Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Glaxo Wellcome UK Ltd, trading as GlaxoSmithKline UK, Stockley Park West, Uxbridge, Middlesex, UB11 1BT
Hypersensitivity to the active substance or any of the excipients listed in section 6.1.
The management of asthma should follow a stepwise programme, and patient response should be monitored clinically and by lung function tests.
Patients' inhaler technique should be checked regularly to make sure that inhaler actuation is synchronised with inspiration to ensure optimum delivery to the lungs. During inhalation, the patient should preferably sit or stand. The inhaler has been designed for use in a vertical position.
Sudden and progressive deterioration in asthma control is potentially life-threatening and consideration should be given to increasing corticosteroid dosage. In patients considered at risk, daily peak flow monitoring may be instituted.
Flixotide Evohaler is not designed to relieve acute symptoms for which an inhaled short-acting bronchodilator is required. Patients should be advised to have such rescue medication available.
Severe asthma requires regular medical assessment, including lung-function testing, as patients are at risk of severe attacks and even death. Increasing use of short-acting inhaled β2-agonists to relieve symptoms indicates deterioration of asthma control. If patients find that short-acting relief bronchodilator treatment becomes less effective, or they need more inhalations than usual, medical attention must be sought. In this situation patients should be reassessed and consideration given to the need for increased anti-inflammatory therapy (e.g. higher doses of inhaled corticosteroids or a course of oral corticosteroids). Severe exacerbations of asthma must be treated in the normal way.
There have been very rare reports of increases in blood glucose levels, in patients with or without a history of diabetes mellitus (See 4.8 ‘Undesirable Effects’). This should be considered in particular 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. Flixotide Evohaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged 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 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 reviewed regularly and reduced to the lowest dose at which effective control of asthma is maintained.
Prolonged treatment with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children aged < 16 years taking higher than licensed doses of fluticasone (typically ≥1000mcg/day) may be at particular risk. Situations, which could potentially trigger acute adrenal crisis, include trauma, surgery, infection or any rapid reduction in dosage. Presenting symptoms are typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, decreased level of consciousness, hypoglycaemia, and seizures. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.
Certain individuals can show greater susceptibility to the effects of inhaled corticosteroid than do most patients.
Administration of high doses, above 1000 mcg daily is recommended through a spacer to reduce side effects in the mouth and throat. However, as systemic absorption is largely through the lungs, the use of a spacer plus 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. A lower dose may be required.(See section 4.2)
The benefits of inhaled fluticasone propionate should minimise the need for oral steroids. However, patients transferred from oral steroids, remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled fluticasone propionate. The possibility of adverse effects may persist for some time. These patients may require specialised advice to determine the extent of adrenal impairment before elective procedures. The possibility of residual impaired adrenal response should always be considered in emergency (medical or surgical) and elective situations likely to produce stress, and appropriate corticosteroid treatment considered.
Lack of response or severe exacerbations of asthma should be treated by increasing the dose of inhaled fluticasone propionate and, if necessary, by giving a systemic steroid and/or an antibiotic if there is an infection.
Replacement of systemic steroid treatment with inhaled therapy sometimes unmasks allergies such as allergic rhinitis or eczema previously controlled by the systemic drug. These allergies should be symptomatically treated with antihistamine and/or topical preparations, including topical steroids.
As with all inhaled corticosteroids, special care is necessary in patients with active or quiescent pulmonary tuberculosis.
Treatment with Flixotide Evohaler should not be stopped abruptly.
The transfer of oral steroid-dependent patients to Flixotide Evohaler and their subsequent management needs special care as recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy, may take a considerable time.
Patients who have been treated with systemic steroids for long periods of time or at a high dose may have adrenocortical suppression. With these patients adrenocortical function should be monitored regularly and their dose of systemic steroid reduced cautiously.
After approximately a week, gradual withdrawal of the systemic steroid is commenced. Decrements in dosages should be appropriate to the level of maintenance systemic steroid, and introduced at not less than weekly intervals. For maintenance doses of prednisolone (or equivalent) of 10mg daily or less, the decrements in dose should not be greater than 1mg per day, at not less than weekly intervals. For maintenance doses of prednisolone in excess of 10mg daily, it may be appropriate to employ cautiously, larger decrements in dose at weekly intervals.
