Symbicort Turbuhaler

Symbicort Turbuhaler

budesonide + formoterol

Manufacturer:

AstraZeneca

Distributor:

AstraZeneca
Full Prescribing Info
Contents
Budesonide, formoterol fumarate dihydrate.
Description
80 mcg/4.5 mcg: Each delivered dose contains as active constituents: budesonide 80 micrograms and formoterol fumarate dihydrate 4.5 micrograms.
For the mono products, the corresponding metered doses are 100 micrograms/inhalation for Budecort Turbuhaler (budesonide), and 6 micrograms/inhalation for Oxis Turbuhaler (formoterol fumarate dihydrate).
160 mcg/4.5 mcg: Each delivered dose contains as active constituents: budesonide 160 micrograms and formoterol fumarate dihydrate 4.5 micrograms.
For the mono products, the corresponding metered doses are 200 micrograms/inhalation for Budecort Turbuhaler (budesonide), and 6 micrograms/inhalation for Oxis Turbuhaler (formoterol fumarate dihydrate).
320 mcg/9 mcg: Each delivered dose contains as active constituents: budesonide 320 micrograms and formoterol fumarate dihydrate 9 micrograms.
For the mono products, the corresponding metered doses are: 400 micrograms/inhalation for Budecort Turbuhaler (budesonide), and 12 micrograms/inhalation for Oxis Turbuhaler (formoterol fumarate dihydrate).
Formoterol fumarate dihydrate is hereafter referred to as 'formoterol'.
Excipients/Inactive Ingredients: Lactose monohydrate (which may contain milk protein residue).
Action
Pharmacotherapeutic group: Adrenergics and other drugs for obstructive airway diseases. ATC code: R03AK07.
Pharmacology: Pharmacodynamics: Mechanisms of action and pharmacodynamic effects: 80 mcg/4.5 mcg & 160 mcg/4.5 mcg: Budesonide/Formoterol (SYMBICORT TURBUHALER) contains budesonide and formoterol, which have different modes of action and show additive effects in terms of reduction of asthma exacerbations. The specific properties of budesonide and formoterol allow the combination to be used both as inflammatory reliever plus maintenance therapy, and as maintenance treatment of asthma.
320 mcg/9 mcg: Budesonide/Formoterol (Symbicort) contains formoterol and budesonide, which have different modes of action and show additive effects in terms of reduction of asthma and COPD exacerbations. The respective mechanisms of action of both drugs are discussed as follows.
Budesonide: 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. The exact mechanism responsible for the anti-inflammatory effect of glucocorticosteroids is unknown.
Formoterol: Formoterol is a selective beta2-adrenergic agonist that when inhaled results in rapid and long-acting relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect is dose dependent, with an onset of effect within 1-3 minutes. The duration of effect is at least 12 hours after a single dose.
Budesonide/Formoterol (SYMBICORT TURBUHALER): Clinical Efficacy in asthma for Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 Budesonide/Formoterol (SYMBICORT TURBUHALER), 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-agonist as needed. There was no sign of attenuation of the anti-asthmatic effect over time.
80 mcg/4.5 mcg: Clinical Efficacy for Budesonide/Formoterol (SYMBICORT) maintenance and reliever therapy in asthma: A total of 12076 asthma patients were included in 5 double-blind clinical studies (4447 were randomised to Budesonide/Formoterol (SYMBICORT) maintenance and reliever therapy) for 6 or 12 months. Patients were required to be symptomatic despite daily use of inhaled glucocorticosteroids. Budesonide/Formoterol (SYMBICORT) maintenance and reliever therapy provided statistically significant and clinically meaningful reductions in severe exacerbations by prolonging time to first event and reducing the event rate (Table 1), as compared with all comparator treatments, including Budesonide/Formoterol (SYMBICORT) at a higher maintenance dose (in Study 735). Symptom control, lung function and reliever use were similar compared with a higher maintenance dose of Budesonide/Formoterol (SYMBICORT), and all three parameters were improved compared with Budesonide/Formoterol (SYMBICORT) at the same maintenance dose or budesonide at a 2 to 4 times higher maintenance dose. (See Table 1.)

