Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Breath Limited, Whiddon Valley, Barnstaple, North Devon, EX32 8NS, United Kingdom
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Budesonide is not indicated for the treatment of acute dyspnoea or status asthmaticus. These conditions should be treated with short acting β-sympathomimetics and other bronchodilators.
The transfer of patients treated with oral corticosteroids to the inhaled corticosteroid and their subsequent management requires special care. The patients should be in a reasonably stable state before initiating a high dose of inhaled corticosteroid in addition to their usual maintenance dose of systemic corticosteroid. After about 10 days, withdrawal of the systemic corticosteroid is started by reducing the daily dose gradually (by for example 2.5 milligrams prednisolone or the equivalent each month) to the lowest possible level. It may be possible to completely replace the oral corticosteroid with inhaled corticosteroid. Transferred patients whose adrenocortical function is impaired may need supplementary systemic corticosteroid during periods of stress e.g. surgery, infection or worsening asthma attacks.
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 of impaired adrenal function. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid treatment should be considered during periods of stress or elective surgery.
During transfer from oral therapy to inhaled budesonide, symptoms may appear that had previously been suppressed by systemic treatment with glucocorticosteroids, for example symptoms of allergic rhinitis, eczema, muscle and joint pain. Specific treatment should be co-administered to treat these conditions.
Some patients may feel unwell in a non-specific way during the withdrawal of systemic corticosteroids despite maintenance or even improvement in respiratory function. Such patients should be encouraged to continue treatment with inhaled budesonide and withdrawal of oral corticosteroid unless there are clinical signs to indicate the contrary, for example signs which might indicate adrenal insufficiency.
As with other inhalation therapies paradoxical bronchospasm may occur, manifested by an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straight away. Budesonide should be discontinued immediately, the patient should be assessed and, if necessary, alternative treatment instituted.
When an acute episode of dyspnoea occurs despite a well monitored treatment, a rapid-acting inhaled bronchodilator should be used and medical reassessment should be considered. If despite maximum doses of inhaled corticosteroids, asthma symptoms are not adequately controlled, patients may require short-term treatment with systemic corticosteroids. In such cases, it is necessary to maintain the inhaled corticosteroid therapy in association with treatment by the systemic route.
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, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of inhaled corticosteroid. The benefits of the corticosteroid therapy and the possible risks of growth suppression must be carefully weighed. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.
Patients who have previously been dependent on oral corticosteroids may, as a result of prolonged systemic corticosteroid therapy, experience effects of impaired adrenal function. Recovery may take a considerable amount of time after cessation of oral corticosteroid therapy and hence oral steroid-dependent patients transferred to budesonide may remain at risk from impaired adrenocortical function for some considerable time. In such circumstances hypothalamic pituitary adrenocortical (HPA) axis function should be monitored regularly.
Oral candidiasis may occur during the therapy with inhaled corticosteroids. This infection may require treatment with appropriate antifungal therapy and in some patients discontinuation of treatment may be necessary (see also section 4.2).
Exacerbation of clinical symptoms of asthma may be due to acute respiratory tract bacterial infections and treatment with appropriate antibiotics may be required. Such patients may need to increase the dose of inhaled budesonide and a short course of oral corticosteroids may be required. A rapid-acting inhaled bronchodilator should be used as “rescue” medication to relieve acute asthma symptoms.
Special care and adequate specific therapeutic control of patients with active and quiescent pulmonary tuberculosis is necessary before commencing treatment with inhaled budesonide. Similarly patients with fungal, viral or other infections of the airways require close observation and special care and should use budesonide only if they are also receiving adequate treatment for such infections.
In patients with excessive mucous secretion in the respiratory tract, short-term therapy with oral corticosteroids may be necessary.
In patients with severe hepatic dysfunction, treatment with inhaled budesonide can result in a reduced elimination rate and hence enhanced systemic availability. Possible systemic effects may then result and therefore HPA axis function in these patients should be monitored at regular intervals.
Concomitant treatment with ketoconazole, HIV protease inhibitors or other potent CYP3A4 inhibitors should be avoided (see section 4.5). If this is not possible the time interval between administration of the two drugs should be as long as possible.
Recent epidemiological studies show that there is an increased incidence of pneumonia in patients with Chronic Obstructive Pulmonary Disease (COPD) treated with inhaled corticosteroids, with an adjusted odds ratio of 1.7 (Reference). Care should be exercised in prescribing budesonide for those patients whose respiratory disease might have a component of COPD.
Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
Budesonide Nebuliser Suspension should be used with a jet nebuliser device. An ultrasonic nebuliser should not be used as this is not appropriate for nebuliser suspensions.
Budesonide Nebuliser Suspension can increase the efficacy of inhaled beta-2-sympathomimetics.
Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.
The metabolism of budesonide is primarily mediated by CYP3A4. Inhibitors of this enzyme, e.g. ketoconazole and itraconazole, can therefore increase systemic exposure to budesonide several times, see section 4.4. Since there are no data to support dosage recommendations, the combination should be avoided. If this is not possible, the period between treatments should be as long as possible and a reduction of the budesonide dose could also be considered. Limited data about this interaction for high-dose inhaled budesonide indicate 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).