Some patients feel unwell in a non-specific way during the withdrawal phase despite maintenance or even improvement of the respiratory function. They should be encouraged to persevere with inhaled fluticasone propionate and to continue withdrawal of systemic steroid, unless there are objective signs of adrenal insufficiency.
Patients weaned off oral steroids whose adrenocortical function is still impaired should carry a steroid warning card indicating that they need supplementary systemic steroid during periods of stress, e.g. worsening asthma attacks, chest infections, major intercurrent illness, surgery, trauma, etc.
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 (see 4.5 Interaction with Other Medicinal Products and Other Forms of Interaction).
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.
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.
Co-treatment with other potent CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects.
Other inhibitors of CYP3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations. Combinations should be avoided unless the benefit outweighs the potential increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.
There are no data on human fertility. Animal studies indicate no effects of fluticasone propionate on male or female fertility.
There are limited data in pregnant women. Administration of fluticasone propionate during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus. It is important, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control is maintained. Treatment with fluticasone propionate should not be stopped abruptly.
Results from a retrospective epidemiological study did not find an increased risk of major congenital malformations following exposure to fluticasone propionate when compared to other inhaled corticosteroids, during the first trimester of pregnancy (see Section 5.1).
Reproductive studies in animals have shown only those effects characteristic of glucocorticosteroids at systemic exposures in excess of those seen at the recommended inhaled therapeutic dose. There is inadequate evidence of safety of fluticasone propionate in human pregnancy. Data on a limited number (200) of exposed pregnancies indicate no adverse effects of Flixotide Evohaler on pregnancy or the health of the foetus/new born child. To date no other relevant epidemological data are available. Administration of corticosteroids to pregnant animals can cause abnormalities of fetal development, including cleft palate and intra-uterine growth retardation. There may therefore be a very small risk of such effects in the human fetus. It should be noted, however, that the fetal changes in animals occur after relatively high systemic exposure. Because Flixotide Evohaler delivers fluticasone propionate directly to the lungs by the inhaled route it avoids the high level of exposure that occurs when corticosteroids are given by systemic routes. Administration of fluticasone propionate during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus (see Section 5.3).
The excretion of fluticasone propionate into human breast milk has not been investigated. When measurable plasma levels were obtained in lactating laboratory rats following subcutaneous administration there was evidence of fluticasone propionate in the breast milk. However, plasma levels in patients following inhaled application of fluticasone propionate at recommended doses are likely to be low.
Administration during lactation should only be considered if the expected benefit to the mother is greater than any possible risk to the child.
Fluticasone propionate is unlikely to produce an effect.
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data) including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. Rare and very rare events were generally determined from spontaneous data.
Very Common: Candidiasis of the mouth and throat
Common: Pneumonia (in COPD patients)
Rare: Oesophageal candidiasis
Hypersensitivity reactions with the following manifestations:
Uncommon: Cutaneous hypersensitivity reactions
Very Rare: Angioedema (mainly facial and oropharyngeal oedema), Respiratory symptoms (dyspnoea and/or bronchospasm), Anaphylactic reactions
Not known: Vision, blurred
Very Rare: Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, glaucoma
Very Rare: Hyperglycaemia (see 4.4 ‘Special Warnings and Precautions for Use’)
Very Rare: Anxiety, sleep disorders, behavioural changes, including hyperactivity and irritability (predominantly in children)
Not known: Depression, aggression (predominantly in children)
Common: Hoarseness/dysphonia
Very Rare: Paradoxical bronchospasm
Unknown: Epistaxis
Very Rare: Dyspepsia
Common: Contusions
Very Rare: Arthralgia
Hoarseness and candidiasis of the mouth and throat (thrush) occurs in some patients. Such patients may find it helpful to rinse out their mouth with water after using the inhaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with Flixotide Evohaler.
Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma (see 4.4 Special Warning and Special Precautions for Use).
As with other inhalation therapy, paradoxical bronchospasm may occur (see 4.4 ‘Special Warnings and Precautions for Use’). This should be treated immediately with a fast-acting inhaled bronchodilator. Flixotide Evohaler should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.
There was an increased reporting of pneumonia in studies of patients with COPD receiving FLIXOTIDE 500 micrograms. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbation frequently overlap.
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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
None reported.
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