4.1. Therapeutic indications

Fostair NEXThaler is indicated in the regular treatment of asthma where use of a combination product (inhaled corticosteroid and long-acting beta2-agonist) is appropriate:

- patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled short-acting beta2-agonist or

- patients already adequately controlled on both inhaled corticosteroids and long-acting beta2-agonists.

Fostair NEXThaler is indicated in adults.

Note: there are no relevant clinical data on the use of Fostair NEXThaler for the treatment of acute asthma attacks.

4.2. Posology and method of administration

Posology

FOSTAIR NEXTHALER is not intended for the initial management of asthma. The dosage of Fostair NEXThaler is individual and should be adjusted to the severity of the disease. This should be considered not only when treatment with combination products is initiated but also when the dose is adjusted. If an individual patient should require a combination of doses other than those available in the combination inhaler, appropriate doses of beta2-agonists and/or corticosteroids by individual inhalers should be prescribed.

Because of its extrafine particle size distribution, dose adjustment is required when patients are transferred to Fostair NEXThaler inhalation powder from a formulation with a non-extrafine particle size distribution. When switching patients from previous treatments, it should be considered that the recommended total daily dose of beclometasone dipropionate for Fostair NEXThaler is lower than that for current beclometasone dipropionate-containing non-extrafine products and should be adjusted to the needs of the individual patient.

Dose recommendations for adults 18 years and above

Two inhalations twice daily.

The maximum daily dose is 4 inhalations daily.

Patients should be regularly reassessed by a doctor, so that the dosage of Fostair NEXThaler remains optimal and is only changed on medical advice. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. When control of symptoms is maintained with the lowest recommended dosage, then the next step-down could include the inhaled corticosteroid alone.

A lower strength of the beclometasone dipropionate component in the same Nexthaler device is available for step-down treatment (Fostair NEXThaler 100/6 micrograms).

Patients should be advised to take Fostair NEXThaler every day even when asymptomatic.

Special populations

There is no need to adjust the dose in elderly patients.

There are no data available for use of Fostair NEXThaler in patients with hepatic or renal impairment (see section 5.2).

Paediatric population

Fostair NEXThaler 200/6 micrograms should not be used in children and adolescents below 18 years.

Method of administration

FOSTAIR NEXTHALER is for inhalation use.

Nexthaler is a breath-operated inhaler. Moderate and severe asthmatic patients were shown to be able to produce sufficient inspiratory flow to trigger inhalation release from Nexthaler (see section 5.1). The delivery of Fostair NEXThaleris flow-independent in the range of inspiratory flow that this patient population can achieve through the inhaler.

Correct use of the Nexthaler inhaler is essential in order for the treatment to be successful. The patient should be advised to read the Patient Information Leaflet carefully and follow the instructions for use as given in the leaflet.

The number of inhalations shown in the window on the shell does not decrease on closing the cover if the patient has not inhaled through the inhaler.

The patient should be instructed to only open the inhaler's cover when needed. In the event that the patient has opened the inhaler but not inhaled, and the cover is closed, the metered dose is moved back to the powder reservoir within the inhaler; the following metered dose can be safely inhaled.

Patients should rinse their mouth or gargle with water or brush their teeth after inhaling (see section 4.4).

INSTRUCTIONS FOR USE OF NEXTHALER INHALER

A. Contents of the Package

For information on the contents of the package, see section 6.5.

If the package contents are not the same as described in section 6.5, return your inhaler to the person who supplied it and get a new one.

B. General Warnings & Precautions

• Do not remove the inhaler from the pouch if you do not intend to use it immediately.

• Only use your inhaler as indicated.

• Keep the cover closed until you need to take a dose from your inhaler.

• When you are not using your inhaler keep it in a clean and dry place.

• Do not attempt to take your Nexthaler inhaler apart for any reason.

C. Key features of your Nexthaler inhaler

Taking a dose from your Nexthaler inhaler requires just three simple steps: Open, Inhale, Close.

D. Before using a new Nexthaler inhaler

1. Open the pouch and take out your inhaler.

o Do not use your inhaler if the pouch is not sealed or it is damaged – return it to the person who supplied it and get a new one.

o Use the label on the box to write down the date you open the pouch.

2. Inspect your inhaler.

o If your inhaler looks broken or damaged, return it to the person who supplied it and get a new one.

3. Check the Dose Counter Window. If your inhaler is brand new you will see “120” in the Dose Counter Window.

o Do not use a new inhaler if the number shown is less than “120” – return it to the person who supplied it and get a new one.

