FLUTIFORM Pressurised inhalation, suspension Ref.[28075] Active ingredients: Eformoterol Fluticasone

The management of asthma should normally follow a stepwise programme and patients' responses should be monitored clinically and by lung function tests.

Flutiform inhaler should not be used to treat acute asthma symptoms for which a fast and short-acting bronchodilator is required. Patients should be advised to have their medicine to be used for relief in an acute asthma attack available at all times.

The prophylactic use of Flutiform inhaler in exercise-induced asthma has not been studied. For such use, a separate rapid-acting bronchodilator should be considered.

Patients should be reminded to take their Flutiform inhaler maintenance dose as prescribed, even when asymptomatic.

Patients should not be initiated on Flutiform inhaler during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Serious asthma-related adverse events and exacerbations may occur during treatment with Flutiform inhaler. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Flutiform inhaler.

Flutiform inhaler should not be used as the first treatment for asthma.

If increasing use of short-acting bronchodilators to relieve asthma is required, if short-acting bronchodilators become less effective, or ineffective or if asthma symptoms persist, the patient should be reviewed by their doctor as soon as possible as any of these may indicate a deterioration in asthma control and their treatment may need to be changed.

Sudden and progressive deterioration in control of asthma is potentially life-threatening and the patient should undergo urgent medical assessment. Consideration should be given to increasing corticosteroid therapy. The patient should also be medically reviewed when the current dosage of Flutiform inhaler has failed to give adequate control of asthma. Consideration should be given to additional corticosteroid therapies.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Flutiform inhaler. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Flutiform inhaler should be used (see section 4.2).

Treatment with Flutiform inhaler should not be stopped abruptly in patients with asthma due to risk of exacerbation. Therapy should be down-titrated under the supervision of a prescriber.

An exacerbation of the clinical symptoms of asthma may be due to an acute respiratory tract bacterial infection and treatment may require appropriate antibiotics, increased inhaled corticosteroids and a short course of oral corticosteroids. A rapid-acting inhaled bronchodilator should be used as rescue medication. As with all inhaled medication containing corticosteroids, Flutiform inhaler should be administered with caution in patients with pulmonary tuberculosis, quiescent tuberculosis or patients with fungal, viral or other infections of the airway. Any such infections must always be adequately treated if Flutiform inhaler is being used.

Flutiform inhaler should be used with caution in patients with thyrotoxicosis, phaeochromocytoma, diabetes mellitus, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, cardiac arrhythmias or severe heart failure.

Potentially serious hypokalaemia may result from high doses of β₂ agonists. Concomitant treatment of β₂ agonists with drugs which can induce hypokalaemia or potentiate a hypokalaemic effect, e.g. xanthine derivatives, steroids and diuretics, may add to a possible hypokalaemic effect of the β₂ agonist. Particular caution is recommended in unstable asthma with variable use of rescue bronchodilators, in acute severe asthma as the associated risk may be augmented by hypoxia and in other conditions when the likelihood for hypokalaemia adverse effects is increased. It is recommended that serum potassium levels are monitored during these circumstances.

Caution must be observed when treating patients with existing prolongation of the QTc interval. Formoterol itself may induce prolongation of the QTc interval.

As for all β₂ agonists, additional blood sugar controls should be considered in diabetic patients.

Care should be taken when transferring patients to Flutiform inhaler therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy.

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straight away. Flutiform inhaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

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 Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). 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.

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 ≥ 1000 micrograms/day) may be at particular risk. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000 micrograms. 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, hypotension, decreased level of consciousness, hypoglycaemia, and seizures. Additional systemic corticosteroid treatment 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 impaired adrenal 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. In situations of possible impaired adrenal function hypothalamic pituitary adrenocortical (HPA) axis function should be monitored regularly.

There is an increased risk of systemic side effects when combining fluticasone propionate with potent CYP3A4 inhibitors (see section 4.5).

The patient should be made aware that this fixed-dose combination inhaler is a prophylactic therapy and as such has to be used regularly even when asymptomatic for optimum benefit.

Use of a spacer device may lead to a possible increase in pulmonary deposition and a potential increase in systemic absorption and systemic adverse events.

As the fractions of fluticasone and formoterol which reach systemic circulation are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe hepatic impairment.

Patients should be advised that Flutiform inhaler contains a very small amount of ethanol (approximately 1.00 mg per actuation); however this amount of ethanol is negligible and does not pose a risk to patients.

Paediatric population

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Possible systemic effects as reported for the individual components of Flutiform inhaler include Cushing’s syndrome, Cushingoid features, adrenal suppression and growth retardation in children and adolescents. Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (see section 4.8)

Limited data are available on the use of Flutiform inhaler in children under 5 years of age. Flutiform inhaler is NOT recommended for use in children under 5 years of age.

No formal drug interaction studies have been performed with Flutiform inhaler.

Flutiform inhaler contains sodium cromoglicate at non-pharmacological levels. Patients should not discontinue any cromoglicate containing medication.

Fluticasone propionate, an individual component of Flutiform inhaler, is a substrate of CYP 3A4. Co-treatment with CYP3A inhibitors (e.g. ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nelfinavir, saquinavir, ketoconazole, telithromycin, cobicistat) is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.

