- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
AsthmaSymbicort Turbohaler is indicated in the regular treatment of asthma where use of a combination (inhaled corticosteroid and long-acting β2 adrenoceptor agonist) is appropriate:- patients not adequately controlled with inhaled corticosteroids and as needed inhaled short-acting β2 adrenoceptor agonists.or- patients already adequately controlled on both inhaled corticosteroids and long-acting β2 adrenoceptor agonists.
COPDSymptomatic treatment of patients with severe COPD (FEV1 < 50% predicted normal) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodilators.
AsthmaSymbicort Turbohaler is not intended for the initial management of asthma. The dosage of the components of Symbicort is individual and should be adjusted to the severity of the disease. This should be considered not only when treatment with combination products is initiated but also when the maintenance dose is adjusted. If an individual patient should require a combination of doses other than those available in the combination inhaler, appropriate doses of β2 adrenoceptor agonists and/or corticosteroids by individual inhalers should be prescribed.The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Patients should be regularly reassessed by their prescriber/health care provider so that the dosage of Symbicort remains optimal. When long-term control of symptoms is maintained with the lowest recommended dosage, then the next step could include a test of inhaled corticosteroid alone.For Symbicort there are two treatment approaches:A. Symbicort maintenance therapy: Symbicort is taken as regular maintenance treatment with a separate rapid-acting bronchodilator as rescue.B. Symbicort maintenance and reliever therapy: Symbicort is taken as regular maintenance treatment and as needed in response to symptoms.
A. Symbicort maintenance therapyPatients 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 inhalation twice daily. Some patients may require up to a maximum of 4 inhalations twice daily.Adolescents (12 17 years): 1-2 inhalations twice daily. In usual practice when control of symptoms is achieved with the twice daily regimen, titration to the lowest effective dose could include Symbicort given once daily, when in the opinion of the prescriber, a long-acting bronchodilator would be required to maintain control.Increasing use of a separate rapid-acting bronchodilator indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy.Children (6 years and older): A lower strength is available for children 6-11 years.Children under 6 years: As only limited data are available, Symbicort is not recommended for children younger than 6 years.
B. Symbicort maintenance and reliever therapyPatients take a daily maintenance dose of Symbicort and in addition take Symbicort as needed in response to symptoms. Patients should be advised to always have Symbicort available for rescue use.Symbicort maintenance and reliever therapy should especially be considered for patients with :• inadequate asthma control and in frequent need of reliever medication• asthma exacerbations in the past requiring medical interventionClose monitoring for dose-related adverse effects is needed in patients who frequently take high numbers of Symbicort as-needed inhalations.
Recommended doses:Adults (18 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. For some patients a maintenance dose of 2 inhalations twice daily may be appropriate. Patients should take 1 additional inhalation as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. Not more than 6 inhalations should be taken on any single occasion.A total daily dose of more than 8 inhalations is not normally needed; however, a total daily dose of up to 12 inhalations could be used for a limited period. Patients using more than 8 inhalations daily should be strongly recommended to seek medical advice. They should be reassessed and their maintenance therapy should be reconsidered.Children and adolescents under 18 years: Symbicort maintenance and reliever therapy is not recommended for children and adolescents.
Recommended doses:Adults: 2 inhalations twice daily
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.
Instructions for correct use of Turbohaler:Turbohaler 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 Symbicort Turbohaler after use• to rinse their mouth out with water after inhaling the maintenance 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 Symbicort Turbohaler due to the small amount of drug dispensed.
Pharmacokinetic interactionsPotent inhibitors of CYP3A4 (eg, ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and HIV protease inhibitors) are likely to markedly increase plasma levels of budesonide and concomitant use should be avoided. If this is not possible the time interval between administration of the inhibitor and budesonide should be as long as possible (section 4.4). In patients using potent CYP3A4 inhibitors, Symbicort maintenance and reliever therapy is not recommended.The potent CYP3A4 inhibitor ketoconazole, 200 mg once daily, increased plasma levels of concomitantly orally administered budesonide (single dose of 3 mg) on average six-fold. When ketoconazole was administered 12 hours after budesonide the concentration was on average increased only three-fold showing that separation of the administration times can reduce the increase in plasma levels. Limited data about this interaction for high-dose inhaled budesonide indicates that marked increase in plasma levels (on average four fold) may occur if itraconazole, 200 mg once daily, is administered concomitantly with inhaled budesonide (single dose of 1000 μg).Pharmacodynamic interactionsBeta-adrenergic blockers can weaken or inhibit the effect of formoterol. Symbicort should therefore not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons.Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), monoamine oxidase inhibitors and tricyclic 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 such as furazolidone and procarbazine, may precipitate hypertensive reactions.There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.Concomitant use of other beta-adrenergic drugs or anticholinergic drugs can have a potentially additive bronchodilating 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.
