Flixotide Nebules 2mg/2ml
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Flixotide Nebules 2mg/2ml.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Plastic ampoules containing 2ml of a buffered, isotonic saline suspension containing 2mg fluticasone propionate
3 PHARMACEUTICAL FORM
Inhalation suspension for nebulisation
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
In adults and adolescents over 16 years Flixotide Nebules can be used:
For prophylactic management of severe chronic asthma in patients requiring high dose inhaled or oral corticosteroid therapy. On introduction of inhaled fluticasone propionate many patients currently treated with oral corticosteroids may be able to reduce significantly, or eliminate, their oral dose.
Flixotide Nebules 2mg/2ml are not licensed for use in children under 16 years and therefore should not be used in this patient population. Current clinical data do not allow appropriate dosage recommendations to be made in this patient population.
Fluticasone propionate given by inhalation has a potent glucocorticoid antiinflammatory action within the lungs. It reduces symptoms and exacerbations of asthma in patients previously treated with bronchodilators alone or with other prophylactic therapy. Relatively brief symptomatic episodes can generally be relieved by the use of fast-acting bronchodilators, but longer-lasting exacerbations require, in addition, the use of corticosteroid therapy as soon as possible to control the inflammation.
4.2 Posology and method of administration
Patients should be made aware of the prophylactic nature of therapy with inhaled fluticasone propionate and that it should be taken regularly even when they are asymptomatic.
If patients find that relief with short-acting bronchodilator treatment becomes less effective or they need more inhalations than usual, medical attention must be sought.
Patients should be given an initial dose of nebulised fluticasone propionate which is appropriate for the severity of their disease. The dosage may be increased until control is achieved or reduced to the minimum effective dose according to the individual response.
Adults and adolescents over 16years: 500-2,000 micrograms twice daily.
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. Prescribers should be aware of the risks of systemic effects when using high doses of corticosteroids (see 4.4 special warnings and precautions for use and 4.8 undesirable effects).
Patients should be given a starting dose of inhaled fluticasone propionate, which is appropriate to the severity of their disease.
The dose should be titrated down to the lowest dose at which effective control of asthma is maintained.
Children 16years and under: Flixotide Nebules 2mg/2ml are not licensed for use in children under 16 years and therefore should not be used in this patient population. Current clinical data do not allow appropriate dosage recommendations to be made in this patient population.
Special patient groups: There is no need to adjust the dose in elderly patients or those with hepatic or renal impairment.
Flixotide Nebules are for inhalation use only. They should be administered as an aerosol produced by a jet nebuliser, as directed by a physician. As drug delivery from nebulisers is variable, the manufacturer’s instructions for using the nebuliser must be followed.
Use of Flixotide Nebules with ultrasonic nebulisers is not generally recommended.
Flixotide Nebules should not be injected or administered orally.
Patients should be made aware of the prophylactic nature of therapy with inhaled fluticasone propionate and that it should be taken regularly.
It is advisable to administer Flixotide Nebules via a mouthpiece to avoid the possibility of atrophic changes to facial skin, which may occur with prolonged use with a face-mask. When a face-mask is used, the exposed skin should be protected using a barrier cream, or the face should be thoroughly washed after treatment.
4.3 Contraindications
Hypersensitivity to any ingredient of the preparation.
4.4 Special warnings and precautions for use
The management of asthma should follow a stepwise programme, and patient response should be monitored clinically and by lung function tests.
Flixotide Nebules 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. Flixotide Nebules are intended for regular daily prophylactic treatment.
Flixotide Nebules are not a substitute for injectable or oral corticosteroids in an emergency (i.e. life threatening asthma).
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 p2-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 Nebules 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 steroids. 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 >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.
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.
Patients should receive a dose appropriate to the severity of their disease; the dose should be titrated to the lowest dose at which effective control of asthma is maintained. If control cannot be maintained, the use of a systemic steroid and/or an antibiotic may be necessary.
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.
During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore,concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects (See Interactions). Treatment with Flixotide Nebules should not be stopped abruptly.
For the transfer of patients being treated with oral corticosteroids: The transfer of oral steroid-dependent patients to Flixotide Nebules 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. Dosage reductions should be appropriate to the level of maintenance systemic steroid, and introduced at not less than weekly intervals. In general, for maintenance doses of prednisolone (or equivalent) of 10mg daily or less, the dosage reductions 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 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 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).
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.
Studies have shown that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations. Nevertheless, care is advised when co-administering potent cytochrome P450 3A4 inhibitors (e.g.ketoconazole) as there is potential for increased systemic exposure to fluticasone propionate.
4.6 Fertility, pregnancy and lactation
Pregnancy
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 Flixotide Nebules deliver fluticasone propionate directly to the lungs by the inhaled route the high level of exposure that occurs when corticosteroids are given by systemic routes is avoided. 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.
