Only the alternative batch release site has been removed. No change to the actual manufacturer/batch release sites.

Update to section 4.4 – addition of Visual Disturbance section (blurred vision)

Update to section 4.8 – addition of Eye Disorders section (blurred vision)

Epistaxis in frequency table as not known

Section 4.8 – Inclusion of adverse reaction

Section 4.8 - adverse event reporting - updated details from IMB to HPRA

Section 4.4 - Special warnings and precautions for use,
Section 4.8 - Undesirable effects,
Section 7 - MARKETING AUTHORISATION HOLDER

4.2 Posology and Method of Administration

The following instruction/warning was added:

Fluticasone propionate for nebulisation should not be injected.

The instruction regarding the prophylactic nature of fluticasone propionate was updated to highlight that it should be taken regularly, even when the patient is asymptomatic.

4.4 Special Warnings and Special Precautions for Use

The following paragraph was added to specify the warning for asthma:

Fluticasone propionate 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.

Added Possible systemic effects Cushing’s syndrome, Cushingoid features

Added the following wording as required following the PhVWP decision:

Possible systemic effects include… a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

Replaced the previous warnings regarding adrenal suppression, adrenal crisis and impaired adrenal reserve with the following:

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 situations, including surgery, which are likely to produce stress and appropriate corticosteroid treatment must be considered.

Added the warning:

Treatment with fluticasone propionate should not be stopped abruptly.

Added the following warning regarding diabetes mellitus:

There have been very rare reports of increases in blood glucose levels (see 4.8 Undesirable Effects) and this should be considered when prescribing to patients with a history of diabetes mellitus.

Replaced the warning on co-administration with Ritonavir to read:

During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression.  Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects (See 4.5 Interaction with Other Medicinal Products and Other Forms of Interaction).

4.5 Interaction with Other Medicaments and Other Forms of Interaction

Replaced the interaction warning regarding ritonavir with the following:

A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations.  During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression.  Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects.

Replaced the warning regarding co-administration with CYP3A inhibitors with a warning regarding other inhibitors of cytochrome P450 3A4, as follows

Studies have shown that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations.  Nevertheless, care is advised when co-administering potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole) as there is potential for increased systemic exposure to fluticasone propionate.

4.6 Pregnancy and Lactation

Added the subheadings ‘Pregnancy’ and ‘Lactation’

4.8 Undesirable Effects

Infections and Infestations

Updated the instructions on how to mitigate the effects of candidiasis of the mouth and throat (thrush) to read:

Such patients may find it helpful to rinse out their mouth with water after using their medication.

Endocrine Disorders

Added very rare undesirable effects Cushing’s syndrome and Cushingoid features

Added the following undesirable effects:

Metabolism and nutrition disorders

Very rare: Hyperglycaemia.

Psychiatric disorders

Very rare: Anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children).

Frequency not known: Depression, aggression (predominantly in children)

Respiratory, Thoracic and Mediastinal Disorders

Updated the instructions on how to mitigate the effects of hoarseness to read:

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

Updated the statement ‘As with other inhalation therapy, paradoxical bronchospasm may occur’ with the following additional statements:

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.  Fluticasone propionate should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.

4.9 Overdose

Updated to include two subsections ‘Signs and symptoms’ and ‘Treatment’

Symptoms and Signs

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.

Treatment

 Patients receiving higher than approved doses should be managed closely and the dose reduced gradually.

1. TRADE NAME OF THE MEDICINAL PRODUCT

Flixotide Nebules 0.5mg/2ml Nebuliser Suspension

Flixotide Nebules 2mg/2ml Nebuliser Suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

3. PHARMACEUTICAL FORM

Nebuliser Suspension (nebuliser liquid).

A white, opaque suspension.

6.2 Incompatibilities

None reported.

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

6.3 Shelf Life

Unopened: 3 years.

Once opened: Use within 12 hours of opening.

6.4 Special Precautions for Storage

Do not store above 30°C.

Store in the original container to protect from light.

Protect from frost.

Do not freeze.

Opened Nebules should be refrigerated and used within 12 hours of opening.

Store upright.

Do not remove nebule from foil except for immediate use.

6.6 Instructions for Use/Handling Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product.

 4.4 Special Warnings and Special Precautions for Use

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 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.

Adrenocortical Function:  Some depression of plasma cortisol may occur in a small number of adult patients on higher doses of Flixotide Nebules.  However, adrenal function and adrenal reserve usually remain within normal range on inhaled fluticasone propionate therapy.  Patients transferred from other inhaled steroids or oral steroids remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled fluticasone propionate.

Patients in a medical or surgical emergency, who in the past have required high doses of other inhaled steroids and/or intermittent treatment with oral steroids, remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled fluticasone propionate.  The extent of the adrenal impairment may require specialist advice before elective procedures.  The possibility of residual impaired adrenal response should always be borne in mind in emergency situations, including surgery, which are likely to produce stress and appropriate corticosteroid treatment must be considered.

Severe asthma requires regular medical assessment, as it could be life-threatening.  Sudden worsening of symptoms may require increased corticosteroid dosage which should be administered under urgent medical supervision.

For the transfer of patients being treated with oral corticosteroids:

·                The transfer of oral steroid-dependent patients to inhaled fluticasone propionate and their subsequent management needs special care as recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy, may take a considerable time.

·                Patients who have been treated with systemic steroids for long periods of time or at a high dose may have adrenocortical suppression.  With these patients adrenocortical function should be monitored regularly and their dose of systemic steroid reduced cautiously.

·                After approximately a week, gradual withdrawal of the systemic steroid is commenced.  Dosage reductions should be appropriate to the level of maintenance systemic steroid, and introduced at not less than weekly intervals.  In general, for maintenance  doses of prednisolone (or equivalent) of 10 mg daily or less, the dosage reductions should not be greater than 1 mg per day, at not less than weekly intervals.  For maintenance doses of prednisolone in excess of 10 mg daily, it may be appropriate to cautiously employ larger reductions in dose at weekly intervals.

·                Some patients feel unwell in a non-specific way during the withdrawal phase despite maintenance or even improvement of the respiratory function.  They should be encouraged to persevere with inhaled fluticasone propionate and to continue withdrawal of systemic steroid, unless there are objective signs of adrenal insufficiency.

·                Patients weaned off oral steroids whose adrenocortical function is still impaired should carry a steroid warning card indicating that they may need supplementary systemic  steroid during periods of stress, e.g.  worsening asthma attacks, chest infections, major intercurrent illness, surgery, trauma, etc.

·                Replacement of systemic steroid treatment with inhaled therapy sometimes unmasks 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).

4.5 Interaction with Other Medicaments and Other Forms of Interaction

Due to the very low plasma concentrations achieved after inhaled dosing clinically significant drug interactions are unlikely.  However, care should be taken when co-administering known CYP3A4 inhibitors, e.g. ritonavir and ketoconazole as there is potential for increased systemic exposure to fluticasone propionate.  This should be taken into account during long term concomitant treatment.

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.

4.6 Pregnancy and Lactation

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 exposures in excess of those seen at 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.

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

In some patients inhaled fluticasone propionate may cause hoarseness.  It may be helpful to gargle 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 Nebules should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.

Cutaneous hypersensitivity reactions have been reported.

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 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
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

5.3 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.