Source: Υπουργείο Υγείας (CY) Revision Year: 2017 Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
Treatment of patients with latent lung tuberculosis, or with fungal or viral infections, require special care.
Non-steroid dependent patients: attainment of therapeutic effect is normally achieved in ten days or less. An initial short (14 days) additional oral corticosteroid therapy can be administered to those patients with excessive bronchial mucous secretion.
Steroid dependent patients: Transfer from an oral steroid regimen to inhaled budesonide should only be undertaken during a relatively stable phase. Initially a high dose of budesonide is administered concomitantly with the oral steroid regimen for approximately ten days. Thereafter the oral steroid dose should be incrementally reduced, usually by 2.5 mg prednisolone or equivalent per month, to the lowest level consistent with good asthma control. Complete substitution of the oral dose with inhaled budesonide is possible in many cases.
Transfer from oral corticosteroid therapy to inhaled budesonide results in a generally lower systemic steroid action that may cause in allergic or arthritic symptoms such as eczema, rhinitis, and joint and muscle pain. Specific therapy for such conditions should be instituted. Additionally, patients may experience feelings of malaise in a non-specific way, even though respiratory function is maintained or improved. Patients should be encouraged to continue with inhaled budesonide during oral therapy withdrawal unless there are clinical indications to the contrary.
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. As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. If a severe reaction occurs, treatment should be reassessed and an alternative therapy instituted if necessary.
Increase in inhaled budesonide dosage, or additional therapy with a short course of oral corticosteroids, may be necessitated in the case of acute asthma exacerbation. If this is accompanied by an infection, appropriate antibiotic therapy should be instituted. Relief of acute asthma symptoms should be by use of a short acting bronchodilator as rescue medication, and the patient should be advised accordingly.
If patients find short-acting bronchodilator treatment ineffective or they need more inhalations than usual, medical attention must be sought. In this situation consideration should be given to the need for or an increase in their regular therapy, e.g. higher doses of inhaled budesonide or the addition of a long – acting beta agonist, or for a course of oral glucocorticosteroid.
In patients previously oral steroid dependent, because of prolonged systemic steroid therapy, may experience impaired adrenal function effects, and recovery may be delayed following cessation of oral steroid therapy. Such patients may remain at risk of impaired adrenal function for a prolonged period, after cessation of oral steroids and therefore regular monitoring of hypothalamic – pituitary – adrenal (HPA) axis function should be done.
Clinically significant adrenal suppression may occur as a result of prolonged high dose therapy with inhaled corticosteroids, especially if dosages higher than those recommended are used. The prescriber should take into consideration that the presenting symptoms of adrenal suppression and crisis are non – specific and include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, consciousness level decreased, hypoglycaemia, and seizures. Acute adrenal crisis may be potentially triggered by infection, trauma, surgery, or a rapid reduction in dosage. The prescriber should remember the importance of regular therapy review, and titration of the dose down to the lowest level at which effective control of asthma is maintained. In cases where a child’s asthma is not controlled on the maximum indicated dosage, despite addition of other therapies, the clinician should refer the patient to a specialist in management of paediatric asthma, rather than increase the dosage and potentiate the risk of adrenal suppression.
For patients undergoing stress or elective surgery, the provision of additional systemic corticosteroid therapy should be considered. Such patients should be provided with a steroid warning card, and should be advised to carry it and produce it whenever necessary.
Therapy with additional systemic steroids or inhaled budesonide should not be abruptly withdrawn.
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.
Influence on growth: 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.
Reduced liver function may affect the elimination of glucocorticosteroids. The plasma clearance following an intravenous dose of budesonide however was similar in cirrhotic patients and in healthy subjects. After oral ingestion systemic availability of budesonide was increased by compromised liver function due to decreased first pass metabolism. The clinical relevance of this to treatment with budesonide is unknown as no data exist for inhaled budesonide, but increases in plasma levels and hence an increased risk of systemic adverse effects could be expected.
In vivo studies have shown that oral administration of ketoconazole and itraconazole (known inhibitors of CYP3A4 activity in the liver and in the intestinal mucosa causes an increase in the systemic exposure to budesonide. Concomitant treatment with ketoconazole and itraconazole or other potent CYP3A4 inhibitors should be avoided (see section 4.). If this is not possible the time interval between administration of the interacting drugs should be as long as possible. A reduction in the dose of budesonide should also be considered.
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.
Frenolyn also contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose – galactose malabsorption should not take this medicine.
Because adrenal function may be suppressed, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values).
The metabolism of budesonide is primarily mediated by CYP3A4, one of the cytochrome p450 enzymes. Inhibitors of this enzyme, e.g. ketoconazole and itrconazole can therefore increase systemic exposure of budesonide (see section 4.4. and section 5.2). Other potent inhibitors of CYP3A4 are also likely to markedly increase plasma levels of budesonide.
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.
Studies in pregnant animals revealed that budesonide administration caused foetal development abnormalities. The relevance of this in man is unknown. Animal studies are not always predictive of the effect in man. 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.. In the event that therapy with glucocorticosteroids during pregnancy cannot be avoided, the use of inhaled glucocorticosteroids would be preferential as they have a lower systemic effect than equipotent anti – asthmatic doses of oral glucocorticosteroids.
Corticosteroids are secreted in breast milk, although there is no specific data on the secretion of budesonide in breast milk. If budesonide administration is considered essential, consideration should be given to discontinuation of breast feeding.
Budesonide has no influence on the ability to drive and use machines.
The following adverse effects have been ranked under headings of frequency using the following convention: 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); Frequency not known (cannot be estimated from the available data).
Rare: There are rare reports of immediate and delayed hypersensitivity reactions, these have included angioedema, skin rash, contact dermatitis, urticaria and bronchospasm.
These are systemic effects that may occur, especially at high doses following prolonged administration, and include adrenal suppression, growth retardation in children and adolescents and reduction in bone mineral density.
Uncommon: anxiety, depression.
Rare: Psychomotor hyperactivity, sleep disorders, aggression, behavioural changes (predominantly in children).
Systemic effects may occur, especially at high doses following prolonged administration, including nervousness, restlessness, depression, behavioural disturbances.
Uncommon: tremor.
Uncommon: cataract, vision, blurred (see also section 4.4).
Systemic effects may occur, especially at high doses following prolonged administration, including glaucoma.
Systemic effects may occur, especially at high doses following prolonged administration, including bruising.
Uncommon: muscle spasm.
Rare: dysphonia, hoarseness
Very rare: In common with other inhalation therapies, paradoxical bronchospasm may occur. In such cases budesonide therapy should be immediately discontinued, and alternative therapy instituted. Fast acting bronchodilators are suitable for treatment of bronchospasm, and treatment should be immediate. Coughing is another possible adverse effect.
Mild irritation of the throat have been reported, as has oropharyngeal Candida sp. infection. Advising the patient to rinse the mouth with water following drug administration minimises the risk of these effects. Candidial infection usually responds to topical antifungal therapy without the necessity of therapy cessation of inhaled budesonide.
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.
Clinical trials with 13119 patients on inhaled budesonide and 7278 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.
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 to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.
Not applicable.
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