The ECG changes and/or hypokalaemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by β agonists, especially when the recommended dose of the β agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of a β agonist with non-potassium sparing diuretics. Xanthine derivates and glucocorticosteroids may add to a possible hypokalaemic effect of the β agonists.

In addition L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards β₂ sympathomimetics.

Concomitant treatment with monoamine oxidase inhibitors, including agents with similar properties such as furazolidone and procarbazine, may precipitate hypertensive reactions.

There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.

Concomitant use of other β adrenergic drugs can have a potentially additive effect.

Hypokalaemia may increase the risk of arrhythmias in patients who are treated with digitalis glycosides.

Formoterol fumarate, as with other β₂ agonists, should be administered with caution to patients being treated with tricyclic antidepressants or monoamine oxidase inhibitors, and during the immediate two week period following their discontinuation, or other drugs known to prolong the QT_c interval such as antipsychotics (including phenothiazines), quinidine, disopyramide, procainamide, and antihistamines. Drugs that are known to prolong the QT_c interval can increase the risk of ventricular arrhythmias (see section 4.4).

If additional adrenergic drugs are to be administered by any route, they should be used with caution, because the pharmacologically predictable sympathetic effects of formoterol may be potentiated.

Beta adrenergic receptor antagonists (β blockers) and formoterol fumarate may inhibit the effect of each other when administered concurrently. Beta blockers may also produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with β blockers and this includes β blockers used as eye drops for treatment of glaucoma. However, under certain circumstances, e.g. as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of β blockers in patients with asthma. In this setting, cardioselective β blockers could be considered, although they should be administered with caution.

Pregnancy

There are limited data on the use of fluticasone propionate and formoterol fumarate, either administered alone or together but administered from separate inhalers, or on the use of this fixed-dose combination, Flutiform inhaler in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Administration of Flutiform inhaler is not recommended during pregnancy, and should only be considered if expected benefit to the mother is greater than any possible risk to the fetus. If this is the case, then the lowest effective dose needed to maintain adequate asthma control should be used.

Because of the potential for β agonist interference with uterine contractility, use of Flutiform inhaler for management of asthma during labour should be restricted to those patients in whom the benefit outweighs the risks.

Breastfeeding

It is not known whether fluticasone propionate or formoterol fumarate are excreted in human breast milk. A risk to the suckling child cannot be excluded. Therefore, a decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Flutiform inhaler therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

There are no data available on effects on fertility following administration of Flutiform inhaler. In animal studies, no effects on fertility have been seen following administration of the individual active substances at clinically relevant doses (see section 5.3).

Flutiform inhaler has no or negligible influence on the ability to drive and use machines.

Undesirable effects which have been associated with Flutiform inhaler during clinical development are given in the table below, listed by system organ class. The following frequency categories form the basis for classification of the undesirable effects as: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straight away. Flutiform inhaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Since Flutiform inhaler contains both fluticasone propionate and formoterol fumarate, the same pattern of undesirable effects as reported for these substances may occur. The following undesirable effects are associated with fluticasone propionate and formoterol fumarate, but have not been seen during the clinical development of Flutiform inhaler:

Fluticasone propionate

Hypersensitivity reactions including, urticaria, pruritus, angiooedema (mainly facial and oropharyngeal), anaphylactic reactions. Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These may include Cushing’s Syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma, contusion, skin atrophy and susceptibility to infections. The ability to adapt to stress may be impaired. The systemic effects described, however, are much less likely to occur with inhaled corticosteroids than with oral corticosteroids. Prolonged treatment with high doses of inhaled corticosteroids may result in clinically significant adrenal suppression and acute adrenal crisis. Additional systemic corticosteroid cover may be required during periods of stress (trauma, surgery, infection).

Formoterol fumarate

Hypersensitivity reactions (including hypotension, urticaria, angioneurotic oedema, pruritus, exanthema), QTc interval prolongation, hypokalaemia, nausea, myalgia, increased blood lactate levels. Treatment with β2 agonists such as formoterol may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.

Hypersensitivity reactions have been reported in patients using inhaled sodium cromoglicate as an active ingredient. Whilst Flutiform inhaler contains only a low concentration of sodium cromoglicate as an excipient, it is unknown if hypersensitivity reactions are dose dependent.

In the unlikely event of a hypersensitivity reaction to Flutiform inhaler, treatment should be initiated in accordance with standard treatment for any other hypersensitivity reaction, which may include the use of antihistamines and other treatment as required. Flutiform inhaler may need to be discontinued immediately and an alternative asthma therapy may need to be initiated if necessary.

Dysphonia and candidiasis may be relieved by gargling or rinsing the mouth with water or brushing the teeth after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst continuing the treatment with Flutiform inhaler.

Paediatric population

Possible systemic effects as reported for the individual components of Flutiform inhaler include Cushing’s syndrome, Cushingoid features, adrenal suppression and growth retardation in children and adolescents. Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability. Studies conducted with Flutiform inhaler demonstrated similar safety and tolerability profile as compared to fluticasone monotherapy in children aged 5-12 years and fluticasone/salmeterol in children aged 4-12. Long term treatment with Flutiform inhaler for 24 weeks in 208 children did not show any indication of growth retardation or adrenal suppression. Another pharmacodynamic study conducted in children aged 5-12 years showed similar lower leg growth rate as measured by knemometry after treatment with Flutiform inhaler as compared to fluticasone monotherapy for 2 weeks.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Not applicable.