Symbicort Turbohaler 200/6

  • Name:

    Symbicort Turbohaler 200/6

  • Company:
    info
  • Active Ingredients:

    Budesonide, Formoterol fumarate dihydrate

  • Legal Category:

    Product subject to medical prescription which may be renewed (B)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 17/09/19

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Summary of Product Characteristics last updated on medicines.ie: 17/9/2019

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AstraZeneca Pharmaceuticals (Ireland) DAC

AstraZeneca Pharmaceuticals (Ireland) DAC

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1 - 0 of 56 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 17 September 2019 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 17 September 2019 PIL

Reasons for updating

  • Change to section 1 - what the product is used for
  • Change to section 3 - how to take/use
  • Change to section 4 - how to report a side effect
  • Change to section 6 - date of revision

Updated on 1 February 2019 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder

Updated on 1 February 2019 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - Marketing authorisation number(s)
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Update to section 7         Change of MAH details

Update to section 8         New licence number

Update to section 10       Update to date of revision of text

Updated on 17 January 2019 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 21 November 2018 SmPC

Reasons for updating

  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Date of revision of text amended from 06/06/2018 to 05/06/2018 (this was a typographical error). 

Updated on 6 June 2018 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Update to section 6.5  - inclusion of a 30 dose pack.

Updated on 6 June 2018 PIL

Reasons for updating

  • Change to section 3 - how to take/use
  • Change to section 6 - what the product looks like and pack contents
  • Change to section 6 - date of revision

Updated on 22 November 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 22 November 2017 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Update to section 4.4     Inclusion of paragraph regarding visual disturbances

Update to section 4.8     Addition of adverse drug reaction under “eye disorders”.

Update to section 10       Update to date of revision of text

Updated on 20 November 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 20 November 2017 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 12 July 2017 SmPC

Reasons for updating

  • Change to section 6.4 - Special precautions for storage
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Update to section 6.4  - Removal of storage restriction

Update to section 10  - Date of revision of text

Updated on 7 July 2017 PIL

Reasons for updating

  • Change to section 5 - how to store or dispose
  • Change to section 6 - date of revision

Updated on 16 February 2017 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Change to section 4.1 – Update to age range

Change to section 4.2 – Update to age range for SMART indication and other editorial changes

Change to section 4.5 – Inclusion of statement regarding Hypokalaemia

Change to section 5.1 – Inclusion of statement regarding efficacy and safety in adolescents and adults

Change to section 10 – Update to date of revision of text

Updated on 15 February 2017 PIL

Reasons for updating

  • Change to section 3 - how to take/use
  • Change to section 4 - possible side effects
  • Correction of spelling/typing errors
  • Improved presentation of PIL

Updated on 21 November 2016 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

 

Change to section 2      Editorial changes in line with QRD v9.1

Change to section 4.1    Editorial changes

Change to section 4.2    Editorial changes

Change to section 4.4    Inclusion of detail regarding Pneumonia in patients with COPD

Change to section 4.5    Editorial changes

Change to section 4.6    Formating changes

Change to section 4.8    Update to Pneumonia side-effect information and editorial and formating changes

Change to section 5.1    Change to pharmacotherapeutic group and editorial changes

Change to section 5.2    Editorial and formating updates

Change to section 10     Update to date of revision of text.

Updated on 18 November 2016 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision
  • Correction of spelling/typing errors

Updated on 25 November 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 4.2 – extended the indication for COPD from Severe COPD with FEV1<50% to COPD with FEV1<70%

Section 4.4 – confirmed the FEV range for clinical studies on COPD patients

Section 4.8 – updated the HPRA contact details

Section 5.1 – included details of moderate COPD studies

Section 10 – date of revision of the text updated to 12th November 2015

Updated on 25 November 2015 PIL

Reasons for updating

  • Change to, or new use for medicine
  • Change to date of revision
  • Change to improve clarity and readability
  • Addition of information on reporting a side effect.

Updated on 10 November 2014 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text
  • Change to improve clarity and readability

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 2 – Editorial QRD changes

Section 4.1 – clarification of population that medicine is indicated in.