E. How to use your Nexthaler inhaler

• If you are not sure you are receiving your dose correctly contact your pharmacist or doctor.

• If you are not sure the dose counter has gone down by one after inhalation, wait until your next scheduled dose and take this as normal. Do not take an extra dose.

E.1. Open

1. Hold your inhaler firmly in the upright position.

2. Check the number of doses left: any number between “1” and “120” shows that there are doses left.

o If the Dose Counter Window shows “0” there are no doses left – dispose of your inhaler and get a new one.

3. Open the cover fully.

4. Before inhaling breathe out as far as is comfortable.

o Do not breathe out through your inhaler.

E.2. Inhale

Whenever possible, stand or sit in an upright position when inhaling.

1. Lift your inhaler up, bring it to your mouth and place your lips around the mouthpiece.

o Do not cover the air vent when holding your inhaler.

o Do not inhale through the air vent.

2. Take a quick and deep breath through your mouth.

o You may notice a taste when you take your dose.

o You may hear or feel a click when you take your dose.

o Do not inhale through your nose.

o Do not remove your inhaler from your lips during the inhalation.

3. Remove your inhaler from your mouth.

4. Hold your breath for 5 to 10 seconds or as long as is comfortable.

5. Breathe out slowly.

o Do not breathe out through your inhaler.

E.3. Close

1. Move your inhaler back to the upright position and close the cover fully.

2. Check that the dose counter has gone down by one.

3. If you need to take another dose, repeat steps E.1 to E.3.

F. Cleaning

• Normally, it is not necessary to clean your inhaler.

• If necessary you may clean your inhaler after use with a dry cloth or tissue.

o Do not clean your inhaler with water or other liquids. Keep it dry.

G. Storage and Disposal

For information on storage conditions and disposal instructions, see section 6.4 and 6.6.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

It is recommended that the dose is tapered when the treatment is discontinued; treatment should not be stopped abruptly.

The management of asthma should normally follow a stepwise programme and patient response should be monitored clinically and by lung function tests.

If patients find the treatment ineffective medical attention must be sought. Increasing use of rescue bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy. 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 the need for increased treatment with corticosteroids, either inhaled or oral therapy, or antibiotic treatment if an infection is suspected.

Patients should not be initiated on Fostair NEXThaler 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 Fostair NEXThaler. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Fostair NEXThaler.

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing, cough and shortness of breath after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. Fostair NEXThaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Fostair NEXThaler is not intended for the initial management of asthma.

For treatment of acute asthma attacks patients should be advised to have their short-acting bronchodilator available at all times.

Patients should be reminded to take Fostair NEXThaler daily as prescribed even when asymptomatic.

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

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged 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 dose of inhaled corticosteroid is titrated 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 aged less than 16 years inhaling higher than recommended doses of beclometasone dipropionate may be at particular risk. 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 cover should be considered during periods of stress or elective surgery.

Patients transferring from oral to inhaled corticosteroids may remain at risk of impaired adrenal reserve for a considerable time. Patients who have required high dose emergency corticosteroid therapy in the past or have received prolonged treatment with high doses of inhaled corticosteroids 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.

Fostair NEXThaler should be administered with caution in patients with active or quiescent pulmonary tuberculosis, fungal and viral infections in the airways.

Fostair NEXThaler should be used with caution (which may include monitoring) in patients with cardiac arrhythmias, especially third degree atrioventricular block and tachyarrhythmias, idiopathic subvalvular aortic stenosis, hypertrophic obstructive cardiomyopathy, ischaemic heart disease, severe heart failure, severe arterial hypertension and aneurysm.

Caution should also be observed when treating patients with known or suspected prolongation of the QTc interval, either congenital or drug induced (QTc > 0.44 seconds). Formoterol itself may induce prolongation of the QTc interval.

Caution is also required when Fostair NEXThaler is used by patients with thyrotoxicosis, diabetes mellitus, phaeochromocytoma and untreated hypokalaemia.

Potentially serious hypokalaemia may result from beta2-agonist therapy. Particular caution is advised in severe asthma as this effect may be potentiated by hypoxia. Hypokalaemia may also be potentiated by concomitant treatment with other drugs which can induce hypokalaemia, such as xanthine derivatives, steroids and diuretics (see section 4.5). Caution is also recommended in unstable asthma when a number of “rescue” bronchodilators may be used. It is recommended that serum potassium levels are monitored in such situations.

The inhalation of formoterol may cause a rise in blood glucose levels. Therefore blood glucose should be closely monitored in patients with diabetes.

