FLIXOTIDE™ Inhaler™

Fluticasone propionate Inhaler (CFC-Free) (50, 125 or 250 micrograms per actuation).

Qualitative and Quantitative Composition

Flixotide 50 Inhaler is a pressurised metered-dose inhaler which delivers 50mcg of fluticasone propionate per actuation into the mouthpiece of a specially designed actuator. Each canister supplies 120 actuations.

Flixotide 125 Inhaler is a pressurised metered-dose inhaler which delivers 125mcg of fluticasone propionate per actuation into the mouthpiece of a specially designed actuator. Each canister supplies 120 actuations.

Flixotide 250 Inhaler is a pressurised metered-dose inhaler which delivers 250mcg of fluticasone propionate per actuation. Each canister supplies 120 actuations.

Pharmaceutical Form

Pressurised metered-dose aerosol.

Clinical Particulars

Therapeutic Indications

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.

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.

Posology and Method of Administration

Flixotide Inhaler (CFC-Free) is for oral inhalation only.

The diagnosis and treatment of asthma should be kept under regular review.

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 Volumatic™ spacer may be used with Flixotide Inhaler (CFC-Free).

Asthma

Adults and children over 16 years of age: 100 to 1000mcg 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.

Many children's asthma will be well controlled using the 50 to 100mcg twice daily dosing regime. For those patients whose asthma is not sufficiently controlled, additional benefit may be obtained by increasing the dose up to 200mcg 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 the individual response.

This presentation of fluticasone propionate may not offer the required paediatric dose, in which case an alternative presentation of fluticasone propionate should be considered (e.g. dry powder inhalers).

Children aged 1 to 4 years: 100mcg twice daily administered via a paediatric spacer device with a face mask.

Inhaled fluticasone propionate is of benefit to younger children in the control of frequent and persistent asthma symptoms.

Clinical trials in 1 to 4 year old children have shown that the optimal control of asthma symptoms is achieved with 100mcg twice daily. Higher doses of inhaled fluticasone propionate are required in younger children compared to older children because of reduced efficiency of drug delivery due to smaller airways, use of a spacer device and increased nasal breathing.

Special patient groups

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

Contra-indications

Hypersensitivity to any ingredient of the preparation.

Special Warnings and Special 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 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 Inhaler (CFC-Free) is not for use in acute asthma 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.

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

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 dose of inhaled corticosteroid is titrated to the lowest dose at which effective control is maintained (see Undesirable Effects).

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.

Adrenal function and adrenal reserve usually remain within the normal range on recommended doses of fluticasone propionate therapy. The benefits of inhaled fluticasone propionate therapy should minimise the need for oral steroids. However, the possibility of adverse effects in patients, resulting from prior or intermittent administration of oral steroids, may persist for some time. The extent of the adrenal impairment may require specialist advice before elective procedures.

The possibility of impaired adrenal response should always be borne in mind in emergency and elective situations likely to produce stress and appropriate corticosteroid treatment must be considered.

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 encouraged to carry a steroid warning card indicating the possible need for additional therapy in times of stress.

In rare cases inhaled therapy may unmask underlying eosinophilic conditions (e.g. Churg Strauss syndrome). These cases have usually been associated with reduction or withdrawal of oral corticosteroid therapy. A direct causal relationship has not been established.

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 Inhaler (CFC-Free) should not be stopped abruptly.

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

Use During Pregnancy and Lactation

Pregnancy

There is inadequate evidence of safety of fluticasone propionate in human pregnancy. Reproductive studies in animals have shown only those effects characteristic of glucocorticosteroids at systemic exposure greatly in excess of the recommended inhaled therapeutic dose. Tests for genotoxicity have shown no mutagenic potential.

However, as with other medicines the 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 foetus.

