SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Flixotide Accuhaler 50 micrograms

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Flixotide Accuhaler is a moulded plastic device containing a foil strip with 28 or 60 regularly placed blisters each containing a mixture of microfine fluticasone propionate (50 micrograms) and larger particle size lactose.

Excipient with known effect:

Lactose

3 PHARMACEUTICAL FORM

Multi-dose dry powder inhalation device.

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.

Flixotide Accuhaler 50 micrograms is recommended for any child who requires prophylactic medication for asthma, including patients not controlled on currently available prophylactic medication.

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.

Flixotide Accuhaler is for oral inhalation use only. Flixotide Accuhaler is suitable for many patients, including those who cannot use a metered-dose inhaler successfully. The dose may be increased until control is achieved or reduced to the minimum effective dose, according to the individual response.

Patients should be made aware of the prophylactic nature of therapy with Flixotide Accuhaler and that it should be taken regularly even when they are asymptomatic. The onset of therapeutic effect is within 4 to 7 days.

Typical starting doses for children over 4years of age:

50 to 100 micrograms twice daily.

Many children’s asthma will be well controlled using the 50 to 100 microgram twice daily dosing regime. For those patients whose asthma is not sufficiently controlled, additional benefit may be obtained by increasing the dose up to 200 micrograms twice daily. The maximum licensed dose in children is 200 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.

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.

4.3    Contraindications

Hypersensitivity to the active substance or any of the excipients listed in section 6.1.

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 Accuhaler 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.

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.

Fluticasone propionate is not for use in acute asthma attacks, but for routine long-term management. Patients will require a fast- and short-acting inhaled bronchodilator to relieve acute asthmatic symptoms.

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 Accuhaler 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.

Certain individuals can show greater susceptibility to the effects of inhaled corticosteroid than do most patients.

Because of the possibility of impaired adrenal response, patients transferring from oral steroid therapy to inhaled fluticasone propionate therapy should be treated with special care, and adrenocortical function regularly monitored.

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.

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.

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 Accuhaler should not be stopped abruptly.

For the transfer of patients being treated with oral corticosteroids: The transfer of oral steroid-dependent patients to Flixotide Accuhaler 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).

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 Accuhaler 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.

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 & Nutrition Disorders	Hyperglycaemia (see 4.4 ‘Special Warnings and Precautions for Use’)	Very Rare
Psychiatric Disorders	Anxiety, sleep disorders, behavioural changes, including hyperactivity and irritability (predominantly in children)	Very Rare
	Depression, aggression (predominantly in children)	Not known
Respiratory, Thoracic & Mediastinal Disorders	Hoarseness/dysphonia Paradoxical bronchospasm Epistaxis	Common Very Rare 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.

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.

If higher than approved doses are continued over prolonged periods, significant adrenocortical suppression is possible. There have been very rare reports of acute adrenal crisis occurring in children exposed to higher than approved doses (typically 1000 micrograms daily and above), over prolonged periods (several months or years); observed features included hypoglycaemia and sequelae of decreased consciousness and/or convulsions. Situations which could potentially trigger acute adrenal crisis include exposure to trauma, surgery, infection or any rapid reduction in dosage.

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 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Fluticasone propionate given by inhalation at recommended doses has a potent glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, 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

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

Lactose.

6.2 Incompatibilities

None reported.

6.3 Shelf life

18 months when not stored above 30°C.

6.4    Special Precautions for Storage

Do not store above 30°C (86°F). Store in a dry place.

Flixotide Accuhaler is sealed in a foil overwrap which should only be opened when it is to be used for the first time. Once opened the foil overwrap should be discarded.

6.5    Nature and contents of container

The powder mix of fluticasone propionate and lactose is filled into a blister strip consisting of a formed base foil with a peelable foil laminate lid. The foil strip is contained within the Accuhaler device.

Flixotide Accuhaler is packaged within a foil overwrap.

6.6 Special precautions for disposal and other handling

The powdered medicine is inhaled through the mouth into the lungs.

The Accuhaler device contains the medicine in individual blisters which are opened as the device is manipulated.

For detailed instructions for use refer to the Patient Information Leaflet in every pack.

7    MARKETING AUTHORISATION HOLDER

Glaxo Wellcome UK Ltd,

Stockley Park West,

Uxbridge,

Middlesex, UB11 1BT

8    MARKETING AUTHORISATION NUMBER(S)

PL 10949/0226

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/09/2008

10 DATE OF REVISION OF THE TEXT

24/02/2015