SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Flixotide 50 micrograms Evohaler

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Flixotide 50 micrograms Evohaler is a pressurised inhalation,    suspension,

delivering 50 micrograms of fluticasone propionate per actuation.

3    PHARMACEUTICAL FORM

Pressurised inhalation, suspension

Flixotide 50 micrograms Evohaler does not contain any chlorofluorocarbons (CFCs).

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Fluticasone propionate given by inhalation offers prophylactic treatment for asthma.

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.

Children: Any child who requires prophylactic medication, 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 Evohaler is for oral inhalation use only. Flixotide Evohaler may be used with a Volumatic spacer device by patients who find it difficult to synchronise aerosol actuation with inspiration of breath.

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

Adults and children over 16years: 100 to 1,000 micrograms twice daily, usually as two twice daily inhalations.

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).

Patients should be given a starting dose of inhaled fluticasone propionate which is appropriate to the severity of their disease.

The dose may be increased until control is achieved or reduced to the minimum effective dose, according to the individual response.

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

Typical starting doses for children over 4 years 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.

The starting dose should be appropriate to the severity of the disease.

The dose should be titrated down to the lowest dose at which effective control of asthma is maintained

Should this particular Flixotide presentation not offer the exact paediatric dose prescribed by the physician, please see data sheets of alternative Flixotide presentation (Accuhaler, Nebules)

Administration of doses above 1000 micrograms (500 micrograms twice daily) should be via a spacer device to help reduce side-effects in the mouth and throat (See Section 4.4)

Special patient groups:

There is no need to adjust the dose in elderly patients or those with hepatic or renal impairment.

4.3. Contra-indications

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.

Patients’ inhaler technique should be checked regularly to make sure that inhaler actuation is synchronised with inspiration to ensure optimum delivery to the lungs. During inhalation, the patient should preferably sit or stand. The inhaler has been designed for use in a vertical position.

Sudden and progressive deterioration in asthma control is potentially life-threatening and consideration should be given to increasing corticosteroid dosage. In patients considered at risk, daily peak flow monitoring may be instituted.

Flixotide Evohaler is not designed to relieve acute symptoms for which an inhaled short-acting bronchodilator is required. Patients should be advised to have such rescue medication available.

Severe asthma requires regular medical assessment, including lung-function testing, as patients are at risk of severe attacks and even death. Increasing use of short-acting inhaled 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 Evohaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, 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.

Administration of high doses, above 1000 mcg daily is recommended through a spacer to reduce side effects in the mouth and throat. However, as systemic absorption is largely through the lungs, the use of a spacer plus metered dose inhaler may increase drug delivery to the lungs. It should be noted that this could potentially lead to an increase in the risk of systemic adverse effects. A lower dose may be required. (See section 4.2)

The benefits of inhaled fluticasone propionate should minimise the need for oral steroids. However, patients transferred from oral steroids, remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled fluticasone propionate. The possibility of adverse effects may persist for some time. These patients may require specialised advice to determine the extent of adrenal impairment before elective procedures. The possibility of residual impaired adrenal response should always be considered in emergency (medical or surgical) and elective situations likely to produce stress, and appropriate corticosteroid treatment considered.

Lack of response or severe exacerbations of asthma should be treated by increasing the dose of inhaled fluticasone propionate and, if necessary, by giving a systemic steroid and/or an antibiotic if there is an infection.

Replacement of systemic steroid treatment with inhaled therapy sometimes unmasks allergies such as allergic rhinitis or eczema previously controlled by the systemic drug. These allergies should be symptomatically treated with antihistamine and/or topical preparations, including topical steroids.

As with all inhaled corticosteroids, special care is necessary in patients with active or quiescent pulmonary tuberculosis.

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 Evohaler should not be stopped abruptly.

For the transfer of patients being treated with oral corticosteroids: The transfer of oral steroid-dependent patients to Flixotide Evohaler and their subsequent management needs special care as recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy, may take a considerable time.

