Allen & Hanburys Ltd

Flixotide Evohaler 50 micrograms per metered dose, pressurised inhalation Suspension

Flixotide Evohaler 125 micrograms per metered dose, pressurised inhalation Suspension

Flixotide Evohaler 250 micrograms per metered dose, pressurised inhalation Suspension

Flixotide Evohaler 50 micrograms per metered dose, pressurised inhalation Suspension:

Each metered dose contains 50 micrograms of Fluticasone propionate.

Flixotide Evohaler 125 micrograms per metered dose, pressurised inhalation Suspension:

Each metered dose contains 125 micrograms of Fluticasone propionate.

Flixotide Evohaler 250 micrograms per metered dose, pressurised inhalation Suspension:

Each metered dose contains 250 micrograms of Fluticasone propionate.

For a full list of excipients, see section 6.1

Pressurised inhalation suspension (pressurised inhalation).

Flixotide Evohaler 50 micrograms per metered dose, pressurised inhalation Suspension:

Pressurised inhalation suspension supplied in an aluminium can with metering valve and actuator.

Flixotide Evohaler 125 micrograms per metered dose, pressurised inhalation Suspension:

Pressurised inhalation suspension supplied in an aluminium can with metering valve and a pink (60 dose) or red (120 dose) actuator.

Flixotide Evohaler 250 micrograms per metered dose, pressurised inhalation Suspension:

Pressurised inhalation suspension supplied in an aluminium can with metering valve and a red (60 dose) or pink (120 dose) actuator.

Flixotide Evohaler is indicated for the treatment and prevention of asthma and COPD.

Flixotide Evohaler is for inhalation by oral inhalation only.

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. The onset of therapeutic effect is 4 to 7 days, although some benefit may be apparent as soon as 24 hours for patients who have not previously received inhaled steroids.

The dosage of fluticasone propionate should be adjusted according to the individual response.

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.

It is intended that each prescribed dose is given by a minimum of 2 inhalations.

In patients who find co-ordination of a pressurised metered-dose inhaler difficult a spacer may be used with Flixotide Evohaler or inhaler.

Asthma:-

Adults and adolescents over 16 years of age:-

− 100 to 1000 micrograms twice daily.

Patients should be given a starting dose of inhaled fluticasone propionate which is appropriate for the severity of their disease:-

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

Alternatively, the starting dose of fluticasone propionate may be gauged at half the total daily dose of beclomethasone dipropionate or equivalent as administered by metered-dose inhaler.

Children over 4 years of age:-

50-100 micrograms twice daily.

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

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

Special patient groups:-

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

Chronic obstructive pulmonary disease (COPD):-

Flixotide Evohaler 50 micrograms per metered dose, pressurised inhalation Suspension:

A higher strength of fluticasone propionate inhaler e.g 250mcg Evohaler or dry powder inhalers would be more appropriate forms for this indication.

Flixotide Evohaler 125 & 250 micrograms per metered dose, pressurised inhalation Suspension:

Adult Dose:

− 500 micrograms twice daily.

Testing your inhaler

Before using for the first time or if your inhaler has not been used for a week or more, remove the mouthpiece cover by gently squeezing the sides of the cover, shake the inhaler well, and release two puffs into the air to make sure that it works.

Using your inhaler

1. Remove the mouthpiece cover by gently squeezing the sides of the cover.

2. Check inside and outside of the inhaler including the mouthpiece for the presence of loose objects.

3. Shake the inhaler well to ensure that any loose objects are removed and that the contents of the inhaler are evenly mixed.

4. Hold the inhaler upright between fingers and thumb with your thumb on the base, below the mouthpiece.

5. Breathe out as far as is comfortable and then place the mouthpiece in your mouth between your teeth and close your lips around it but do not bite it.

6. Just after starting to breathe in through your mouth press down on the top of the inhaler to release fluticasone propionate while still breathing in steadily and deeply.

7. While holding your breath, take the inhaler from your mouth and take your finger from the top of the inhaler. Continue holding your breath for as long as is comfortable.

8. If you are to take further puffs keep the inhaler upright and wait about half a minute before repeating stages 3 to 7.

9. Afterwards, rinse your mouth with water and spit it out.

10. Replace the mouthpiece cover by firmly pushing and snapping the cap into position.

IMPORTANT

Do not rush Stages 5, 6 and 7. It is important that you start to breathe in as slowly as possible just before operating your inhaler.

Practise in front of a mirror for the first few times. If you see 'mist' coming from the top of the inhaler or the sides of your mouth you should start again from stage 2.

