Allen & Hanburys Ltd

Flixotide Nebules 0.5mg/2ml Nebuliser Suspension

Flixotide Nebules 2mg/2ml Nebuliser Suspension

Flixotide Nebules 0.5mg/2ml Nebuliser Suspension:

Each nebule contains 0.5mg Fluticasone propionate in a 2ml suspension.

Each ml of suspension contains 0.25mg Fluticasone propionate.

Flixotide Nebules 2mg/2ml Nebuliser Suspension:

Each nebule contains 2 mg Fluticasone propionate in a 2ml suspension.

Each ml of suspension contains 1 mg Fluticasone propionate.

For a full list of excipients, see section 6.1

Nebuliser Suspension (nebuliser liquid).

A white, opaque suspension.

Adults and adolescents over 16 years of age:

• Prophylactic management in severe asthma (patients requiring high dose inhaled or oral corticosteroid therapy).

• Treatment of acute exacerbations of asthma.

Children and adolescents from 4 to 16 years of age:

• Treatment of acute exacerbations of asthma.

Flixotide Nebules should be administered as an aerosol produced by a jet nebuliser, as directed by a physician. As drug delivery can be affected by a wide range of criteria, please refer to the directions recommended by the manufacturer of the nebuliser equipment.

Use of Flixotide Nebules with ultrasonic nebulisers is not generally recommended.

Fluticasone propionate for nebulisation is intended for oral inhalation, and use of a mouthpiece is recommended. If use of a face mask is necessary, nasal inhalation may occur.

Patients should be made aware of the prophylactic nature of therapy with inhaled fluticasone propionate and that it should be taken regularly. Maximal improvement in asthma may be achieved within 4 to 7 days of starting treatment. However, fluticasone propionate has been shown to have a therapeutic effect as soon as 24 hours after starting treatment 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.

To aid administration of small volumes of the suspension, or if a prolonged delivery time is desirable, fluticasone propionate suspension for nebulisation may be diluted immediately before use with sodium chloride injection BP.

As many nebulisers operate on a continuous flow basis, it is likely that nebulised drug will be released in the local environment. Flixotide Nebules should therefore be administered in a well ventilated room, particularly in hospitals when several patients may be using nebulisers at the same time.

Dosage:

Adults and adolescents over 16 years: For the prophylactic management and treatment of acute exacerbations of asthma, take 500-2000mcg twice daily.

Children and adolescents from 4 to 16 years: For the treatment of acute exacerbations of asthma only, take 1000mcg twice daily

Patients should be given an initial dose of nebulised fluticasone propionate which is appropriate for the severity of their disease. The dosage should then be adjusted until control is achieved or reduced to the minimum effective dose according to the individual response.

A dose at the upper end of the range is recommended for the treatment of acute exacerbations of asthma for up to 7 days after exacerbation. Consideration should then be given to reducing the dosage.

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

Flixotide Nebules are contra-indicated in patients with a history of hypersensitivity to any of its components.

Fluticasone propionate for nebulisation should not be injected.

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 beta-2 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 Nebules are not for use alone in the relief of symptoms arising from acute bronchospasm when a short-acting inhaled bronchodilator (e.g. salbutamol ) is also required. Flixotide Nebules are intended for regular daily treatment and as anti-inflammatory therapy in acute exacerbations of asthma.

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.

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 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.

Flixotide Nebules are not a substitute for injectable or oral corticosteroids in an emergency situation.

Patients receiving treatment with nebulised fluticasone propionate must be warned that if their clinical condition deteriorates they should not increase the dose or the frequency of administration, but should seek medical advice.

It is advisable to administer the nebulised fluticasone propionate via a mouthpiece to avoid the possibility of atrophic changes of facial skin which may occur with prolonged use with a face-mask.

When a face mask is used, the exposed skin should be protected by use of barrier cream or by thorough washing of the face after use.

Prolonged therapy with inhaled Flixotide Nebules should be reduced gradually, and not be stopped abruptly, other than under medical supervision.

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 is inadequate evidence of safety of fluticasone propionate in human pregnancy. Reproductive studies in animals have shown only those effects characteristic of gluco-corticosteroids at systemic exposure greatly in excess of the recommended inhaled therapeutic dose. Tests for genotoxicity have shown no mutagenic potential. However, as with other drugs 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 milk. However plasma levels in patients following inhaled application of fluticasone propionate at recommended doses are likely to be low.

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 after inhalation from the nebuliser. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with nebulised Fluticasone propionate.

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

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 potent 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.

Following intravenous administration the pharmacokinetics of fluticasone propionate are proportional to the dose, and can be described by three exponentials. Fluticasone propionate is extensively distributed within the body (Vss is approximately 300L) and has a very high clearance (estimated to be Cl 1.1L/min) indicating extensive hepatic extraction. Peak plasma concentrations are reduced by approximately 98% within 3-4 hours, and only low plasma concentrations are associated with the terminal half-life, which is approximately 8 hours.

Following oral administration of fluticasone propionate, 87-100% of the dose is excreted in the faeces. Following doses of either 1 or 16 mg, up to 20% and 75% respectively, is excreted in the faeces as parent compound. Absolute oral bioavailability is negligible (<1%) due to a combination of incomplete absorption from the gastro-intestinal tract and extensive first pass metabolism.

Following inhaled dosing, systemic absolute bioavailability of nebulised fluticasone propionate in healthy volunteers is estimated as 8% compared to up to 26% received from the metered dose inhaler presentation. Systemic absorption of fluticasone propionate occurs mainly through the lungs, and is initially rapid, then prolonged.

Plasma binding is 91%. Fluticasone propionate is extensively metabolised by CYP3A4 enzyme to an inactive carboxylic acid derivative. As fluticasone propionate is given at very low doses, any effect on co-administered drugs is unlikely. In clinical programmes, there were no reports of suspected drug interactions whilst patients were on inhaled fluticasone propionate therapy.

The limited data for paediatric pharmacokinetics show consistency with the adult findings.

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.

Polysorbate 20

Sorbitan monolaurate

Monosodium phosphate dihydrate

Dibasic sodium phosphate anhydrous

Sodium Chloride

Water for Injection

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Unopened: 3 years.

Once opened: Use within 12 hours of opening.

Do not store above 30°C.

Store in the original container to protect from light.

Do not freeze.

Opened Nebules should be refrigerated.

Store upright.

Do not remove nebule from foil except for immediate use.

Flixotide Nebules are presented in 2.5 ml medical grade low density polythene containers. Each nebule contains 2ml of solution and is individually wrapped in a foil blister; blisters are supplied as packs of 10 in cardboard cartons.

Refer to the manufacturer's instructions for nebuliser use.

It is important to ensure the contents of your Nebule are well mixed before use. While holding the Nebule horizontally by the labelled tab, “flick” the other end a few times until the entire contents of the Nebule are completely mixed.

Shake gently before use.

To open - twist tab at the top of the Nebule.

Dilution:

Dilute with Sodium Chloride Injection BP immediately before use, if required. The diluted product should be a white semi opaque suspension

Do not use the product if discoloured.

Discard unused suspension in bowl of nebuliser.

It is advisable to administer via a mouth piece.

If using a face mask, protect the skin with barrier cream, or wash face thoroughly after treatment.

GlaxoSmithKline (Ireland) Limited

Stonemasons Way,

Rathfarnham,

Dublin 16

Trading as:

Allen & Hanburys

Flixotide Nebules 0.5mg/2ml Nebuliser Suspension:

PA 1077/44/16

Flixotide Nebules 2mg/2ml Nebuliser Suspension:

PA 1077/44/17

5th February 1999/10^th October 2008

August 2010