Flixotide Nebules 0.5mg / 2ml

1. Name Of The Medicinal Product

Flixotide Nebules 0.5mg/2ml

2. Qualitative And Quantitative Composition

Plastic ampoules containing 2ml of a buffered, isotonic saline suspension containing 0.5mg 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.

Children and adolescents from 4 to 16 years of age:

Treatment of acute exacerbations of asthma. Subsequent maintenance dosing may be more conveniently accomplished using a pressurised metered dose inhaler or powder formulation.

Fluticasone propionate given by inhalation has a potent glucocorticoid anti-inflammatory 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

Adults and adolescents over 16 years: 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 and adolescents from 4 to 16 years of age: 1000 mcg twice daily

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

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 ?2-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

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.

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.

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.

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 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.

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 (

System Organ Class

Adverse Event

Frequency

Infections and Infestations

Candidiasis of the mouth and throat

Pneumonia (in COPD Patients)

Very Common

Common

Immune System Disorders

Hypersensitivity reactions with the following 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 Disorders

Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, glaucoma

Very Rare

Metabolism and Nutrition Disorders

Hyperglycaemia (see 4.4 'Special Warnings and Precautions for Use')

Very Rare

Gastrointestinal Disorders

Dyspepsia

Very Rare

Musculoskeletal and Connective Tissue Disorders

Arthralgia

Very Rare

Psychiatric Disorders

Anxiety, sleep disorders, behavioural changes, including hyperactivity and irritability (predominantly in children)

Depression, aggression (predominantly in children)

Very Rare

Not known

Respiratory, Thoracic and

Hoarseness/dysphonia

Common

Mediastinal Disorders

Paradoxical bronchospasm

Very Rare

Skin & Subcutaneous Tissue Disorders

Contusions

Common

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 inhalation from the nebuliser. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with Flixotide Nebules.

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 bronchodilators. Flixotide Nebules 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 fluticasone propionate 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, 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

Generally, 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. However, corticosteroid overdosage effects were produced in juvenile rats at systemic fluticasone propionate doses similar to the maximum paediatric dose. 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 non-sensitising in animal models.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Polysorbate 20

Sorbitan laurate

Monosodium phosphate dihydrate

Dibasic sodium phosphate anhydrous

Sodium Chloride

Water for Injection

6.2 Incompatibilities

None reported.

6.3 Shelf Life

36 months unopened.

6.4 Special Precautions For Storage

Flixotide Nebules should not be stored above 30°C. Keep container in the outer carton. Protect from freezing. Store upright.

The blister pack should be opened immediately before use. Opened Nebules should be refrigerated and used within 12 hours of opening.

6.5 Nature And Contents Of Container

2.5ml low density polyethylene ampoules wrapped in a double foil blister, in boxes of 10 or 20.

The foil blister pack consists of a base and lidding foil. The base foil of the blister consists of aluminium (60 microns) coated on the outside with polyamide and on the inside with polyvinylchloride. The lidding consists of paper bonded to polyethyleneterephthalate bonded to aluminium (20 microns), with a coating of vinyl/acrylate lacquer on the inner surface.

6.6 Special Precautions For Disposal And Other Handling

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.

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 10949/0297

9. Date Of First Authorisation/Renewal Of The Authorisation

21 August 1998

10. Date Of Revision Of The Text

23 August 2011

11. Legal Category

POM

Read More:

Flixotide Diskhaler 250 mcg

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 ?2-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 (

System Organ Class

Adverse Event

Frequency

Infections & Infestations

Candidiasis of the mouth and throat

Pneumonia (in COPD patients)

Very Common

Common

Immune System Disorders

Hypersensitivity reactions with the following manifestations:

Cutaneous hypersensitivity reactions

Angioedema (mainly facial and oropharyngeal oedema),

Respiratory symptoms (dyspnoea and/or bronchospasm),

Anaphylactic reactions

 

Uncommon

Very Rare

Very Rare

Very Rare

Endocrine Disorders

Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, glaucoma

Very Rare

Metabolism & Nutrition Disorders

Hyperglycaemia (see 4.4 'Special Warnings and Precautions for Use')

Very Rare

Gastrointestinal Disorders

Dyspepsia

Very Rare

Musculoskeletal & Connective Tissue Disorders

Arthralgia

Very Rare

Psychiatric Disorders

Anxiety, sleep disorders, behavioural changes, including hyperactivity and irritability (predominantly in children)

Depression, aggression (predominantly in children)

Very Rare

Unknown

Respiratory, Thoracic & Mediastinal Disorders

Hoarseness/dysphonia

Paradoxical bronchospasm

Common

Very Rare

Skin & Subcutaneous Tissue Disorders

Contusions

Common

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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Flixotide Diskhaler 250 mcg

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