihaler: Store the inhaler with the mouthpiece down.
Always replace the mouthpiece cover after using Symbicort Rapihaler.
Shelf-life: Rapihaler: The shelf life after removal from the foil pouch is 3 months.
ATC Classification
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.
Presentation/Packing
80/4.5 mcg turbuhaler 60 doses. 160/4.5 mcg turbuhaler 60 doses, 120 doses. 320/9 mcg turbuhaler 60 doses. 80/2.25 mcg rapihaler 120 actuations. 80/4.5 mcg rapihaler 120 actuations. 160/4.5 mcg rapihaler 120 actuations.
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