If your doctor has been given you different instructions for using your inhaler, please follow them carefully. Tell your doctor if you have any difficulties.

Cleaning

Your inhaler should be cleaned at least once a week.

1. Remove the mouthpiece cover.

2. Do not remove the canister from the plastic casing.

3. Wipe the inside and outside of the mouthpiece with a dry cloth or tissue.

4. Replace the mouthpiece cover.

DO NOT PUT THE METAL CANISTER INTO WATER.

Hypersensitivity to any ingredient of the preparation.

The management of asthma should follow a stepwise programme and patient response should be monitored clinically and by lung function tests.

Increasing use of short-acting inhaled β₂-agonists to control asthma symptoms indicates deterioration of asthma control. Under these conditions, the patient's therapy plan should be reassessed.

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 for use in acute attacks, but for routine long-term management. Patients will require a fast- and short-acting inhaled bronchodilator to relieve acute asthmatic symptoms.

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.

There was an increased reporting of pneumonia in studies of patients with COPD receiving FP 500 micrograms (see Section 4.8). Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbation frequently overlap.

Patients' inhaler technique should be checked to make sure that inhaler actuation is synchronised with inspiration to ensure optimum delivery of the drug to the lungs.

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.

Following introduction of inhaled fluticasone propionate, withdrawal of systemic therapy should be gradual and patients are encouraged to carry a steroid warning cards indicating the possible need for additional therapy in times of stress.

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained.

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored.

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

Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children and adolescents < 16 years taking high doses of fluticasone propionate (typically 1000mcg/day) may be at particular risk. Very rare cases of adrenal suppression and acute adrenal crisis have been described with doses of fluticasone between 500mcg and less than 1000mcg. 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, hypoglycemia and seizures. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

The benefits of inhaled fluticasone propionate therapy should minimise the need for oral steroids, but patients transferring from oral steroids may remain at risk of impairedadrenal reserve for a considerable time. Patients who have required high dose emergency corticosteroid therapy in the past may also be at risk. This possibility of residual impairment should always be borne in mind in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment must be considered. The extent of the adrenal impairment may require specialist advice before elective procedures.

Similarly replacement of systemic steroid treatment with inhaled therapy may unmask 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 Evohaler should not be stopped abruptly.

As with all inhaled corticosteroids, 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).

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.

There are insufficient data on the use of fluticasone propionate during pregnancy and lactation in man to assess the possible harmful effects. In animal studies foetal abnormalities occur after administration of glucocorticosteroids (see 5.3 Preclinical Safety Data).

Administration of fluticasone propionate to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.

The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women.

There are no data available for human breast milk. Fluticasone propionate is excreted into breast milk in rats. Administration of fluticasone propionate to women who are breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

Fluticasone propionate is unlikely to produce an effect.

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) and very rare ( <1/10,000) including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. Rare and very rare events were generally determined from spontaneous data.

Infections and Infestations

Candidiasis (thrush) of the mouth and throat occurs in some patients. The incidence of candidiasis may be relieved by gargling with water using the Evohaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Flixotide Evohaler.

Common: Pneumonia (in COPD patients).

Immune System Disorders

Uncommon: Cutaneous hypersensitivity reactions.

Very rare: Angioedema (mainly facial and oropharyngeal oedema), respiratory symptoms (dyspnoea and/or bronchospasm) and anaphylactic reactions.

Endocrine Disorders

Very rare: Adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, glaucoma.

Respiratory, Thoracic and Mediastinal Disorders

Hoarseness can occur in some patients. Hoarseness may be relieved by gargling with water after using the product.

Very rare: Paradoxical bronchospasm.

As with other inhalation therapy, paradoxical bronchospasm may occur.

Skin and subcutaneous tissue disorders

Common: Contusions

Acute: 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.

Chronic overdose of inhaled of fluticasone propionate: Refer to section 4.4: risk of adrenal suppression. 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.

Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.

COPD clinical trials

TORCH was a 3-year study to assess the effect of treatment with Seretide Diskus 50/500mcg bd, salmeterol Diskus 50mcg bd, fluticasone propionate (FP) Diskus 500mcg bd or placebo on all-cause mortality in patients with COPD. COPD patients with a baseline (prebronchodilator) FEV₁ <60% of predicted normal were randomised to double-blind medication. During the study, patients were permitted usual COPD therapy with the exception of other inhaled corticosteroids, longacting bronchodilators and long-term systemic corticosteroids. Survival status at 3 years was determined for all patients regardless of withdrawal from study medication. The primary endpoint was reduction in all cause mortality at 3 years for Seretide vs Placebo.

