Allen & Hanburys Ltd

Flixotide Diskus 50 micrograms, Inhalation powder, pre-dispensed

Flixotide Diskus 100 micrograms, Inhalation powder, pre-dispensed

Flixotide Diskus 250 micrograms, Inhalation powder, pre-dispensed

Flixotide Diskus 500 micrograms, Inhalation powder, pre-dispensed

Flixotide Diskus 50 micrograms

Each blister each contains 50 micrograms fluticasone propionate.

Excipients: Each blister contains 11.82mg lactose (as monohydrate)

Flixotide Diskus 100 micrograms

Each blister each contains 100 micrograms fluticasone propionate.

Excipients: Each blister contains 11.9mg lactose (as monohydrate)

Flixotide Diskus 250 micrograms

Each blister each contains 250 micrograms fluticasone propionate.

Excipients: Each blister contains 11.6mg lactose (as monohydrate)

Flixotide Diskus 500 micrograms

Each blister each contains 500 micrograms fluticasone propionate.

Excipients: Each blister contains 11.4mg lactose (as monohydrate)

For a full list of excipients, see section 6.1.

Inhalation powder, pre-dispensed

Fine, white to off-white powder.

Asthma

Fluticasone propionate has a marked anti-inflammatory effect in the lungs. It reduces symptoms and exacerbations of asthma in patients previously treated with bronchodilator alone or with other prophylactic therapy. In the majority of patients it has no effect on adrenal function or reserve at the recommended doses.

Severe asthma requires regular medical assessment as death may occur. Patients with severe asthma have constant symptoms and frequent exacerbations, with limited physical capacity, and PEF values below 60% predicted at baseline with greater than 30% variability, usually not returning entirely to normal after a bronchodilator. These patients will require high dose inhaled (see dosage instructions) or oral corticosteroid therapy. Sudden worsening of symptoms may require increased corticosteroid dosage which should be administered under urgent medical supervision.

Adults

Prophylactic management in:-

- Mild asthma (PEF values greater than 80% predicted at baseline with less than 20% variability): Patients requiring intermittent symptomatic bronchodilator asthma medication on more than an occasional basis.

- Moderate asthma (PEF values 60-80% predicted at baseline with 20-30% variability): Patients requiring regular asthma medication and patients with unstable or worsening asthma on currently available prophylactic therapy or bronchodilator alone.

- Severe asthma (PEF values less than 60% predicted at baseline with greater than 30% variability): Patients with severe chronic asthma. On introduction of inhaled fluticasone propionate many patients who are dependent on systemic corticosteroids for adequate control of symptoms may be able to reduce significantly or to eliminate their requirement for oral corticosteroids.

Children:-

Any child who requires preventive asthma medication, including patients not controlled on currently available prophylactic medication.

Chronic Obstructive Pulmonary Disease (COPD)

In COPD, fluticasone propionate has been shown to reduce symptoms and produce a sustained improvement in lung function.

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

Asthma

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.

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.

Adults and children 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 to 100 micrograms twice daily.

Children should be given a starting dose of inhaled fluticasone propionate which is appropriate for the severity of their disease, this may be 50 to 100 micrograms twice daily.

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

Chronic Obstructive Pulmonary Disease (COPD)

Adult dose:-

500 micrograms twice daily.

Special patient groups:-

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

Hypersensitivity to any ingredient of the preparation (see Pharmaceutical Particulars – List of excipients).

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 Diskus 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.

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 impaired adrenal 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 Diskus should not be stopped abruptly.

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

Particular care should be taken to minimise use of topical corticosteroids in patients with immunosuppression.

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. Reproductive studies in animals have shown only those effects characteristic of glucocorticosteroids at systemic exposures in excess of those seen at the recommended inhaled therapeutic dose. (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 Diskus. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Flixotide Diskus.

Common: Pneumonia (in COPD patients).

Immune System Disorders

Endocrine Disorders

Possible systemic effects (see 4.4 Special Warnings and Special Precautions for Use) include:

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

Respiratory, Thoracic and Mediastinal Disorders

Common: Hoarseness.

