1. Name Of The Medicinal Product
FlixotideTM DiskhalerTM250 Micrograms
2. Qualitative And Quantitative Composition
Fluticasone Propionate (micronised) 250 micrograms
3. Pharmaceutical Form
Inhalation Powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Fluticasone propionate given by inhalation offers preventative treatment for asthma. At recommended doses it has a potent glucocorticoid anti-inflammatory action within the lungs, with a lower incidence and severity of adverse effects than those observed when corticosteroids are administered systemically.
Prophylactic management in:-
Adults
Mild asthma:
Patients requiring intermittent symptomatic bronchodilator asthma medication on a regular daily basis.
Moderate asthma:
Patients with unstable or worsening asthma despite prophylactic therapy or bronchodilator alone.
Severe asthma:
Patients with severe chronic asthma and those who are dependent on systemic corticosteroids for adequate control of symptoms. On introduction of inhaled fluticasone propionate many of these patients may be able to reduce significantly, or to eliminate, their requirement for oral corticosteroids.
Route of administration: by inhalation.
4.2 Posology And Method Of Administration
The onset of therapeutic effect is within 4 to 7 days.
Adults and children over 16 years: 100 to 1,000 micrograms twice daily.
Patients should be given a starting dose of inhaled fluticasone propionate, which is appropriate to the severity of their disease.
Prescribers should be aware that fluticasone propionate is as effective as other inhaled steroids approximately at half the microgram daily dose. For example, a 100mcg of fluticasone propionate is approximately equivalent to 200mcg dose of beclometasone dipropionate (CFC containing) or budesonide.
Due to the risk of systemic effects, doses above 500 micrograms twice daily should be prescribed only for adult patients with severe asthma where additional clinical benefit is expected, demonstrated by either an improvement in pulmonary function and/or symptom control, or by a reduction in oral corticosteroid therapy (see 4.4 Special Warnings and Precautions for Use and 4.8 Undesirable Effects).
Typical Adult Starting Doses:
For patients with mild asthma, a typical starting dose is 100 micrograms twice daily. In moderate and more severe asthma, starting doses may need to be 250 to 500 micrograms twice daily. Where additional clinical benefit is expected, doses of up to 1000 micrograms twice daily may be used. Initiation of such doses should be prescribed only by a specialist in the management of asthma (such as a consultant physician or general practitioner with appropriate experience).
The dose should be titrated down to the lowest dose at which effective control of asthma is maintained.
Flixotide Diskhaler 250 micrograms is not suitable for use in children.
The maximum licensed dose in children is 200 micrograms twice daily.
Special patient groups:
There is no need to adjust the dose in elderly patients or those with hepatic or renal impairment.
4.3 Contraindications
Flixotide preparations are contra-indicated in patients with a history of hypersensitivity to any of their components.
4.4 Special Warnings And Precautions For Use
Flixotide Diskhalers are 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 Diskhaler 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, cataract and glaucoma 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
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.
When changing from a dry powder inhaler to a metered dose inhaler, administration of high doses, above 1000 mcg daily, is recommended through a spacer to reduce side effects in the mouth and throat. However, this may increase drug delivery to the lungs. As systemic absorption is largely through the lungs, there may be an increase in the risk of systemic adverse effects. A lower dose may be required.
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.
For the transfer of patients being treated with oral corticosteroids:
The transfer of oral steroid-dependent patients to Flixotide 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 started by reducing the daily dose by one milligram prednisolone, or its equivalent. For maintenance doses of prednisolone in excess of 10mg daily, it may be appropriate to cautiously use larger reductions 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 transferred from 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.
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.
Treatment with Flixotide Diskhalers should not be stopped abruptly.
Special care is necessary in patients with active or quiescent pulmonary tuberculosis.
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).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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.
4.6 Pregnancy And Lactation
There is inadequate evidence of safety of fluticasone propionate in human pregnancy. 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 fluticasone propionate is delivered 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.