Other potent CYP3A4 inhibitors such as erythromycin, clarithromycin, ritonavir and saquinavir are also likely to markedly increase plasma concentrations of budesonide.
Cimetidine had a weak but clinically insignificant inhibiting effect on hepatic metabolism of budesonide.
Raised plasma concentrations of and enhanced effects of corticosteroids have been observed in women also treated with oestrogens and contraceptive steroids, but no effect has been observed with budesonide and concomitant intake of low dose combination oral contraceptives.
The suppressive effect on adrenal function is additive if used concomitantly with systemic or intranasal steroids.
Because adrenal function may be suppressed, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values).
Most results from prospective epidemiological studies and world-wide post-marketing data have not been able to detect an increased risk for adverse effects for the foetus and newborn child from the use of inhaled budesonide during pregnancy. It is important for both foetus and mother to maintain an adequate asthma treatment during pregnancy. As with other drugs administered during pregnancy, the benefit of the administration of budesonide for the mother should be weighed against the risks to the foetus.
Budesonide is excreted in breast milk. However, at therapeutic doses of budesonide no effects on the suckling child are anticipated. Budesonide can be used during breast feeding.
Maintenance treatment with inhaled budesonide (200 or 400 micrograms twice daily) in asthmatic nursing women results in negligible systemic exposure to budesonide in breast-fed infants.
In a pharmacokinetic study, the estimated daily infant dose was 0.3% of the daily maternal dose for both dose levels, and the average plasma concentration in infants was estimated to be 1/600th of the concentrations observed in maternal plasma, assuming complete infant oral bioavailability. Budesonide concentrations in infant plasma samples were all less than the limit of quantification.
Based on data from inhaled budesonide and the fact that budesonide exhibits linear PK properties within the therapeutic dosage intervals after nasal, inhaled, oral and rectal administrations, at therapeutic doses of budesonide, exposure to the suckling child is anticipated to be low.
Inhaled budesonide has no or negligible influence on the ability to drive and use machines.
The following definitions apply to the incidence of undesirable effects: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Rare: Immediate and delayed hypersensitivity reactions* including rash, contact dermatitis, urticaria, angioedema and anaphylactic reaction.
Rare: Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation**
Uncommon: Cataracts*, Vision, blurred (see also section 4.4)
Not known: Glaucoma
Uncommon: Anxiety*, depression*
Rare: Restlessness, nervousness, behavioural changes (predominantly in children)
Not known: Sleep disorders, psychomotor activity, aggression
Common: Hoarseness, cough, throat irritation
Rare: Bronchospasm, dysphonia
Common: Oral mucosal irritation, difficulty in swallowing
Rare: Bruising, skin reactions, pruritus, erythema
Uncommon: Muscle spasms
Rare: Growth retardation
Very rare: Bone density decreased
Uncommon: Tremor
* refer to Description of selected adverse reactions: facial skin irritation, cataract, anxiety, depression below
** refer to Paediatric population, below
Facial irritation, as an example of a hypersensitivity reaction, has occurred in some cases when a nebuliser with a face mask has been used. To prevent irritation the facial skin should be washed with water after use of the face mask.
In-placebo controlled studies, cataract was also uncommonly reported in the placebo group.
Clinical trials with 13,119 patients on inhaled budesonide and 7,278 patients on placebo have been pooled. The frequency of anxiety was 0.52% on inhaled budesonide and 0.63% on placebo; that of depression was 0.67% on inhaled budesonide and 1.15% on placebo.
There is an increased risk of pneumonia in patients with newly diagnosed COPD starting treatment with inhaled corticosteroids. However a weighted assessment of 8 pooled clinical trials involving 4643 COPD patients treated with budesonide and 3,643 patients randomized to non-ICS treatments did not demonstrate an increased risk for pneumonia. The results from the first 7 of these 8 trials have been published as a meta-analysis.
Treatment with inhaled budesonide may result in candida infection in the oropharynx. Experience has shown that candida infection occurs less often when inhalation is performed before meals and/or when the mouth is rinsed after inhalation. In most cases this condition responds to topical anti-fungal therapy without discontinuing treatment with inhaled budesonide.
Coughing can usually be prevented by inhaling a beta-2 agonist (e.g. terbutaline) 5-10 minutes before administration of Budesonide 0.5mg Nebuliser Suspension.
Occasionally, signs or symptoms of systemic glucocorticosteroid-side effects may occur with inhaled glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous corticosteroid exposure, and individual sensitivity. These may include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma, and susceptibility to infections. The ability to adapt to stress may be impaired. The systemic effects described, however, are much less likely to occur with inhaled budesonide than with oral corticosteroids.
Due to the risk of growth retardation in the paediatric population, growth should be monitored as described in section 4.4.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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