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 (pre-bronchodilator) 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, long-acting 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 percentage of patients who died within 3 years due to COPD-related causes was 6.0% for placebo, 6.1% for salmeterol, 6.9% for FP and 4.7% for Seretide.

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 fluticasone propionate for each of the available inhaler devices has been estimated from within and between study comparisons of inhaled and intravenous pharmacokinetic data. In healthy adult subjects the absolute bioavailability has been estimated for fluticasone propionate Accuhaler/Diskus (7.8%), fluticasone propionate Diskhaler (9.0%) and fluticasone propionate Evohaler (10.9%) respectively. 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 in excess of those 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.

Lactose monohydrate (which contains milk proteins)

Not applicable

Do not store above 30°C.

The Diskus 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.

The inhalation powder is contained in blisters held on a formed PVC coated base, with a peelable foil laminate lid. The strip is contained in a moulded plastic device. The plastic device is packaged within a foil overwrap.The plastic devices are available in cardboard containers, which hold a 1 x 28 dose or 1 x 60 dose Diskus.

The Diskus is sealed in a foil overwrap. The overwrap provides moisture protection and should only be opened when you are ready to use it for the first time. Once opened the foil overwrap should be discarded.

CLOSED:

When you take your Diskus out of its box and remove the foil overwrap, it will be in the closed position.

OPENED:

A new Diskus contains 28 or 60 doses of your medicine. The dose indicator tells you how many doses are left.

This Diskus contains 28 or 60 individually protected doses of your medicine, in powder form.

Each dose is accurately measured and hygienically protected. It requires no maintenance and no refilling.

The dose indicator on top of your Accuhaler/Diskus tells you how many doses are left. Numbers 5 to 0 will appear in RED, to warn you when there are only a few doses left.

The Diskus is easy to use. When you need a dose, just follow the five simple steps illustrated:

1. Open.

2. Slide.

3. Inhale.

4. Close.

5. Rinse.

How your Diskus works:

Sliding the lever of your Diskus opens a small hole in the mouthpiece and unwraps a dose, ready for you to inhale it. When you close the Diskus, the lever automatically moves back to its original position, ready for your next dose when you need it. The outer case protects your Diskus when it is not in use.

1. Open

To open your Diskus, hold the outer case in one hand and put the thumb of your other hand on the thumbgrip. Push your thumb away from you as far as it will go.

2. Slide

Hold your Diskus with the mouthpiece towards you. Slide the lever away from you, as far as it will go - until it clicks. Your Diskus is now ready to use. Every time the lever is pushed back, a dose is made available for inhaling. This is shown by the dose counter. Do not play with the lever as this releases doses which will be wasted.

3. Inhale

Before you start to inhale the dose, read through this section carefully.

Hold the Diskus away from your mouth. Breathe out as far as is comfortable. Remember - never breathe into your Diskus.

Put the mouthpiece to your lips. Breathe in steadily and deeply - through the Diskus, not through your nose.

Remove the Diskus from your mouth.

Hold your breath for about 10 seconds, or for as long as is comfortable.

Breathe out slowly.

4. Close

To close your Diskus, put your thumb in the thumbgrip, and slide the thumbgrip back towards you, as far as it will go.

When you close the Diskus, it clicks shut. The lever automatically returns to its original position and is reset. Your Diskus is now ready for you to use again.

5. Rinse

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

If you have been instructed to take two inhalations you must close the Diskus and repeat stages 1 to 4.

REMEMBER:

• Keep your Diskus dry.

• Keep it closed when not in use.

• Never breathe into your Diskus.

• Only slide the lever when you are ready to take a dose.

• Do not exceed the stated dose.

• Keep out of reach of children.

GlaxoSmithKline (Ireland) Limited,

Stonemasons Way,

Rathfarnham,

Dublin 16

Trading as:

Allen & Hanburys

2^nd December 1996 / 2^nd December 2006

April 2011