The secretion of fluticasone propionate in human breast milk has not been investigated. Subcutaneous administration of fluticasone propionate to lactating laboratory rats produced measurable plasma levels and evidence of fluticasone propionate in the milk. However, plasma levels in humans after inhalation at recommended doses are likely to be low.
When fluticasone propionate is used in breast feeding mothers the therapeutic benefits must be weighed against the potential hazards to mother and baby.
4.7 Effects On Ability To Drive And Use Machines
Fluticasone propionate is unlikely to produce an effect.
4.8 Undesirable Effects
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (
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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 Diskhaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Flixotide Diskhaler.
Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma (see 4.4 Special Warnings 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 Diskhaler 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.
4.9 Overdose
Acute: Inhalation of the drug in doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not necessitate emergency action being taken.
In these patients treatment with fluticasone propionate by inhalation should be continued at a dose sufficient to control asthma adrenal function recovers in a few days and can be verified by measuring plasma cortisol.
Chronic: refer to section 4.4: risk of adrenal suppression.
Monitoring of adrenal reserve may be indicated. Treatment with inhaled fluticasonepropionate should be continued at a dose sufficient to control asthma.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Fluticasone propionate given by inhalation at recommended doses has a potent glucocorticoid anti-inflammatory action within the lungs, with a lower incidence and severity of adverse effects than those observed when corticosteroids are administered systemically.
5.2 Pharmacokinetic Properties
Systemic absolute bioavailability of fluticasone propionate is estimated at 12-26% of an inhaled dose, dependent on presentation. Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged. The remainder of the dose may be swallowed.
Absolute oral bioavailability is negligible (<1%) due to a combination of incomplete absorption from the GI tract and extensive first-pass metabolism. 87-100% of an oral dose is excreted in the faeces, up to 75% as parent compound. There is also a non-active major metabolite.
After an intravenous dose, fluticasone propionate is extensively distributed in the body. The very high clearance rate indicates extensive hepatic clearance.
5.3 Preclinical Safety Data
No clinically relevant findings were observed in preclinical studies.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose Ph Eur
6.2 Incompatibilities
None known
6.3 Shelf Life
24 months
6.4 Special Precautions For Storage
Whilst the disks provide good protection to the blister contents from the effects of the atmosphere, they should not be exposed to extremes of temperature and should not be stored above 30oC. A disk may be kept in the diskhaler at all times but a blister should only be pierced immediately prior to use. Failure to observe this instruction will affect the operation of the diskhaler.
6.5 Nature And Contents Of Container
A circular double-foil (PVC/Aluminium) disk with four blisters, containing a mixture of fluticasone propionate and lactose. The foil disk is inserted into the Diskhaler device.
The following packs are registered: 5, 7, 10, 14 or 15 disks with or without a diskhaler. Refill packs of 5, 7, 10, 14 or 15 disks. A starter pack consisting of diskhaler pre-loaded with one disk (with or without a peak flow meter and diary card). A starter pack plus a spare disk (with or without a peak flow meter and diary card).
The following packs are marketed: cartons containing 14 disks (14x4 blisters), together with a Diskhaler inhaler. Cartons containing 5 disks (5x4 blisters) together with a Diskhaler inhaler (250 micrograms and 500 micrograms hospital packs only). Refill packs containing 14 disks (14x4 blisters).
6.6 Special Precautions For Disposal And Other Handling
See Patient Information Leaflet for detailed instructions.
Administrative Data
7. Marketing Authorisation Holder
Glaxo Wellcome UK Ltd
trading as Allen & Hanburys
Stockley Park West
Uxbridge,
Middlesex
UB11 1BT
8. Marketing Authorisation Number(S)
PL 10949/0007
9. Date Of First Authorisation/Renewal Of The Authorisation
25 February 1993
10. Date Of Revision Of The Text
23 August 2011
11. LEGAL STATUS
POM.
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