Click on icon to see table/diagram/image

In Study 735, Budesonide/Formoterol (SYMBICORT) maintenance and reliever therapy significantly prolonged the time to the first exacerbation (see Figure 1) compared to the other treatment groups. The rate of exacerbations was reduced by 28% compared to twice the maintenance dose of Budesonide/Formoterol (SYMBICORT) with terbutaline as reliever. Lung function, symptom control, and reliever use were similar in all treatment groups.

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In Study 734, Budesonide/Formoterol (SYMBICORT) maintenance and reliever therapy prolonged the time to the first exacerbation compared to Budesonide/Formoterol (SYMBICORT) at the same maintenance dose with either formoterol or terbutaline as reliever (see Figure 2). 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 Studies 673, 668 and 667, Budesonide/Formoterol (SYMBICORT) maintenance and reliever therapy prolonged the time to the first exacerbation compared to Budesonide/Formoterol (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. Across the 3 studies, the rate of exacerbations was reduced by 45-76%. Symptoms and reliever use were reduced and lung function improved compared with all other treatments. For children (118 randomised to Budesonide/Formoterol (SYMBICORT) maintenance and reliever therapy in study 673), the exacerbation rate was reduced by 70-79%.
In the 5 long-term studies, patients (adults and adolescents) receiving Budesonide/Formoterol (SYMBICORT) maintenance and reliever therapy was allowed 12 inhalations per day (maintenance and as needed) without being reassessed. On average, no reliever inhalation was used on 57% of treatment days and 0-2 reliever inhalations on 87% of treatment days. There was no sign of development of tolerance over time.
In 2 studies with patients seeking medical attention due to acute asthma symptoms, Budesonide/Formoterol (SYMBICORT) provided rapid and effective relief of bronchoconstriction similar to salbutamol and formoterol.
160 mcg/4.5 mcg: Clinical Efficacy for Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 agonist) plus short-acting inhaled bronchodilator as needed.
In the SYGMA 2 study, Budesonide/Formoterol (SYMBICORT TURBUHALER) 160/4.5 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 Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 treatment' 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 Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever therapy compared to patients on as-needed short-acting β2 agonist treatment. Statistically significantly smaller increases were observed for Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 clinical studies (4447 were randomised to Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy - therapy B) for 6 or 12 months. Patients were required to be symptomatic despite daily use of inhaled glucocorticosteroids. Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy provided statistically significant and clinically meaningful reductions in severe exacerbations by prolonging time to first event and reducing the event rate (Table 2), as compared with all comparator treatments, including Budesonide/Formoterol (SYMBICORT TURBUHALER) at a higher maintenance dose (in Study 735). Symptom control, lung function and reliever use were similar compared with a higher maintenance dose of Budesonide/Formoterol (SYMBICORT TURBUHALER), and all three parameters were improved compared with Budesonide/Formoterol (SYMBICORT TURBUHALER) at the same maintenance dose or budesonide at a 2 to 4 times higher maintenance dose. (See Table 2.)

Click on icon to see table/diagram/image

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 Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever therapy - therapy A) over the 1 year treatment period (see Figure 1a), 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 Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 Figure 3 and Figure 4).

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In Study 735, Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy (therapy B) significantly prolonged the time to the first exacerbation (see Figure 5) compared to the other treatment groups. The rate of exacerbations was reduced by 28% compared to twice the maintenance dose of Budesonide/Formoterol (SYMBICORT TURBUHALER) with terbutaline as reliever. Lung function, symptom control, and reliever use were similar in all treatment groups.

