SUMMARY OF spc changes

(Changes in red)

1. NAME OF THE MEDICINAL PRODUCT

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

6.6 Instructions for Use and Handling

Patients should be carefully instructed in correct use of the 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.

SUMMARY OF spc changes (marked in red)

1. NAME OF THE MEDICINAL PRODUCT

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

6.4 Special Precautions for Storage

Do not store above 30ºC.

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.

6.5 Nature and Contents of Container

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.

4.6 Pregnancy and Lactation

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 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.

4.8 Undesirable Effects

Adverse events are listed below by system organ class and frequency.  Frequencies are defined as: very common ( ©ø1/10), common ( ©ø1/100 and <1/10), uncommon ( ©ø1/1000 and <1/100), rare ( ©ø1/10,000 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
Very common:          Candidiasis of mouth and throat.

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

Hypersensitivity reactions with the following manifestations have been reported:

Uncommon:      Cutaneous hypersensitivity reactions.

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

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

5.1 Pharmacodynamic Properties

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 p¡Â0.05.

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.

5.2 Pharmacokinetic Properties

The absolute bioavailability of inhaled 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 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.

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 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.

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.

Increasing use of short-acting inhaled â2-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 ³ 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 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).

4.8 Undesirable Effects

Adverse events are listed below by system organ class and frequency.  Frequencies are defined as: very common ( ³1/10), common ( ³1/100 and <1/10), uncommon ( ³1/1000 and <1/100), rare ( ³1/10,000 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
Very common:  Candidiasis of mouth and throat.

Candidiasis (thrush) of the mouth and throat occurs in some patients. The incidence of candidiasis may be relieved by gargling with water after 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

Hypersensitivity reactions with the following manifestations have been reported:

Uncommon:      Cutaneous hypersensitivity reactions.

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

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.

For a full list of excipients, see section 6.1.