|SOC||Frequency||Adverse Drug reaction|
|Infections and infestations||Common||Candida infections in the oropharynx|
|Immune system disorders||Rare||Immediate and delayed hypersensitivity reactions, e.g. exanthema, urticaria, pruritus, dermatitis, angioedema and anaphylactic reaction|
|Endocrine disorders||Very rare||Cushing's syndrome, adrenal suppression, growth retardation, decrease in bone mineral density|
|Metabolism and nutrition disorders||Rare||Hypokalaemia|
|Psychiatric disorders||Uncommon||Aggression, psychomotor hyperactivity, anxiety, sleep disorders|
|Very rare||Depression, behavioural changes (predominantly in children)|
|Nervous system disorders||Common||Headache, tremor|
|Very rare||Taste disturbances|
|Eye disorders||Very rare||Cataract and glaucoma|
|Rare||Cardiac arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia, extrasystoles|
|Very rare||Angina pectoris. Prolongation of QTc-interval|
|Vascular disorders||Very rare||Variations in blood pressure|
|Respiratory, thoracic and mediastinal disorders||Common||Mild irritation in the throat, coughing, hoarseness|
|Skin and subcutaneous tissue disorders||Uncommon||Bruises|
|Musculoskeletal and connective tissue disorders||Uncommon||Muscle cramps|
Mechanisms of action and pharmacodynamic effectsSymbicort contains formoterol and budesonide, 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 either as maintenance and reliever therapy or as maintenance treatment of asthma.
BudesonideBudesonide is a glucocorticosteroid which when inhaled has a 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.
FormoterolFormoterol is a selective β2 adrenoceptor 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.
AsthmaClinical efficacy for budesonide/formoterol maintenance therapy 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 budesonide/formoterol 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 adrenoceptor agonist as needed. There was no sign of attenuation of the anti-asthmatic effect over time. Two 12-week paediatric studies have been performed in which 265 children aged 6-11 years were treated with a maintenance dose of budesonide/formoterol (2 inhalations of 80 micrograms /4.5 micrograms/inhalation twice daily), and a short acting beta2-adrenoceptor agonist as needed. In both studies, lung function was improved and the treatment was well tolerated compared to the corresponding dose of budesonide alone.
Clinical efficacy for budesonide/formoterol maintenance and reliever therapyA total of 12076 asthma patients were included in 5 double-blind clinical studies (4447 were randomised to budesonide/formoterol maintenance and reliever therapy) for 6 or 12 months. Patients were required to be symptomatic despite use of inhaled glucocorticosteroids. Budesonide/formoterol 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 budesonide/formoterol at a higher maintenance dose with terbutaline as reliever (study 735) and budesonide/formoterol 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 budesonide/formoterol 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.Table 2 Overview of severe exacerbations in clinical studies
|Study No. Duration||Treatment groups||n||Severe exacerbationsa|
|Study 735 6 months||Budesonide/formoterol 160/4.5 µg bd + as needed||1103||125||0.23b|
|Budesonide/formoterol 320/9 µg bd + terbutaline 0.4 mg as needed||1099||173||0.32|
|Salmeterol/fluticasone 2 x 25/125 µg bd + terbutaline 0.4 mg as needed||1119||208||0.38|
|Study 734 12 months||Budesonide/formoterol 160/4.5 µg bd + as needed||1107||194||0.19b|
|Budesonide/formoterol 160/4.5 µg bd + formoterol 4.5 µg as needed||1137||296||0.29|
|Budesonide/formoterol 160/4.5 µg bd + terbutaline 0.4 mg as needed||1138||377||0.37|
COPDIn two 12-month studies, the effects 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 severe COPD was evaluated. Median FEV1 at inclusion in the trials was 36% of predicted normal. The mean number of exacerbations per year (as defined above) was significantly reduced with budesonide/formoterol 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 budesonide/formoterol 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, budesonide/formoterol was not superior to treatment with formoterol alone.
AbsorptionThe fixed-dose combination of budesonide and formoterol, 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 the fixed-dose combination 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 the fixed-dose combination. 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 the powder inhaler ranged from 32% to 44% of the delivered dose. The systemic bioavailability is approximately 49% of the delivered dose. In children 6-16 years of age the lung deposition falls in the same range as in adults for the same given dose. The resulting plasma concentrations were not determined.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 the powder inhaler ranged from 28% to 49% of the delivered dose. The systemic bioavailability is about 61% of the delivered dose.
Distribution and metabolismPlasma 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.
EliminationThe 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 budesonide or formoterol in patients with renal failure are unknown. The exposure of budesonide and formoterol may be increased in patients with liver disease.
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