If anaesthesia with halogenated anaesthetics is planned, it should be ensured that Fostair NEXThaler is not administered for at least 12 hours before the start of anaesthesia as there is a risk of cardiac arrhythmias.

Patients should be advised to rinse the mouth or gargle with water or brush the teeth after inhaling the prescribed dose to minimise the risk of oropharyngeal fungal infections and dysphonia.

The medicninal product contains lactose. Lactose contains small amounts of milk proteins, which may cause allergic reactions. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Visual disturbance

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.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

Beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes.

Beclomethasone is less dependent on CYP3A metabolism than some other corticosteroids, and in general interactions are unlikely; however the possibility of systemic effects with concomitant use of strong CYP3A inhibitors (e.g. ritonavir, cobicistat) cannot be excluded, and therefore caution and appropriate monitoring is advised with the use of such agents.

Pharmacodynamic interactions

Beta-adrenergic blockers can weaken or inhibit the effect of formoterol. Fostair NEXThaler should therefore not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons.

The use of other beta-adrenergic drugs may have potentially additive effects, therefore caution is required when theophylline or other beta-adrenerigic drugs are prescribed concomitantly with formoterol.

Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, certain antihistamines (e.g. terfenadine), monoamine oxidase inhibitors and tricyclic antidepressants can prolong the QTc-interval and increase the risk of ventricular arrhythmias.

In addition L-dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards beta2-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 treatment with xanthine derivatives, steroids, or diuretics may potentiate a possible hypokalaemic effect of beta2-agonists (see section 4.4). Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.

4.6. Fertility, pregnancy and lactation

Fertility

There are no data in humans. In animal studies in rats, the presence of beclometasone dipropionate at high doses in the combination was associated with reduced female fertility and embryotoxicity (see section 5.3).

Pregnancy

There are no relevant clinical data on the use of Fostair NEXThaler in pregnant women. Animal studies using beclometasone dipropionate and formoterol combination showed evidence of toxicity to reproduction and to the fetuses after high systemic exposure (see section 5.3). High doses of corticosteroids administered to pregnant animals are known to cause abnormalities of fetal development including cleft palate and intra-uterine growth retardation. Because of the tocolytic actions of beta2-sympathomimetic agents particular care should be exercised in the run up to delivery. Formoterol should not be recommended for use during pregnancy and particularly at the end of pregnancy or during labour unless there is no other (safer) established alternative.

Administration of Fostair NEXThaler during pregnancy should only be considered if the expected benefits outweigh the potential risks.

Lactation (Breast-feeding)

There are no relevant clinical data on the use of Fostair NEXThaler during lactation in humans.

Although no data from animal experiments are available, it is reasonable to assume that beclometasone dipropionate is secreted in milk, like other corticosteroids.

While it is not known whether formoterol passes into human breast milk, it has been detected in the milk of lactating animals.

Administration of Fostair NEXThaler to women who are breast-feeding should be considered if the expected benefits outweigh the potential risks. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Fostair NEXThaler therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7. Effects on ability to drive and use machines

Fostair NEXThaler has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

The most common adverse reaction is tremor. In a 12-week clinical trial with Fostair NEXThaler 100/6 micrograms, tremor was seen only with the highest dose regimen (400/24 micrograms daily), appeared most frequently at the beginning of treatment and was mild in intensity. No patient was withdrawn from the trial as a result of tremor.

Clinical Trials Experience in asthma patients

The safety of Fostair NEXThaler 100/6 micrograms was assessed in active- and placebo-controlled clinical trials in which 719 patients aged 12 and older with asthma of varying severity were exposed to the drug. The incidence of adverse reactions in the table below relates to asthmatic patients aged 12 years and older and is based upon the safety findings of two pivotal clinical trials where Fostair NEXThaler 100/6 micrograms was administered at the doses recommended in this SmPC for a period of 8-12 weeks. No psychiatric disorders were observed in the clinical trials with Fostair NEXThaler 100/6 micrograms but they are included in the table as a potential class-effect of inhaled corticosteroids.

Undesirable effects which have been associated with beclometasone dipropionate and formoterol administered as a fixed combination (Fostair NEXThaler) are given below, listed by system organ class. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to < 1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data).