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In Study 734, Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy (therapy B) prolonged the time to the first exacerbation compared to Budesonide/Formoterol (SYMBICORT TURBUHALER) at the same maintenance dose with either formoterol or terbutaline as reliever (see Figure 6). 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 Studies 673, 668 and 667, Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy (therapy B) prolonged the time to the first exacerbation compared to Budesonide/Formoterol (SYMBICORT TURBUHALER) 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. Across the 3 studies, the rate of exacerbations was reduced by 45-76%. Symptoms and reliever use were reduced and lung function improved compared with all other treatments. For children (118 randomised to Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy (therapy B) in study 673), the exacerbation rate was reduced by 70-79%.
In the 5 long-term studies, patients (adults and adolescents) receiving Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy (therapy B) was allowed 12 inhalations per day (maintenance and as needed) without being reassessed. On average, no reliever inhalation was used on 57% of treatment days and 0-2 reliever inhalations on 87% of treatment days. There was no sign of development of tolerance over time.
In 2 separate studies with patients seeking medical attention due to acute asthma symptoms, Budesonide/Formoterol (SYMBICORT TURBUHALER) provided rapid and effective relief of bronchoconstriction similar to salbutamol and formoterol.
160 mcg/4.5 mcg & 320 mcg/9 mcg: Clinical Efficacy in Chronic Obstructive Pulmonary disease COPD: In two 12-month studies in patients with COPD, Budesonide/Formoterol (SYMBICORT TURBUHALER) was superior to placebo, formoterol and budesonide regarding lung function and showed a significant reduction in the exacerbation rate compared with placebo and formoterol. Thus, the contribution of both budesonide and formoterol to the effect of Budesonide/Formoterol (SYMBICORT TURBUHALER) was demonstrated. Budesonide/Formoterol (SYMBICORT TURBUHALER) was also superior to placebo regarding symptoms and quality of life. The treatment was well tolerated.
Pharmacokinetics: Absorption: Budesonide/Formoterol (SYMBICORT TURBUHALER) and the corresponding monoproducts (Budecort Turbuhaler and Oxis Turbuhaler, respectively) have been shown to be bioequivalent with regard to systemic exposure of budesonide and formoterol, respectively.
There was no evidence of pharmacokinetic interactions between budesonide and formoterol.
Pharmacokinetic parameters for the respective substances were comparable after the administration of budesonide and formoterol as monoproducts or as Budesonide/Formoterol (SYMBICORT TURBUHALER).
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 Pulmicort Turbuhaler ranged from 32% to 44% of the delivered dose. The systemic bioavailability is approximately 49% of the delivered dose. In children, the plasma concentration and lung deposition fall in the same range as in adults.
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 Oxis Turbuhaler ranged from 28% to 49% of the delivered dose. The systemic availability 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 (approximately 90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxy-budesonide and 16α-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 eliminated by metabolism in the liver followed by renal excretion. After inhalation, 8% to 13% of the delivered dose of formoterol is excreted unmetabolised in the urine. Formoterol has a high systemic clearance (approx 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 excreted 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 (approx 1.2 L/min) and the plasma elimination half-life after IV dosing averages 4 hours.
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 and formoterol in elderly and 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 was similar whether budesonide or formoterol were given in combination or separately. The effects were associated with pharmacological actions and dose dependent.
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 (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 man.
Indications/Uses
Asthma: Budesonide/Formoterol (SYMBICORT TURBUHALER) is indicated in the treatment of asthma where use of a combination (inhaled corticosteroid and long-acting beta2-agonist) is appropriate.
160 mcg/4.5 mcg: Budesonide/Formoterol (SYMBICORT TURBUHALER) 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.
Budesonide/Formoterol (SYMBICORT TURBUHALER) is suitable for any asthma severity, where the use of inhaled corticosteroids is appropriate.
160 mcg/4.5 mcg & 320 mcg/9 mcg: COPD: Budesonide/Formoterol (SYMBICORT TURBUHALER) is indicated in the regular treatment of patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD), with frequent symptoms and a history of exacerbations.
Dosage/Direction for Use
80 mcg/4.5 mcg: The dosage of Budesonide/Formoterol (SYMBICORT TURBUHALER) should be individualised according to disease severity.
When control has been achieved, the dose should be titrated to the lowest dose at which effective control of symptoms is maintained.
For Budesonide/Formoterol (SYMBICORT) there are two alternative therapies: Budesonide/Formoterol (SYMBICORT ) maintenance and reliever therapy (SMART): Budesonide/Formoterol (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 Budesonide/Formoterol (SYMBICORT) available for rescue use at all times. A separate inhaler for rescue use is not necessary.
