Symbicort Turbohaler 400/12

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

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

^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