Section 4.2 - Editorial QRD changes

Section 4.3 - Editorial QRD changes

Section 4.4 - Editorial QRD changes, movement of paediatric population section.

Section 4.5 – Removal of MOI interaction and editorial QRD changes

Section 4.6 – Addition of Fertility information and editorial QRD changes

Section 4.8 – Update to include recent data that better reflects the current knowledge regarding pneumonia. Information added on oropharyngeal thrush, addition of AE reporting information and editorial QRD changes

Section 5.1 – Editorial QRD changes

Section 5.2 – Addition of information on Linearity/Non-linearity and editorial QRD changes

Section 6.6 – Editorial QRD changes

Section 9 – Update to “date of last renewal”

Section 10 – Update to "Date of Revision"

Updated on 6 November 2014 PIL

Reasons for updating

  • Change to drug interactions
  • Change to how the medicine works
  • Change to further information section
  • Change to date of revision
  • Change to improve clarity and readability
  • Addition of information on reporting a side effect.

Updated on 9 August 2013 PIL

Reasons for updating

  • Improved electronic presentation

Updated on 15 March 2013 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

- Section 5.1 Pharmacodynamic properties
Addition of paediatric data.
-Section 10 updated date of revision of text

Updated on 13 March 2013 PIL

Reasons for updating

  • Change to date of revision
  • Change to dosage and administration

Updated on 7 December 2011 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 4.4

 

Paragraph 9 – following text added to end of paragraph

 

, and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children) (see section 4.8).

Section 4.8

 

Table 1

 

Psychiatric disorders

 

Uncommon changed to:

 

Aggression, psychomotor hyperactivity, anxiety, sleep disorders

 

Very rare changed to:

 

Depression, behavioural changes (predominantly in children)

 


Section 10

 

Date of revision changed to 25th November 2011

Updated on 6 December 2011 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to date of revision
  • Improved electronic presentation

Updated on 29 September 2011 PIL

Reasons for updating

  • Change to drug interactions
  • Change to date of revision

Updated on 29 September 2011 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

 

Section 4.5

Amended to

Pharmacokinetic interactions

Potent 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 (see section 4.4).

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 increases 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).

Section 10


Date of Revision changed to 14th September 2011

Updated on 27 April 2011 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text
  • Change to section 4.4 - Special warnings and precautions for use

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

200-6

 

Section 2

Second paragraph replaced with,

 

“Each metered dose contains: budesonide 200 micrograms/inhalation and formoterol fumarate dihydrate 6 micrograms/inhalation.”

 

Section 4.1

Throughout section, the word ‘beta’ replaced with ‘β2 adrenoceptor’.

 

Section 4.2

New first paragraph, reads as,

 

” Route of administration: For inhalation use.”

 

Final paragraph under A.Symbicort maintenance therapy changed.  Now reads as,

 

Children under 6 years: As only limited data are available, Symbicort is not recommended for children younger than 6 years.”

Section 4.4

Minor and significant changes made throughout section, now reads as,

 

Special warning and precautions for use

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 (see section 4.2). 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 e.g. 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 their Symbicort maintenance dose 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 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 section 4.2).

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

As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing and shortness of breath after dosing. If the patient experiences paradoxical bronchospasm Symbicort should be discontinued immediately, the patient should be assessed and an alternative therapy instituted if necessary. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway.

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 Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma.

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of inhaled corticosteroid to the lowest dose at which effective control of asthma is maintained, if possible. 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 1cm) 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 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. Recovery may take a considerable amount of time after cessation of oral steroid therapy and hence oral steroid‑dependent patients transferred to inhaled budesonide may remain at risk from impaired adrenal function for some considerable time. In such circumstances HPA axis function should be monitored regularly.

The prolonged treatment with high doses of inhaled corticosteroids, particularly higher than recommended doses, may also result in clinically significant adrenal suppression. Therefore additional systemic corticosteroid cover should be considered during periods of stress such as severe infections or elective surgery. Rapid reduction in the dose of steroids can induce acute adrenal crisis. Symptoms and signs which might be seen in acute adrenal crisis may be somewhat vague but may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, decreased level of consciousness, seizures, hypotension and hypoglycaemia.