There was a trend towards improved survival in subjects treated with Seretide compared with placebo over 3 years however this did not achieve the statistical significance level p0.05.

The mean number of moderate to severe exacerbations per year was significantly reduced with Seretide as compared with treatment with salmeterol, FP and placebo (mean rate in the Seretide group 0.85 compared with 0.97 in the salmeterol group, 0.93 in the FP group and 1.13 in the placebo). This translates to a reduction in the rate of moderate to severe exacerbations of 25% (95% CI: 19% to 31%; p<0.001) compared with placebo, 12% compared with salmeterol (95% CI: 5% to 19%, p=0.002) and 9% compared with FP (95% CI: 1% to 16%, p=0.024). Salmeterol and FP significantly reduced exacerbation rates compared with placebo by 15% (95% CI: 7% to 22%; p<0.001) and 18% (95% CI: 11% to 24%; p<0.001) respectively.

Health Related Quality of Life, as measured by the St George's Respiratory Questionnaire (SGRQ) was improved by all active treatments in comparison with placebo. The average improvement over three years for Seretide compared with placebo was -3.1 units (95% CI: -4.1 to -2.1; p<0.001), compared with salmeterol was -2.2 units (p<0.001) and compared with FP was 1.2 units (p=0.017). A 4-unit decrease is considered clinically relevant.

The estimated 3-year probability of having pneumonia reported as an adverse event was 12.3% for placebo, 13.3% for salmeterol, 18.3% for FP and 19.6% for Seretide (Hazard ratio for Seretide vs placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). There was no increase in pneumonia related deaths; deaths while on treatment that were adjudicated as primarily due to pneumonia were 7 for placebo, 9 for salmeterol, 13 for FP and 8 for Seretide. There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% Seretide; Hazard ratio for Seretide vs placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248.

The absolute bioavailability of inhaled fluticasone propionate in healthy subjects varies between approximately 10-30% of the nominal dose depending on the inhalation device used. In patients with asthma or COPD a lesser degree of systemic exposure to inhaled fluticasone propionate has been observed.

Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged. The remainder of the inhaled dose may be swallowed but contributes minimally to systemic exposure due to the low aqueous solubility and pre-systemic metabolism, resulting in oral availability of less than 1%. There is a linear increase in systemic exposure with increasing inhaled dose.

The disposition of fluticasone propionate is characterised by high plasma clearance (1150ml/min), a large volume of distribution at steady-state (approximately 300l) and a terminal half-life of approximately 8 hours.

Plasma protein binding is (91%).

Fluticasone propionate is cleared very rapidly from the systemic circulation. The main pathway is metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Other unidentified metabolites are also found in the faeces.

The renal clearance of fluticasone propionate is negligible. Less than 5% of the dose is excreted in urine, mainly as metabolites. The main part of the dose is excreted in faeces as metabolites and unchanged drug.

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, HFA134a, 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.

Norflurane (Hydrofluroalkane (HFA) 134a)

Not applicable.

2 years

Do not store above 30°C.

Do not refrigerate or freeze.

Store in the original package.

Avoid storage in direct sunlight or heat.

The canister contains a pressurised liquid. Do not expose to temperatures above 50^oC. Do not pierce the canister, even when apparently empty.

The suspension is contained in an internally lacquered aluminium alloy can sealed with a metering valve. The canisters are fitted into plastic actuators incorporating an atomising orifice and fitted with dustcaps.

Flixotide Evohaler 50 micrograms per metered dose, pressurised inhalation Suspension:

Is available in pack size 120 metered doses per inhaler.

Flixotide Evohaler 125 & 250 micrograms per metered dose, pressurised inhalation Suspension:

Is available in two pack sizes, 60 or 120 metered doses per inhaler. Not all pack sizes may be marketed.

Patients should be carefully instructed in the correct use of the inhaler.

Shake before use.

GlaxoSmithKline (Ireland) Limited,

Stonemasons Way,

Rathfarnham,

Dublin 16

Trading as:

Allen and Hanburys

Flixotide Evohaler 50 micrograms per metered dose, pressurised inhalation Suspension:

PA 1077/44/13

Flixotide Evohaler 125 micrograms per metered dose, pressurised inhalation Suspension:

PA 1077/44/14

Flixotide Evohaler 250 micrograms per metered dose, pressurised inhalation Suspension:

PA 1077/44/15

Flixotide Evohaler 50 micrograms per metered dose, pressurised inhalation Suspension:

20^th December 2000/10^th October 2008

Flixotide Evohaler 125 & 250 micrograms per metered dose, pressurised inhalation Suspension:

8^th January 1999/10^th October 2008

January 2011