Breast-feeding
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 (>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) including isolated reports and not known (cannot be estimated from the available data). Very common, common and uncommon events were generally determined from clinical trial data. Rare and very rare events were generally determined from spontaneous data.
|
System Organ Class |
Adverse Event |
Frequency |
|
Infections & |
Candidiasis of the mouth and throat |
Very |
|
Infestations |
Common | |
|
Pneumonia (in COPD patients) |
Common | |
|
Oesophageal candidiasis |
Rare | |
|
Immune System |
Hypersensitivity reactions with the following | |
|
Disorders |
manifestations: | |
|
Cutaneous hypersensitivity reactions |
Uncommon | |
|
Angioedema (mainly facial and oropharyngeal oedema), |
Very Rare | |
|
Respiratory symptoms (dyspnoea and/or bronchospasm), |
Very Rare | |
|
Anaphylactic reactions |
Very Rare | |
|
Endocrine |
Cushing’s syndrome, Cushingoid features, |
Very Rare |
|
Disorders |
adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, glaucoma | |
|
Metabolism & |
Hyperglycaemia (see 4.4 ‘Special Warnings and |
Very Rare |
|
Nutrition Disorders |
Precautions for Use’) | |
|
Psychiatric |
Anxiety, sleep disorders, behavioural changes, |
Very Rare |
|
Disorders |
including hyperactivity and irritability (predominantly in children) | |
|
Depression, aggression (predominantly in children) |
Not known | |
|
Respiratory, Thoracic & |
Hoarseness/dysphonia |
Common |
|
Mediastinal Disorders |
Paradoxical bronchospasm |
Very Rare |
|
Epistaxis |
Not known | |
|
Gastrointestinal Disorders |
Dyspepsia |
Very Rare |
|
Skin & Subcutaneous Tissue Disorders |
Contusions |
Common |
|
Musculoskeletal & Connective Tissue Disorders |
Arthralgia |
Very Rare |
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 Accuhaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Flixotide Accuhaler.
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 Accuhaler 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 of suspected adverse reactions
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.
4.9 Overdose
Acute inhalation of fluticasone propionate doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not need emergency action as adrenal function is recovered in a few days, as verified by plasma cortisol measurements.
However if higher than recommended dosage is continued over prolonged periods, some degree of adrenal suppression may result. Monitoring of adrenal reserve may be necessary. In cases of fluticasone propionate overdose, therapy may still be continued at a suitable dosage for symptom control.
Chronic: refer to section 4.4: risk of adrenal suppression.
Monitoring of adrenal reserve may be indicated. Treatment with inhaled fluticasone propionate should be continued at a dose sufficient to control asthma.
Treatment
Patients receiving higher than approved doses should be managed closely and the dose reduced gradually.
5.1 Pharmacodynamic properties
Fluticasone propionate given by inhalation at recommended doses has a potent glucocorticoid anti-inflammatory action within the lungs, which results in reduced symptoms and exacerbations of asthma.
5.2 Pharmacokinetic properties
Following inhaled dosing, systemic availability of the nebulised fluticasone propionate in healthy volunteers is estimated at 8% as compared with up to 26% received from the metered dose inhaler 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
Toxicology has shown only those class effects typical of potent corticosteroids, and these only at doses greatly in excess of that proposed for therapeutic use. No novel effects were identified in repeat dose toxicity tests, reproductive studies or teratology studies. Fluticasone propionate is devoid of mutagenic activity in vitro and in vivo and showed no tumorigenic potential in rodents. It is both non-irritant and nonsensitising in animal models.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Polysorbate 20 Ph. Eur
Sorbitan laurate Ph. Eur
Monosodium phosphate dihydrate Ph. Eur
Dibasic sodium phosphate anhydrous USP Sodium Chloride Ph. Eur Water for Injection Ph. Eur
6.2 Incompatibilities
None reported.
6.3 Shelf life
3 years unopened.
In-use shelf-life:
The flow wrap pack should be opened immediately before use. Once Flixotide Nebules have been removed from their flow wrap pack they should be used within 28 days.
Opened Nebules should be stored in a fridge and used within 12 hours of opening.
6.4 Special precautions for storage
Flixotide Nebules should not be stored above 30oC. Keep the container in the outer carton in order to protect from light. Do not freeze. Store upright. For storage conditions after first opening of the medicinal product, see section 6.3.
6.5 Nature and contents of container
2.5ml low density polyethylene ampoules provided as a strip of Nebules in a foil flow wrap, in boxes of 10 or 20.
Not all pack sizes may be marketed.
Each card of five Flixotide Nebules is wrapped and sealed with a flow wrap foil. The foil is composed of polyester on the outer surface, aluminium as the middle layer and low density polyethylene on the inner surface.
6.6 Special precautions for disposal
It is important to ensure that the contents of the Nebule are well mixed before use. While holding the Nebule horizontally by the labelled tab, ‘flick’ the other end a few times and shake. Repeat this process several times until the entire contents of the Nebule are completely mixed. To open the Nebule, twist off the tab.
Dilution: Flixotide Nebules may be diluted with Sodium Chloride Injection BP if required, to aid administration of small volumes or if a prolonged delivery time is desirable. Any unused suspension remaining in the nebuliser should be discarded.
For detailed instructions please refer to the Patient Information Leaflet in every pack.
The nebuliser must be used according to the manufacturer’s instructions. It is advisable to administer Flixotide Nebules via a mouthpiece (see Posology and method of administration).
As many nebulisers operate on a continuous flow basis, it is likely that some nebulised drug will be released into the local environment. Flixotide Nebules should therefore be administered in a well-ventilated room, particularly in hospitals where several patients may be using nebulisers at the same time.
7 MARKETING AUTHORISATION HOLDER
Glaxo Wellcome UK Ltd,
Stockley Park West,
Uxbridge,
Middlesex, UB11 1BT
8 MARKETING AUTHORISATION NUMBER(S)
PL 10949/0298
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
21/08/1998
10 DATE OF REVISION OF THE TEXT
24/02/2015