Lactation

The excretion of fluticasone propionate into human breast milk has not been investigated. When measurable plasma levels were obtained in lactating laboratory rats following subcutaneous administration there was evidence of fluticasone propionate in the breast milk. However, plasma levels in patients following inhaled application of fluticasone propionate at recommended doses are likely to be low.

Effects on Ability to Drive and Use Machines

Fluticasone propionate is unlikely to produce an effect.

Interaction with Other Medicinal Products and Other Forms of Interaction

Due to the very low plasma concentrations achieved after inhaled dosing clinically significant drug interactions are unlikely. Care should be taken when co-administering known strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) as there is potential for increased systemic exposure to fluticasone propionate.

Undesirable Effects

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 inhaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Flixotide Inhaler (CFC-Free).

In some patients inhaled fluticasone propionate may cause hoarseness. It may be helpful to rinse out the mouth with water immediately after inhalation.

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. Flixotide Inhaler (CFC-Free) should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.

Cutaneous hypersensitivity reactions have been reported.

Rare cases of facial and oropharyngeal oedema have been reported.

Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. (see Special Warnings and Special Precautions for Use).

Overdose

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. However if higher than recommended dosage is continued over prolonged periods, some degree of adrenal suppression may result. 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.

Pharmacological Properties

Pharmacodynamic properties

Fluticasone propionate given by inhalation at recommended doses has a potent glucocorticoid anti-inflammatory action within the lungs which results in reduced symptoms and exacerbations of asthma.

Pharmacokinetic properties

The absolute bioavailability of inhaled fluticasone propionate varies between approximately 10-30% of the nominal dose depending on the inhalation device used. 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 moderately high (91%). Fluticasone propionate is cleared very rapidly from the systemic circulation, principally by metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. The renal clearance of fluticasone propionate is negligible (<0.2%) and less than 5% as the metabolite. Care should be taken when co-administering known CYP3A4 inhibitors, as there is potential for increased systemic exposure to fluticasone propionate.

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.

Pharmaceutical Particulars

List of excipients

HFA 134a

Incompatibilities

None reported.

Shelf life

2 years.

Special precautions for storage

Flixotide Inhaler (CFC-Free) should be stored below 30ºC.

Protect from frost and direct sunlight.

As with most inhaled medications 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.

Nature and contents of container

Flixotide Inhaler (CFC-Free) comprises a suspension of fluticasone propionate in the non-CFC propellant HFA 134a. The suspension is contained in an aluminium alloy can sealed with a metering valve. The canisters are fitted into plastic actuators incorporating an atomising orifice and fitted with dustcaps. Flixotide Inhaler (CFC-Free) has been formulated in three strengths, 50mcg, 125mcg or 250mcg of fluticasone propionate per actuation, 120 actuations per inhaler.

Instructions for use/handling

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 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 and check the mouthpiece inside and outside to see that it is clean.
2. Shake the inhaler well.
3. Hold the inhaler upright between fingers and thumb with your thumb on the base, below the mouthpiece.
4. 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.
5. 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.
6. 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.
7. If you are to take further puffs keep the inhaler upright and wait about half a minute before repeating steps 2 to 6.

The mouthpiece cover is replaced by firmly pushing and snapping the cap into position.

Important

Do not rush stages 4, 5 and 6. 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 your inhaler or the sides of your mouth you should start again from stage 2.

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

Children

Young children may need help and an adult may need to operate the inhaler for them. Encourage the child to breathe out and operate the inhaler just after the child starts to breathe in. Practice the technique together. Older children or people with weak hands should hold the inhaler with both hands. Put the two forefingers on top of the inhaler and both thumbs on the base below the mouthpiece.

Cleaning

Your inhaler should be cleaned at least once a week.

1. Pull the metal canister out of the plastic casing of the inhaler and remove the mouthpiece cover.
2. Wipe the plastic casing and mouthpiece cover with a damp cloth.
3. Leave to dry in a warm place. Avoid excessive heat.
4. Replace the canister and mouthpiece cover.

Do not out the metal canister into water.

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