Allen & Hanburys Ltd

1.         NAME OF THE MEDICINAL PRODUCT

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

4.2       Posology and Method of Administration

……………..etc

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.  If it has not been used for several days shake it well and release one puff 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 metal canister from the plastic casing of the inhaler and remove the mouthpiece cover.
2. Rinse the actuator thoroughly under warm running water Do not remove the canister from the plastic casing.
3. Dry the actuator THOROUGHLY inside and out Wipe the inside and outside of the mouthpiece with a dry cloth or tissue.
4. Replace the metal canister and mouthpiece cover.

 DO NOT PUT THE METAL CANISTER INTO WATER.

1.         NAME OF THE MEDICINAL PRODUCT

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

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION
 

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

3.         PHARMACEUTICAL FORM

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.

6.4     Special Precautions for Storage

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 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 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 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).

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 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
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.