Symbicort Special Precautions

Turbuhaler: It is recommended that the dose be tapered when long-term treatment is discontinued and should not be stopped abruptly.
If the patients finds the treatment ineffective, or if the prescribed maximum daily dose of SYMBICORT is exceeded, the patient must be encouraged to contact the doctor. Sudden and progressive deterioration in control of asthma is potentially life-threatening, so the patient must be encouraged to contact the doctor for assessment. In this situation consideration should be given to the need for increased therapy with corticosteroids, e.g. a course of oral corticosteroids, or additional antibiotic treatment in concomitant infection.
The patient must be advised to have their rescue inhaler available at all times, either SYMBICORT (for patients using SYMBICORT as maintenanqe and reliever therapy) or a separate rapid-acting bronchodilator (for patients using SYMBCORT as maintenance therapy only).
Treatment with SYMBICORT Turbuhaler should not be initiated to treat severe exacerbations. Patients should be reminded to take their SYMBICORT maintenance dose as prescribed, even when asymptomatic.
The reliever inhalations of SYMBICORT 160/4.5 mcg/dose turbuhaler should be taken in response to symptoms but is not intended for regular prophylactic use e.g. before exercise.
As with other inhalation therapy, paradoxical bronchospasm may occur, with an increase in wheezing immediately after administration. SYMBICORT should then be discontinued; treatment should be reassessed and alternative therapy instituted if necessary.
Systemic effects may occur with inhalation treatment with all corticosteroids, particularly at high doses in long periods of treatment. These effects are less likely to occur with inhalation treatment than with oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataracts and glaucoma.
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy must be re-evaluated with the aim of reducing the dose of inhaled corticosteroid. The benefits of corticosteroid therapy and the possible risks of growth suppression must be carefully weighed against each other. In addition, consideration should be given to referring the patient to a specialist in paediatric pulmonary diseases.
Limited data from long-term studies suggest that most children and adolescents who are treated with inhaled budesonide will ultimately achieve their adult target height. However, an initial small but temporary reduction in growth (approximately 1 cm) has been observed. This reduction in growth generally occurs within the first year of treatment.
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.
Physicians should closely follow the growth of children and adolescents taking long term corticosteroids by any route, and weigh the benefits of the corticosteroid therapy against the possible risk of growth suppression.
Care should be taken in the treatment of patients who are transferred from systemic steroid therapy to SYMBICORT if there is reason to suppose that pituitary-adrenocortical function is impaired.
Inhaled budesonide therapy normally reduces the need for oral steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time.
Patients who have required high dose emergency corticosteroid therapy in the past or had prolonged treatment with high doses of inhaled corticosteroids, may also be at risk.
Additional systemic corticosteroid cover should be considered during periods of stress or in elective surgery.
To minimise the risk of oropharyngeal candida infection, the patient should be instructed to rinse their mouth out with water after each inhalation of the maintenance dose. If oropharyngeal candida infection occurs, the patient should also rinse their mouth with water after each reliever inhalation.
Concomitant treatment with itraconazole, ritonavir or other potent CYP3A4 inhibitors should be avoided (see Interactions). If this is not possible the time interval between administration of the interacting drugs should be as long as possible.
SYMBICORT must be administered with caution in patients with thyrotoxicosis, phaeochromocytoma, diabetes mellitus, untreated hypokalaemia, hypertrophic obstructive cardiomyopathy, idiopathic sub-valvular aortic stenosis, severe hypertension, aneurysm or other severe heart disease such as ischaemic heart disease, tachyarrhythmia 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 beta₂-agonists. Concomitant treatment with beta₂-agonists and drugs which can induce hypokalaemia or potentiate a hypokalaemic effect, e.g. xanthine derivatives, steroids and diuretics, may potentiate a possible hypokalaemic effect of beta₂-agonists. 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 of complications in the form of hypokalaemia is increased. It is recommended that serum potassium levels are monitored in these circumstances.
As with all beta₂-agonists, additional blood glucose controls should be considered in diabetic patients.
SYMBICORT contains lactose (less than 1 mg per 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.