Clinical studies have demonstrated that Budesonide/Formoterol (SYMBICORT) maintenance and reliever therapy provides clinically meaningful reductions in severe exacerbations while maintaining symptom control, compared to Budesonide/Formoterol (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 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.
Children (4 years and older): The usual maintenance dose is 1 inhalation once daily. 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 4 inhalations should be taken on any single occasion.
A total daily dose of more than 8 inhalations for adults and adolescents and 4 inhalations for children is normally not needed, however a total daily dose of up to 12 inhalations for adults and adolescents and 8 inhalations for children can be used temporarily. If the patient experiences deteriorating symptoms after taking the appropriate maintenance therapy and additional as needed inhalations, the patient should be reassessed for alternative explanations of persisting symptoms.
Budesonide/Formoterol (SYMBICORT) maintenance therapy: Budesonide/Formoterol (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.
Adults (18 years and older): 1-2 inhalations once or twice daily. In some cases up to a maximum of 4 inhalations twice daily may be required as maintenance dose or temporarily during worsening of asthma.
Adolescents (12-17 years): 1-2 inhalations once or twice daily. During worsening of asthma the dose may temporarily be increased to a maximum of 4 inhalations twice daily.
Children (4 years and older): 1-2 inhalations twice daily. Maximum daily dose: 4 inhalations.
Increasing use of a separate rapid acting bronchodilator indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy.
General information: The patient should be instructed to take the maintenance dose of Budesonide/Formoterol (SYMBICORT TURBUHALER) even when asymptomatic for optimal benefit.
There are no special dosing requirements for elderly patients.
There are no data available for use of Budesonide/Formoterol (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 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 in the patient information leaflet which is packed together with each inhaler.
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 Budesonide/Formoterol (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 Turbuhaler due to the small amount of drug dispensed.
160 mcg/4.5 mcg: The dosage of Budesonide/Formoterol (SYMBICORT TURBUHALER) should be individualised according to disease severity.
Asthma: Budesonide/Formoterol (SYMBICORT TURBUHALER) can be used according to different treatment approaches: A. Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever therapy.
B. Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy.
As an alternative, Budesonide/Formoterol (SYMBICORT TURBUHALER) can be used in a fixed dose therapy: C. Symbicort maintenance therapy.
Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever therapy (patients with mild disease): Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 Budesonide/Formoterol (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 Budesonide/Formoterol (SYMBICORT TURBUHALER) available for relief of symptoms.
Clinical studies have demonstrated that Budesonide/Formoterol (SYMBICORT TURBUHALER) 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).
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 (4 years and older): Efficacy and safety of Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever therapy in children 4-11 years have not been studied.
Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy: When maintenance treatment with a combination of inhaled corticosteroid and long-acting β2 agonist is required, Budesonide/Formoterol (SYMBICORT TURBUHALER) is taken as anti-inflammatory reliever therapy and in addition, patients take a daily maintenance dose of Budesonide/Formoterol (SYMBICORT TURBUHALER). The as needed inhalations provide both rapid relief of symptoms and improved overall asthma control. Patients should be advised to have Budesonide/Formoterol (SYMBICORT TURBUHALER) available for relief of symptoms at all times. A separate inhaler for relief of symptoms is not necessary.
Clinical studies have demonstrated that Budesonide/Formoterol (SYMBICORT TURBUHALER) anti-inflammatory reliever plus maintenance therapy provides clinically meaningful reductions in severe exacerbations while maintaining symptom control, compared to Budesonide/Formoterol (SYMBICORT TURBUHALER) 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 normally not needed, however a total daily dose of up to 12 inhalations can be used temporarily. If the patient experiences 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 (4 years and older): A lower strength is available for children 4-11 years.
Budesonide/Formoterol (SYMBICORT TURBUHALER) maintenance therapy (fixed dose): When maintenance treatment with a combination of inhaled corticosteroid and long-acting β2 agonist is required, Budesonide/Formoterol (SYMBICORT TURBUHALER) is taken as a fixed daily dose treatment, with a separate short-acting bronchodilator for relief of symptoms. Patients should be advised to have their separate short-acting bronchodilator available for relief of symptoms at all times.
