Pneumonia in patients with COPD: An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.
There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products.
Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.
Risk factors for pneumonia in patients with COPD include current smoking status, older age, low body mass index (BMI) and severe COPD.
Visual disturbance: 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.
Bronchospasm: PULMICORT is not indicated for rapid relief of bronchospasm. PULMICORT is therefore not suitable as sole therapy for the treatment of status asthmaticus or other acute exacerbations of asthma where intensive measures are required.
If patients find short-acting bronchodilator treatment ineffective, or they need more inhalations than usual, medical attention must be sought. This indicates a worsening of the underlying conditions, and warrants a reassessment of the therapy.
Oral corticosteroid usage: Particular care is needed in patients who are being transferred from oral corticosteroids to PULMICORT, since they may remain at risk of impaired adrenal function for some considerable time (see Potential systemic effect of inhaled corticosteroids: HPA axis suppression and adrenal insufficiency as follows). These patients should be instructed to carry an appropriate warning card (see Clinical Management: Patients - Oral corticosteroid dependent under Dosage & Administration).
Patients previously receiving high doses of systemic steroids may regain earlier allergic symptoms such as rhinitis and eczema when transferred from oral therapy to PULMICORT due to the reduced systemic steroid effect of budesonide (see Clinical Management: Patients - oral corticosteroid dependent under Dosage & Administration).
Potential systemic effects of inhaled corticosteroids: Inhaled steroids are designed to direct glucocorticoid delivery to the lungs in order to reduce overall systemic glucocorticoid exposure and side effects. However inhaled steroids may have adverse effects; possible systemic effects of inhaled steroids include depression of the HPA axis, reduction of bone density, cataracts and glaucoma and retardation of growth rate in children. In steroid-dependent patients, prior systemic steroid usage may be a contributing factor (see previously mentioned Oral corticosteroid usage), but such effects may occur amongst patients who use only inhaled steroids regularly.
HPA axis suppression and adrenal insufficiency: Dose-dependent HPA axis suppression (as indicated by 24 hour urinary and/or plasma cortisol AUC) has been observed with inhaled budesonide, although the physiological circadian rhythms of plasma cortisol were preserved. This indicates that the HPA axis suppression may represent a physiological adaption in response to inhaled budesonide, not necessarily adrenal insufficiency. The lowest dose that results in clinically relevant adrenal insufficiency has not been established. Very rare cases of clinically relevant adrenal dysfunction have been reported in patients using inhaled budesonide at recommended doses.
Particular care is needed in patients who are being transferred from oral corticosteroids to PULMICORT, since they may remain at risk of impaired adrenal function for some considerable time (see Oral corticosteroid usage as previously mentioned). Patients who have required high dose emergency corticosteroid therapy, prolonged treatment at the highest recommended dose of inhaled corticosteroids or patients administering concomitant medication metabolised by CYP3A4 (see Interactions) may also be at risk. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress such as trauma, surgery, infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Monitoring for signs of adrenal dysfunction is advisable in these patient groups. For these patients additional systemic glucocorticosteroid cover should be considered during periods of stress, severe asthma attack or elective surgery.
Bone density: Whilst corticosteroids may have an effect on bone mass at high doses, long term follow up (3 - 6 years) studies of budesonide treatment in adults at recommended doses, have not demonstrated a negative effect on bone mass compared to placebo, including one study conducted in patients with a high risk of osteoporosis. The lowest dose that does effect bone mass has not been established.
Bone mineral density measurements in children should be interpreted with caution as an increase in bone area in growing children may reflect an increase in bone volume. In three large medium to long term (12 months - 6 years) studies in children (5-16 years), no effects on bone mineral density were observed after treatment with Pulmicort (189 - 1322μg/day) compared to nedocromil, placebo or age matched controls. However, in a randomised 18 month study (n=176; 5-10 years), bone mineral density was significantly decreased by 0.11g/cm2 (p=0.023) in the group treated with inhaled budesonide via Turbuhaler compared with the group treated with inhaled disodium cromoglycate. The dose of budesonide was 400μg twice daily for 1 month, 200μg twice daily for 5 months and 100μg twice daily for 12 months and the dose of disodium cromoglycate 10mg three times daily. The clinical significance of this result remains uncertain.
Growth: Long term studies show that children treated with inhaled budesonide ultimately achieve adult target height. However, an initial reduction of growth velocity (approximately 1cm) has been observed and is generally within the first year of treatment.
Rare individuals may be exceptionally sensitive to inhaled corticosteroids. Height measurements should be performed to identify patients with increased sensitivity. The potential growth effects of prolonged treatment should be weighed against the clinical benefit. To minimise the systemic effects of inhaled corticosteroids, each patient should be titrated to his/her lowest effective dose (see DOSAGE & ADMINISTRATION).
Infections and tuberculosis: High doses of glucocorticosteroids may mask some signs of existing infection and new infections may appear during their use. Special care is needed in patients with active or quiescent pulmonary tuberculosis or fungal, bacterial or viral infections of the respiratory system.
Hepatic function: Reduced liver function may affect the elimination of corticosteroids. This may be clinically relevant in patients with severely compromised liver function.
Positive pressure delivery systems: Respiratory drugs should not be used with positive pressure delivery systems (eg. IPPB) in pulmonary conditions involving pneumothorax, air cysts or mediastinal emphysema unless special drainage is performed.
Carcinogenicity and mutagenicity: The carcinogenic potential of budesonide has been evaluated in mouse and rat at oral doses up to 200 and 50μg/kg/day, respectively. No oncogenic effect was noted in the mouse. One study indicated an increased incidence of brain gliomas in male Sprague-Dawley rats given budesonide, however the results were considered equivocal. Further studies performed in male Sprague-Dawley and Fischer rats showed that the incidence of gliomas in the budesonide-treated rats was low and did not differ from that in the reference glucocorticoid groups or the controls. It has been concluded that treatment with budesonide does not increase the incidence of brain tumours in the rat.
In male rats dosed with 10, 25 and 50μg/kg/day, those receiving 25 and 50μg/kg/day showed an increased incidence of primary hepatocellular tumours. This was observed in all three steroid groups (budesonide, prednisolone, triamcinolone acetonide) in a repeat study in male Sprague-Dawley rats thus indicating a class effect of corticosteroids.
The mutagenic potential of budesonide was evaluated in 6 different test systems. No mutagenic or clastogenic effects of budesonide were found.