Clinical studies and meta-analyses indicate that treatment of COPD with inhaled corticosteroids may lead to an increased risk of pneumonia. However, the absolute risk for budesonide is small. A meta-analysis of 11 COPD double blind trials including 10,570 patients did not demonstrate a statistically significant increased risk of pneumonia in patients treated with budesonide (with or without formoterol) compared to non-budesonide containing treatments (placebo or formoterol). The incidence rate of pneumonia reported as a serious adverse event was 1.9% per year on budesonide containing treatments and 1.5% per year on non-budesonide containing treatments. The pooled hazard ratio comparing all budesonide containing versus non-budesonide containing treatments was 1.15 (95% CI: 0.83, 1.57). The pooled hazard ratio comparing budesonide/formoterol versus formoterol or placebo was 1.00 (95% CI: 0.69, 1.44). A causal relationship with budesonide-containing products has not been established.
Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap (160/4.5 mcg/dose).
Effects on ability to drive and use machines: SYMBICORT has no or negligible influence on the ability to drive and use machines.
Rapihaler: Treatment of asthma; or COPD (160/4.5 mcg/dose) should be in accordance with current national treatment guidelines.
Patients with asthma should have a personal asthma action plan designed in association with their general practitioner. This plan should incorporate a stepwise treatment regime which can be instituted if the patient's asthma improves or deteriorates. It is recommended that the dose is tapered when long-term treatment is discontinued and should not be stopped abruptly.
Sudden and progressive deterioration in control of asthma; or COPD (160/4.5 mcg/dose) 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 (eg a course of oral corticosteroids) or antibiotic treatment if a bacterial infection is present. Patients should be advised to seek medical attention if they find the treatment in effectiveor they have exceeded the prescribed dose of Symbicort.
Patients should be advised to have their rescue inhaler available at all times, either Symbicort (for asthma patients on Symbicort maintenance and reliever therapy) or a separate rapid-acting bronchodilator (for other patients using Symbicort as maintenance therapy only).
Symbicort therapy should not be initiated to treat a severe exacerbation.
Oral corticosteroid usage: Symbicort should not be used to initiate treatment with inhaled steroids in patients being transferred from oral steroids. Care should be taken when commencing Symbicort treatment, particularly if there is any reason to suspect that adrenal function is impaired from previous systemic steroid therapy.
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, in higher than recommended doses, inhaled steroids may have adverse effects; possible systemic effects of inhaled steroids include depression of the HPA axis, reduction of bone density, cataract and glaucoma, and retardation of growth rate in children and adolescents. In steroid-dependent patients, prior systemic steroid usage may be a contributing factor but such effects may occur amongst patients who use only inhaled steroids regularly.
HPA axis suppression and adrenal insufficiency: Dose-dependant 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 represents 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.
Clinically important disturbances of the HPA axis and/or adrenal insufficiency induced by severe stress (eg trauma, surgery, infection in particular gastroenteritis or other conditions associated with severe electrolyte loss) may be related to inhaled budesonide in specific patient populations. These are patients switched from oral corticosteroids (see Oral corticosteroid usage as previously mentioned) and patients administering concomitant medication metabolised by CYP3A4 (see Interactions). Monitoring for signs of adrenal dysfunction is advisable in these patient groups. For these patients additional systemic glucocorticosteroid treatment should be considered during periods of stress, a 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 to 6 years) studies of budesonide treatment in adults at recommended doses, have not demonstrated a negative effect on bone mass compared to placebo, including a 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 3 large, medium-to-long-term (12 months to 6 years) studies in children (5 to 16 years), no effects on bone-mineral density were observed after treatment with budesonide (189 to 1322 μg/day) compared to nedocromil, placebo or age matched controls. However, in a randomised 18 month paediatric study (n=176; 5 to 10 years), bone-mineral density was significantly decreased by 0.11 g/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 400 g twice daily for 1 month, 200 g twice daily for 5 months, and 100 μg twice daily for 12 months, and the dose of disodium cromoglycate 10 mg 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 1 cm) has been observed and is generally within the first year of treatment. Physicians should closely follow the growth of children and adolescents taking long-term corticosteroids.