Recommended doses: Adults (18 years and older): 1-2 inhalations twice daily. In some cases, up to a maximum of 4 inhalations twice daily may be required as maintenance dose or temporarily during worsening of asthma.
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 (4 years and older): 1 inhalation twice daily. Maximum daily dose: 2 inhalations.
When control has been achieved, the dose should be titrated to the lowest dose at which effective control of symptoms is maintained.
COPD: Adults (18 years and older): 2 inhalations twice daily. Maximum daily dose: 4 inhalations.
General information: If patients take Budesonide/Formoterol (SYMBICORT TURBUHALER) as a maintenance therapy, they should be instructed to take the maintenance dose of Budesonide/Formoterol (SYMBICORT TURBUHALER) even when asymptomatic for optimal benefit.
There are no special dosing requirements for elderly patients.
There are no data available for use of Budesonide/Formoterol (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 diseases.
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 in the patient information leaflet which is packed together with each inhaler.
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 Budesonide/Formoterol (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 Turbuhaler due to the small amount of drug dispensed.
320 mcg/9 mcg: The dosage of Budesonide/Formoterol (Symbicort Turbuhaler) should be individualised according to disease severity.
When control has been achieved, the dose should be titrated to the lowest dose at which effective control of symptoms is maintained.
BUDESONIDE/FORMOTEROL (SYMBICORT) MAINTENANCE THERAPY: Budesonide/Formoterol (Symbicort) taken as regular maintenance treatment, with a separate rapid-acting bronchodilator as rescue. Patients should be adviced to have their separate rapid-acting bronchodilator available for rescue use at all times.
Recommended doses: Asthma: Adults (18 years and older): 1 inhalation once or twice daily. In some cases up to a maximum of 2 inhalations twice daily may be required as maintenance dose or temporarily during worsening of asthma.
Adolescents (12-17 years): 1 inhalation once or twice daily. During worsening of asthma the dose may temporarily be increased to a maximum of 2 inhalations twice daily.
Children (4 years and older): Efficacy and safety have not been studied in children for Budesonide/Formoterol (Symbicort) 320/9 micrograms/inhalation.
Budesonide/Formoterol (Symbicort) 320/9 micrograms/inhalation should be used as Budesonide/Formoterol (Symbicort) maintenance therapy only. Lower strengths are available for the Budesonide/Formoterol (Symbicort) maintenance and reliever therapy regimen.
COPD: Adult (18 years and older): 1 inhalation twice daily. Maximum daily dose: 2 inhalations.
General information: The patient should be instructed to take the maintenance dose of Budesonide/Formoterol (Symbicort Turbuhaler) even when asymptomatic for optimal benefit.
There are no special dosing requirements for elderly patients.
There are no data available for use of Budesonide/Formoterol (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 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 in the patient information leaflet which is packed together with each inhaler.
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 Budesonide/Formoterol (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 Turbuhaler due to the small amount of drug dispensed.
Overdosage
An overdose of formoterol would likely lead to effects that are typical for beta2-adrenergic agonists: tremor, headache, palpitations, and tachycardia. Hypotension, metabolic acidosis, hypokalemia 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 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 may appear.
Contraindications
Hypersensitivity to budesonide, formoterol or inhaled lactose.
Special Precautions
Budesonide/Formoterol (SYMBICORT TURBUHALER) is not expected to adversely affect the ability to drive or use machines.
80 mcg/4.5 mcg: It is recommended that the dose is tapered when long-term treatment is discontinued and should not be stopped abruptly.
If patients find the treatment ineffective, or exceed the highest recommended dose of Budesonide/Formoterol (SYMBICORT TURBUHALER), medical attention must be sought. Sudden and progressive deterioration in control of asthma 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 an infection is present.
Treatment with Budesonide/Formoterol (SYMBICORT TURBUHALER) should not be initiated to treat a severe exacerbation.
Physicians should closely follow the growth of children and adolescents taking long-term corticosteroids by any route, and weigh the benefits of the corticosteroid therapy against the possible risk of growth suppression (see Pharmacology: Pharmacodynamics under Actions).
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 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.
Budesonide/Formoterol (SYMBICORT TURBUHALER) should be administered with caution in patients with severe cardiovascular disorders (including heart rhythm abnormalities), diabetes mellitus, untreated hypokalaemia or thyrotoxicosis.
High doses of beta2-agonists can lower s-potassium by inducing a redistribution of potassium from the extracellular to the intracellular compartment, via stimulation of Na+/K+-ATPase in muscle cells. The clinical importance of this effect is uncertain.
Budesonide/Formoterol (SYMBICORT TURBUHALER) contains lactose (<1 mg/inhalation). This amount does not normally cause problems in lactose intolerant people.
