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The management of asthma should normally follow a stepwise programme and patient response should be monitored clinically and by lung function tests.
Seretide should not be used to treat acute asthma symptoms for which a fast and short acting bronchodilator is required. Patients should be advised to have their medicinal product to be used for relief in an acute asthma attack available at all times.
Patients should not be initiated on Seretide 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 Seretide. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Seretide.
Increasing use of short-acting bronchodilators to relieve asthma symptoms indicates deterioration of asthma control and patients should be reviewed by a physician.
Sudden and progressive deterioration in control of asthma is potentially life-threatening and the patient should undergo urgent medical assessment.Consideration should be given to increasing corticosteroid therapy. The patient should also be medically reviewed where the current dosage of Seretide has failed to give adequate control of asthma. Consideration should be given to additional corticosteroid therapies.
Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Seretide. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Seretide should be used.
Treatment with Seretide should not be stopped abruptly.
As with all inhaled medication containing corticosteroids, Seretide should be administered with caution in patients with pulmonary tuberculosis.
Rarely, Seretide may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Therefore Seretide should be used with caution in patients with severe cardiovascular disorders, heart rhythm abnormalities, diabetes mellitus, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium.
There have been very rare reports of increases in blood glucose levels and this should be considered when prescribing to patients with a history of diabetes mellitus.
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. Seretide should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
Care should be taken when transferring patients to Seretide therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy.
Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long 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. It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced 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 corticosteroid is regularly monitored.
Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children and adolescents
Systemic absorption of salmeterol and fluticasone propionate is largely through the lungs. As the use of a spacer device with a metered dose inhaler may increase drug delivery to the lungs it should be noted that this could potentially lead to an increase in the risk of systemic adverse effects. Single dose pharmacokinetic data have demonstrated that the systemic exposure to salmeterol and fluticasone propionate may be increased as much as two-fold when the AeroChamber Plus spacer device is used with Seretide inhaler as compared with the Volumatic spacer device.
The benefits of inhaled fluticasone propionate therapy should minimise 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 may also be at risk. This possibility of residual impairment should always be borne in mind in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment must be considered. The extent of the adrenal impairment may require specialist advice before elective procedures.
Ritonavir can greatly increase the concentration of fluticasone propionate in plasma. Therefore, concomitant use should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects. There is also an increased risk of systemic side effects when combining fluticasone propionate with other potent CYP3A inhibitors.
There was an increased reporting of lower respiratory tract infections (particularly pneumonia and bronchitis) in a 3 year study in patients with Chronic Obstructive Pulmonary Disease (COPD) receiving Seretide compared with placebo. In a 3 year COPD study, older patients, patients with a lower body mass index (
Data from a large clinical trial (the Salmeterol Multi-Center Asthma Research Trial, SMART) suggested African-American patients were at increased risk of serious respiratory-related events or deaths when using salmeterol compared with placebo (see section 5.1). It is not known if this was due to pharmacogenetic or other factors. Patients of black African or Afro-Caribbean ancestry should therefore be asked to continue treatment but to seek medical advice if asthma symptoms remained uncontrolled or worsen whilst using Seretide.
Interaction with other medicinal products and other forms of interaction
Both non-selective and selective beta-blockers should be avoided in patients with asthma, unless there are compelling reasons for their use.
Concomitant use of other beta-adrenergic containing drugs can have a potentially additive effect.
Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after inhaled dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by fluticasone propionate are unlikely.
In an interaction study in healthy subjects with intranasal fluticasone propionate, ritonavir (a highly potent cytochrome P450 3A4 inhibitor) 100 mg b.i.d. increased the fluticasone propionate plasma concentrations several hundred fold, resulting in markedly reduced serum cortisol concentrations. Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase in fluticasone propionate plasma levels is expected. Cases of Cushing's syndrome and adrenal suppression have been reported. The combination should be avoided unless the benefit outweighs the increased risk of systemic glucocorticoid side-effects.
In a small study in healthy volunteers, the slightly less potent CYP3A inhibitor ketoconazole increased the exposure of fluticasone propionate after a single inhalation by 150%. This resulted in a greater reduction of plasma cortisol as compared with fluticasone propionate alone. Co-treatment with other potent CYP3A inhibitors, such as itraconazole, is also expected to increase the systemic fluticasone propionate exposure and the risk of systemic side-effects. Caution is recommended and long-term treatment with such drugs should if possible be avoided.
Pregnancy and lactation
There are insufficient data on the use of salmeterol and fluticasone propionate during pregnancy and lactation in man to assess the possible harmful effects. In animal studies foetal abnormalities occur after administration of beta-2-adrenoreceptor agonists and glucocorticosteroids.
Administration of Seretide to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women.
There are no data available for human breast milk. Both salmeterol and fluticasone propionate are excreted into breast milk in rats. Administration of Seretide to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.
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