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/tuberculosis: Signs of existing infection may be masked by the use of high doses of glucocorticosteroids 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.
Sensitivity to sympathomimetic amines: In patients with increased susceptibility to sympathomimetic amines (eg inadequately controlled hyperthyroidism), eformoterol should be used with caution.
Cardiovascular disorders: β₂-agonists have an arrhythmogenic potential that must be considered before commencing treatment for bronchospasm.
The effects of eformoterol in acute as well as chronic toxicity studies were seen mainly on the cardiovascular system and consisted of hyperaemia, tachycardia, arrhythmias and myocardial lesions. These are known pharmacological manifestations seen after administration of high doses of β₂-adrenoceptor agonists.
Patients with pre-existing cardiovascular conditions may be at greater risk of developing adverse cardiovascular effects following administration of β₂-adrenoreceptor agonists. Caution is advised when eformoterol is administered to patients with severe cardiovascular disorders such as ischaemic heart disease, tachyarrythmias or severe heart failure.
Hipokalaemia: High doses of β₂-agonists can lower serum potassium by inducing a redistribution of potassium from the extracellular to the intracellular compartment, via stimulation of Na⁺/K⁺-ATPase in muscle cells.
Potentially serious hypokalaemia may result. Particular caution is advised in acute exacerbation as the associated risk may be augmented by hypoxia. The hypokalaemic effect may be potentiated by concomitant treatments (see Interactions). Patients receiving digoxin are particularly sensitive to hypokalaemia. Serum potassium levels should therefore be monitored in such situations.
Diabetes: Due to the blood-glucose increasing effects of β₂-stimulants, extra blood glucose controls are initially recommended when diabetic patients are commenced on eformoterol.
Impaired renal and hepatic function: The effect of decreased liver and kidney function on the pharmacokinetics of eformoterol and budesonide are not known. As budesonide and eformoterol are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver disease.
Carcinogenicity: The carcinogenic potential of the budesonide/eformoterol combination has not been investigated in animal studies.
In eformoterol carcinogenicity studies performed by AstraZeneca, there was a dose dependent increase in the incidence of uterine leiomyomas in mice dosed orally at 0.1, 0.5, and 2.5 mg/kg/day for 2 years, and a mesovarian leiomyoma was observed in a female rat dosed by inhalation at 0.13 mg/kg/day for 2 years. The effects observed are expected findings with high-dose exposure to β₂-agonists.
Eformoterol carcinogenicity studies performed by other companies used systemic exposure levels 800 to 4800-fold higher than those expected upon clinical use of eformoterol (based on an 18 μg daily dose).
Some carcinogenicity activity was observed in rats and mice. However, in view of the dose levels at which these effects were observed and the fact that eformoterol is not mutagenic (except for very weak activity at high concentrations in one test system), it is concluded that the cancer risk in patients treated with eformoterol fumarate is no greater than for other β₂-adrenoceptor agonists.
The carcinogenic potential of budesonide has been evaluated in the mouse and rat at oral doses up to 200 and 50 μg/kg/day respectively. In male rats dosed with 10, 25, and 50 μg budesonide/kg/day, those receiving 25 and 50 μg/kg/day showed an increased incidence of primary hepatocellular tumours. In a repeat study, this effect was observed in a number of steroid groups (budesonide, prednisolone, triamcinolone acetonide), thus indicating a class effect of corticosteroids.
Genotoxicity: Individually, budesonide and eformoterol were not genotoxic in a series of assays for gene mutations (except for a slight increase in reverse mutation frequency in Salmonella typhimurium at high concentrations of eformoterol), chromosomal damage and DNA repair. The combination of budesonide and eformoterol has not been tested in genotoxicity assays.
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 opthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serious chrorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
COPD population: Clinical studies and meta-analyses indicate that treatment of COPD with inhaled corticosteroids may lead to an increased risk of pneumonia.
Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap (160/4.5 mcg/dose).
Effects on Ability to Drive and Use Machines: Driving or using machinery should be undertaken with caution until the effect of Symbicort Rapihaler on the individual is established. Symbicort Rapihaler does not generally affect the ability to drive or use machinery.