Treatment with supplementary systemic steroids or inhaled budesonide should not be stopped abruptly.

During transfer from oral therapy to Symbicort, a generally lower systemic steroid action will be experienced which may result in the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiated for these conditions. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of oral glucocorticosteroids is sometimes necessary.

 

To minimise the risk of oropharyngeal candida infection, the patient should be instructed to rinse their mouth out with water after inhaling the maintenance dose. If oropharyngeal thrush occurs, patients should also rinse their mouth with water after the as-needed inhalations.

Concomitant treatment with itraconazole, ritonavir or other potent CYP3A4 inhibitors should be avoided (see section 4.5). 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 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 β2 adrenoceptor agonists. Concomitant treatment of β2 adrenoceptor agonists with drugs which can induce hypokalaemia or potentiate a hypokalaemic effect, e.g xanthine-derivatives, steroids and diuretics, may add to a possible hypokalaemic effect of the β2-adrenoceptor agonist. Particular caution is recommended in unstable asthma with variable use of rescue bronchodilators, in acute severe asthma as the associated risk may be augmented by hypoxia and in other conditions when the likelihood for hypokalaemia is increased. It is recommended that serum potassium levels are monitored during these circumstances.

As for all β2 adrenceptor agonists, additional blood glucose controls should be considered in diabetic patients.

Symbicort Turbohaler contains lactose monohydrate (<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.”

Section 4.6

The words, ”preclinical safety data” removed from second and third paragraphs.

 

Section 4.8

Text changes and new table, now reads as,

 

Undesirable effects

Since Symbicort contains both budesonide and formoterol, the same pattern of undesirable effects as reported for these substances may occur. No increased incidence of adverse reactions has been seen following concurrent administration of the two compounds. The most common drug related adverse reactions are pharmacologically predictable side-effects of β2 adrenoceptor agonist therapy, such as tremor and palpitations. These tend to be mild and usually disappear within a few days of treatment. In a 3-year clinical trial with budesonide in COPD, skin bruises and pneumonia occurred at a frequency of 10% and 6%, respectively, compared with 4% and 3% in the placebo group (p<0.001 and p<0.01, respectively).

Adverse reactions, which have been associated with budesonide or formoterol, are given below, listed by system organ class and frequency. Frequencies are defined as: very common (³1/10), common (³1/100 to <1/10), uncommon (³1/1000 to <1/100), rare (³1/10 000 to <1/1000) and very rare (<1/10 000).

Table 1

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

Very rare

Hyperglycaemia

Psychiatric disorders

Uncommon

Agitation, restlessness, nervousness, sleep disturbances

Very rare

Depression, behavioural disturbances (mainly in children)

Nervous system disorders

Common

Headache, tremor

Uncommon

Dizziness

Very rare

Taste disturbances

Eye disorders

Very rare

Cataract and glaucoma

Cardiac disorders

Common

Palpitations

Uncommon

Tachycardia

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

Rare

Bronchospasm

Gastrointestinal disorders

Uncommon

Nausea

Skin and subcutaneous tissue disorders

Uncommon

Bruises

Musculoskeletal and connective tissue disorders

Uncommon

Muscle cramps

 

Candida infection in the oropharynx is due to drug deposition. Advising the patient to rinse the mouth out with water after each dose will minimise the risk. Oropharyngeal Candida infection usually responds to topical anti-fungal treatment without the need to discontinue the inhaled corticosteroid.

As with other inhalation therapy, paradoxical bronchospasm may occur very rarely, affecting less than 1 in 10,000 people, with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway. Symbicort should be discontinued immediately, the patient should be assessed and an alternative therapy instituted if necessary.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing’s Syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. Increased susceptibility to infections and impairment of the ability to adapt to stress may also occur. Effects are probably dependent on dose, exposure time, concomitant and previous steroid exposure and individual sensitivity.