System Organ Class

Adverse Reaction

Frequency

Infections and infestations

Nasopharyngitis

Uncommon

Oral candidiasis

Uncommon

Metabolism and nutrition disorders

Hypertriglyceridaemia

Uncommon

Psychiatric disorders

Psychomotor hyperactivity, sleep disorders, anxiety, depression, aggression, behavioural changes (predominantly in children)

Frequency not known

Eye disorders

Vision, blurred (see also section 4.4)

Frequency not known

Nervous system disorders

Tremor

Common

Headache

Uncommon

Cardiac disorders

Tachycardia

Uncommon

Sinus bradycardia

Uncommon

Angina pectoris

Uncommon

Myocardial ischaemia

Uncommon

Respiratory, thoracic and mediastinal disorders

Throat irritation, exacerbation of asthma

Uncommon

Dyspnoea

Uncommon

Oropharyngeal pain

Uncommon

Dysphonia

Uncommon

Cough

Uncommon

Gastrointestinal disorders

Nausea

Uncommon

General disorders and administration site conditions

Fatigue

Uncommon

Irritability

Uncommon

Investigations

Electrocardiogram QT prolonged

Uncommon

Cortisol free urine decreased

Uncommon

Blood cortisol decreased

Uncommon

Blood potassium increased

Uncommon

Blood glucose increased

Uncommon

Electrocardiogram poor r-wave progression

Uncommon

Among the observed adverse reactions those typically associated with formoterol are: tremor, headache, tachycardia, sinus bradycardia, angina pectoris, myocardial ischaemia, QT prolongation.

Among the observed adverse reactions those typically associated with beclometasone dipropionate are: nasopharyngitis, oral candidiasis, dysphonia, throat irritation, irritability, cortisol free urine decreased, blood cortisol decreased, blood glucose increased.

Additional adverse reactions not observed in the clinical experience with Fostair NEXThaler but typically associated with the inhaled administration of beclometasone dipropionate are other oral fungal infections. Taste disturbances have occasionally been reported during inhaled corticosteroid therapy.

See section 4.4 for measures to minimize the occurrence of oral fungal infections, oral candidiasis and dysphonia.

Systemic effects of inhaled corticosteroids (e.g. beclometasone dipropionate) may occur particularly when administered at high doses prescribed for prolonged periods, these may include Cushing's Syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract and glaucoma (see also section 4.4).

Additional adverse reactions not observed in the clinical experience with therapeutic doses of Fostair NEXThaler 100/6 micrograms but typically associated with the administration of beta2-agonist such as formoterol are palpitations, atrial fibrillation, ventricular extrasystoles, tachyarrhythmia, potentially serious hypokalaemia and increase/decrease of blood pressure. Insomnia, dizziness, restlessness, and anxiety have occasionally been reported during inhaled formoterol therapy. Formoterol may also induce muscle cramps, myalgia.

Hypersensitivity reactions including rashes, urticaria, pruritus and erythema and oedema of the eye, face, lips and throat (angioedema) have been reported.

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing, cough and shortness of breath after dosing (see also section 4.4).

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 Website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

The highest recommended dose of Fostair NEXThaler in a single administration is 2 inhalations. Four cumulative inhalations of Fostair NEXThaler (total beclometasone dipropionate 800 micrograms, formoterol 24 micrograms given as a single dose) have been studied in asthmatic patients. The cumulative treatment did not cause abnormal, clinically relevant effect on vital signs and neither serious nor severe adverse reactions were observed (see also section 4.8).

For the pressurised inhalation solution formulation, inhaled doses of up to twelve cumulative actuations of 100/6 micrograms each (total beclometasone dipropionate 1200 micrograms, formoterol 72 micrograms) have been studied in asthmatic patients. The cumulative treatments did not cause abnormal effect on vital signs and neither serious nor severe adverse events were observed.

Excessive doses of formoterol may lead to effects that are typical of beta2-adrenergic agonists: nausea, vomiting, headache, tremor, somnolence, palpitations, tachycardia, ventricular arrhythmias, prolongation of QTc interval, metabolic acidosis, hypokalaemia, hyperglycaemia.

In case of overdose of formoterol, supportive and symptomatic treatment is indicated. Serious cases should be hospitalised. Use of cardioselective beta-adrenergic blockers may be considered, but only subject to extreme caution since the use of beta-adrenergic blocker medication may provoke bronchospasm. Serum potassium should be monitored.

Acute inhalation of beclometasone dipropionate doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not need emergency action as adrenal function recovers in a few days, as verified by plasma cortisol measurements. In these patients treatment should be continued at a dose sufficient to control asthma.

Chronic overdose of inhaled beclometasone dipropionate: risk of adrenal suppression (see section 4.4.). Monitoring of adrenal reserve may be necessary. Treatment should be continued at a dose sufficient to control asthma.