Patients who have been treated with systemic steroids for long periods of time or at a high dose may have adrenocortical suppression. With these patients adrenocortical function should be monitored regularly and their dose of systemic steroid reduced cautiously.

After approximately a week, gradual withdrawal of the systemic steroid is commenced. Decrements in dosages should be appropriate to the level of maintenance systemic steroid, and introduced at not less than weekly intervals. For maintenance doses of prednisolone (or equivalent) of 10mg daily or less, the decrements in dose should not be greater than 1mg per day, at not less than weekly intervals. For maintenance doses of prednisolone in excess of 10mg daily, it may be appropriate to employ cautiously, larger decrements in dose at weekly intervals.

Some patients feel unwell in a non-specific way during the withdrawal phase despite maintenance or even improvement of the respiratory function. They should be encouraged to persevere with inhaled fluticasone propionate and to continue withdrawal of systemic steroid, unless there are objective signs of adrenal insufficiency.

Patients weaned off oral steroids whose adrenocortical function is still impaired should carry a steroid warning card indicating that they need supplementary systemic steroid during periods of stress, e.g. worsening asthma attacks, chest infections, major intercurrent illness, surgery, trauma, etc.

Ritonavir can greatly increase the concentration of fluticasone propionate in plasma. Therefore, concomitant use should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects. There is also an increased risk of systemic side effects when combining fluticasone propionate with other potent CYP3A inhibitors (see 4.5 Interaction with Other Medicinal Products and Other Forms of Interaction).

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. Cotreatment 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. Data on a limited (200) of exposed pregnancies indicate no adverse effects of Flixotide Evohaler on pregnancy or the health of the foetus/new born child. To date no other relevant epidemiological data are available. Administration of corticosteroids to pregnant animals can cause abnormalities of fetal development, including cleft palate and intra-uterine growth retardation. There may therefore be a very small risk of such effects in the human fetus. It should be noted, however, that the fetal changes in animals occur after relatively high systemic exposure. Because Flixotide Evohaler delivers fluticasone propionate directly to the lungs by the inhaled route it avoids the high level of exposure that occurs when corticosteroids are given by systemic routes. Administration of fluticasone propionate during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus.

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 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 a reduction of both 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

In healthy subjects the mean systemic bioavailability of Flixotide Evohaler is 28.6%. In patients with asthma (FEV₁ < 75% predicted) the mean systemic absolute bioavailability was reduced by 62 %. Systemic absorption occurs mainly through the lungs and has been shown to be linearly related to dose over the dose range 500 to 2000 micrograms. Absorption is initially rapid then prolonged and 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 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 non-sensitising in animal models.

The non-CFC propellant, HFA 134a, has been shown to have no toxic effect at very high vapour concentrations, far in excess of those likely to be experienced by patients, in a wide range of animal species exposed daily for periods of two years.

The use of HFA 134a as a propellant has not altered the toxicity profile of fluticasone propionate compared to that using the conventional CFC propellant.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

HFA 134a

6.2. Incompatibilities

None reported.

6.3. Shelf Life

24 months

6.4 Special precautions for storage

Do not store above 30°C (86°F). Do not refrigerate or freeze. Protect from frost and direct sunlight.

As with most medicines in pressurised canisters, the therapeutic effect of this medication may decrease when the canister is cold.

The canister should not be punctured, broken or burnt even when apparently empty.

Replace the mouthpiece cover firmly and snap it into position.

6.5. Nature and Contents of Container

An inhaler comprising an aluminium alloy can sealed with a metering valve, actuator and dust cap. Each canister contains 120 metered actuations of 50 micrograms of fluticasone propionate.(60 metered actuation hospital packs are available).

Special precautions for disposal and other handling

The aerosol spray is inhaled through the mouth into the lungs. After shaking the inhaler the patient should exhale, the mouthpiece should be placed in the mouth and the lips closed around it. The actuator is depressed to release a spray, which must coincide with inspiration of breath.

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 10949/0324

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/10/2005

10 DATE OF REVISION OF THE TEXT

24/02/2015