Treatment with β2 adrenoceptor agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.”

 

Section 4.9

Minor text change to first paragraph, now reads as,

 

An overdose of formoterol would likely lead to effects that are typical for β2 adrenoceptor agonists: tremor, headache, palpitations. Symptoms reported from isolated cases are tachycardia, hyperglycaemia, hypokalaemia, prolonged QTc-interval, arrhythmia, nausea and vomiting. Supportive and symptomatic treatment may be indicated. A dose of 90 micrograms administered during three hours in patients with acute bronchial obstruction raised no safety concerns.”

Section 5.1

Minor text changes throughout section, now reads as,

 

Pharmacodynamic properties

Pharmacotherapeutic group: Adrenergics and other drugs for obstructive airway diseases.

ATC-code: R03AK07

Mechanisms of action and pharmacodynamic effects

Symbicort 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.

Budesonide

Budesonide 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.

Formoterol

Formoterol is a selective β2adrenoceptor 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

Asthma

Clinical 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.

In a 12-week paediatric study 85 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 β2 adrenoceptor agonist as needed. 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 therapy
A total of 12076 asthma patients were included in 5 double-blind efficacy and safety 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 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 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

Events

Events/ patient-year

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

a       Hospitalisation/emergency room treatment or treatment with oral steroids

b      Reduction in exacerbation rate is statistically significant (P value <0.01) for both comparisons

 


In 2 other studies with patients seeking medical attention due to acute asthma symptoms, budesonide/formoterol provided rapid and effective relief of bronchoconstriction similar to salbutamol and formoterol.


COPD

In 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.”

 

Section 5.2

Minor text changes throughout section, now reads as,

 

Pharmacokinetic properties

Absorption

The 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 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 budesonide or formoterol in patients with renal failure are unknown. The exposure of budesonide and formoterol may be increased in patients with liver disease.”

 

Section 6.5

Minor change, now reads as,

 

Symbicort Turbohaler is an inspiratory flow-driven, multidose powder inhaler. The inhaler is white with a red turning grip. The inhaler is made of different plastic materials (PP, PC, HDPE, LDPE, LLDPE, PBT).  In each secondary package there are 1, 2, 3, 10 or 18 inhaler(s) containing 60 or 120 doses. Not all pack-sizes may be marketed.”

 

Section 10

11th April 2011

Updated on 21 April 2011 PIL

Reasons for updating

  • Change to date of revision
  • Change due to harmonisation of PIL

Updated on 29 July 2010 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 6.4 - Special precautions for storage
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

SPC changes Symbicort TBH 200-6

Section 4.4

9th paragraph, final sentence reads,

“Possible systemic effects include Cushing’s syndrome, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma.”

 

Section 4.8

Deletions and additions to Cardiac disorders, Endocrine disorders and Eye disorders, now reads:

 

Cardiac disorders

Common

Palpitations

Uncommon

Tachycardia

Rare

Cardiac arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia, extrasystoles

Very rare

Angina pectoris. Prolongation of QTc-interval

Endocrine disorders

Very rare

Cushing’s syndrome, adrenal suppression, growth retardation, decrease in bone mineral density

Eye disorders

Very rare

Cataract and glaucoma

 

Section 6.4

Section now reads,

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

 

Section 9

Update to date of last renewal,

“19 February 2010”

 

Section 10

Update to revision of text,

“11 June 2010”

Updated on 1 July 2010 PIL

Reasons for updating

  • Change to storage instructions

Updated on 16 November 2009 SmPC

Reasons for updating

  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 4.4 Paragraph 16

Sentence omitted- now added:

If this is not possible the time interval between administration of the interacting drugs should be as long as possible.

Section 4.5 Last paragraph

Word deleted so sentence now reads:

Budesonide and formoterol have not been observed to interact with any other drugs used in the treatment of asthma.

Updated on 16 October 2008 SmPC

Reasons for updating

  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 16 October 2008 PIL

Reasons for updating

  • New PIL for medicines.ie