160 mcg/4.5 mcg: Dosing advice: 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 inhaled corticosteroids should not be considered unless it is temporarily required to confirm the diagnosis of asthma.
Deterioration of disease: If patients find the treatment ineffective, or exceed the highest recommended dose of Budesonide/Formoterol (SYMBICORT TURBUHALER), 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, eg, 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.
Transfer from oral 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.
Excipients: Budesonide/Formoterol (SYMBICORT TURBUHALER) contains lactose (<1 mg/inhalation). This amount does not normally cause problems in lactose intolerant people.
Caution with special diseases: Budesonide/Formoterol (SYMBICORT TURBUHALER) should be administered with caution in patients with severe cardiovascular disorders (including heart rhythm abnormalities), diabetes mellitus, untreated hypokalaemia or thyrotoxicosis.
High doses of β2 agonists can lower serum potassium by inducing a redistribution of potassium from the extracellular to the intracellular compartment, via stimulation of Na+/K+- ATPase in muscle cells. The clinical importance of this effect is uncertain.
COPD population: 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.
Use in Children: Physicians should closely follow the growth of children and adolescents taking long-term corticosteroids by any route, and weigh the benefits of the corticosteroid therapy against the possible risk of growth suppression (see Pharmacology: Pharmacodynamics under Actions).
320 mcg/9 mcg: It is recommended that the dose is tapered when long-term treatment is discontinued and should not be stopped abruptly.
If patients find the treatment ineffective, or exceed the prescribed dose of Budesonide/Formoterol (SYMBICORT TURBUHALER), medical attention must be sought. Increasing use of rapid acting bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the therapy. In asthma, consideration should be given to the need for increased therapy with Budesonide/Formoterol (SYMBICORT TURBUHALER) or the addition of inhaled corticosteroids and/or long acting beta2-agonists or a course of oral corticosteroids. In COPD, consideration should be given to the need for adding a course of oral corticosteroids, and/or antibiotic treatment if an infection is present.
Patients should be advised to have their rapid-acting bronchodilator available at all times.
Treatment with Budesonide/Formoterol (SYMBICORT TURBUHALER) should not be initiated to treat a severe exacerbation.
Physicians should closely follow the growth of children and adolescents taking long-term corticosteroids by any route, and weigh the benefits of the corticosteroid therapy against the possible risk of growth suppression (see Pharmacology: Pharmacodynamics under Actions).
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.
Budesonide/Formoterol (SYMBICORT TURBUHALER) should be administered with caution in patients with severe cardiovascular disorders (including heart rhythm abnormalities), diabetes mellitus, untreated hypokalaemia or thyrotoxicosis.
High doses of beta2-agonists can lower s-potassium by inducing a redistribution of potassium from the extracellular to the intracellular compartment, via stimulation of Na+/K+-ATPase in muscle cells. The clinical importance of this effect is uncertain.
Budesonide/Formoterol (SYMBICORT TURBUHALER) contains lactose (<1 mg/inhalation). This amount does not normally cause problems in lactose intolerant people.
Use In Pregnancy & Lactation
For Budesonide/Formoterol (SYMBICORT TURBUHALER) or the concomitant treatment with budesonide and formoterol, no clinical data on exposed pregnancies are available. Data from an embryo-fetal development study in the rat, using the Budesonide/Formoterol (SYMBICORT) pMDI formulation, showed no evidence of any additional effect from the combination or evidence of any effects attributable to the excipients on the rodent.
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 (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Data on approximately 2500 exposed pregnancies indicate no increased teratogenic risk associated with the use of inhaled budesonide.
During pregnancy, Budesonide/Formoterol (SYMBICORT TURBUHALER) should only be used after special consideration, especially during the first three months and shortly before delivery. The lowest effective dose of budesonide needed to maintain adequate asthma control should be used.
A Clinical Pharmacology Study has shown that inhaled budesonide is excreted in breast milk. However, budesonide was not detected in nursing infant blood samples. Based on pharmacokinetic parameters, the plasma concentration in the child is estimated be less than 0.17% of the mother's plasma concentration. Consequently, no effects due to budesonide are anticipated in breast-fed children whose mothers are receiving therapeutic doses of Budesonide/Formoterol (SYMBICORT). 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 Budesonide/Formoterol (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 Budesonide/Formoterol (SYMBICORT TURBUHALER) contains both budesonide and formoterol, the same type and intensity 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-agonist therapy, such as tremor and palpitations. These tend to be mild and disappear within a few days of treatment.
Adverse reactions, which have been associated with budesonide or formoterol, are given as follows in Table 3. (See Table 3.)

Click on icon to see table/diagram/image
Drug Interactions
Pharmacokinetic interactions: The metabolism of budesonide is primarily mediated by the enzyme CYP3A4. Inhibitors of this enzyme, eg, ketoconazole, may therefore increase systemic exposure to budesonide. This is of limited clinical importance for short-term (1-2 weeks) treatment with ketoconazole, but should be taken into consideration during long-term treatment with ketoconazole.
Pharmacodynamic interactions: Beta-adrenergic blockers (including eye drops) can weaken or inhibit the effect of formoterol.
Budesonide and formoterol have not been observed to interact with any other drug used in the treatment of asthma.
Caution For Usage
Instructions for Use, Handling and Disposal: Please read the complete instructions carefully before starting the medication.
Budesonide/Formoterol (SYMBICORT TURBUHALER): Powder for Inhalation.
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 Budesonide/Formoterol (SYMBICORT 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 to turn 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 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 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 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 approximately how many doses are left in the inhaler, starting with 60 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 the patient 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 other 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.
Incompatibilities: Not applicable.
Storage
Store at a temperature not exceeding 30°C. Store with cover tightened.
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 mcg/4.5 mcg turbuhaler 60 doses. 160 mcg/4.5 mcg turbuhaler 60 doses. 320 mcg/9 mcg turbuhaler 60 doses.
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