Fostair NEXThaler 100 micrograms/6 micrograms aerosol inhalation powder - Summary of Product Characteristics (2023)

Each 10 mg dose of inhalation powder contains:

100 micrograms of anhydrous beclomethasone dipropionate and 6 micrograms of formoterol fumarate dihydrate.

This corresponds to a delivered dose (the dose that comes out of the mouthpiece) of 81.9 micrograms of anhydrous beclomethasone dipropionate and 5.0 micrograms of formoterol fumarate dihydrate.

Excipients with known effect:

Each puff contains 9.9 mg of lactose monohydrate.

For the complete list of excipients see section 6.1.

inhale dust.

The multidose inhaler contains a white or almost white powder.

asma

Fostair NEXThaler is indicated in the regular treatment of asthma when a combination pill (inhaled corticosteroid and long-acting beta-corticosteroid) is used.₂-agonist) is suitable:

- Patients inadequately controlled with inhaled short-acting beta and “as needed” inhaled corticosteroids₂-agonist or

- Patients already adequately controlled with inhaled corticosteroids and long-acting beta-corticosteroids₂-agonists.

Fostair NEXThaler is indicated in adult patients.

COPD

Symptomatic treatment of patients with severe COPD (FEV₁< 50% predicted normal) and a history of recurrent exacerbations with significant symptoms despite regular therapy with long-acting bronchodilators.

Fostair Nexthaler is for inhalation use.

ASMA

Fostair NEXThaler is not intended for the initial treatment of asthma. The dosage of Fostair NEXThaler is individual and must be adjusted according to the severity of the disease. This must be taken into account not only when starting treatment with combined products, but also when adjusting the dose. If an individual patient requires a combination of doses different from those available in the combination inhaler, the appropriate beta doses should be used.₂-Agonists and/or corticosteroids should be prescribed in individual inhalers.

Due to the extra-fine particle size distribution, dose adjustment is required when switching patients from a non-extra-fine particle size distribution formulation to Fostair NEXThaler Inhalation Powder. When switching patients from previous treatments, the recommended total daily dose of beclomethasone dipropionate for Fostair NEXThaler should be considered less than that of current products containing non-extrafine beclomethasone dipropionate and adjusted to the individual patient's needs. However, patients who switch to Fostair Nexthaler inhalation powder will decreaseEmployerThe pressurized inhalation solution does not require dose adjustment.

There are two treatment approaches:

A.maintenance therapy: Fostair NEXThaler is taken as regular maintenance therapy with a separate fast-acting bronchodilator as needed.

B.maintenance and relief therapy: Fostair NEXThaler is taken as regular maintenance therapy and as needed in response to asthma symptoms.

A. Maintenance therapy

Patients should be advised to keep their separate rapid-acting bronchodilator available at all times for emergency use.

Dosage recommendations for adults 18 years and older:

One or two puffs twice a day.

The maximum daily dose is 4 inhalations per day.

B. Maintenance and rescue therapy

Patients take their daily maintenance dose of Fostair Nexthaler plus additional Fostair Nexthaler as needed in response to asthma symptoms. Patients should be advised to always have Fostair NEXThaler on hand for emergency use.

Maintenance and reliever therapy with Fostair NEXThaler should be considered particularly in patients with:

• Asthma is not fully controlled and requires reliever medication

• Previous exacerbations of asthma that required medical intervention

Close monitoring of dose-related adverse reactions is required in patients who frequently receive large amounts of Fostair NEXThaler inhalations as needed.

Dosage recommendations for adults 18 years and older:

The recommended maintenance dose is 1 puff twice a day (one puff in the morning and one puff in the evening).

Patients should take 1 additional inhalation as needed in response to symptoms. If the symptoms persist after a few minutes, an additional inhalation should be carried out.

The maximum daily dose is 8 inhalations.

Patients who frequently require daily rescue inhalations should be strongly advised to consult a physician. Your asthma should be reassessed and your maintenance therapy reconsidered.

Dosage recommendations for children and adolescents under 18 years of age:

The safety and efficacy of Fostair NEXThaler in children and adolescents below 18 years of age have not been established. For safety reasons, Fostair Nexthaler must not be used in children aged 5 to 11 years. Data available in this age group are summarized in sections 5.1 and 5.2. Currently available clinical data in adolescents aged 12 to 17 years are summarized in sections 4.8 and 5.1, but no recommendation on a posology can be made.

Patients should be checked regularly by a doctor to ensure that the dose of Fostair Nexthaler remains optimal and is only changed on medical advice. The dose should be adjusted to the lowest dose at which effective control of symptoms is maintained. If symptom control is maintained with the lowest recommended dose, the next step may involve an inhaled corticosteroid alone.

Patients should be advised to take Fostair NEXThaler daily, even if they are asymptomatic.

COPD

Dosage recommendations for adults 18 years and older:

Two inhalations twice a day.

special patient groups

No dose adjustment is necessary in elderly patients.

There are no data on the use of Fostair Nexthaler in patients with hepatic or renal impairment (see section 5.2).

administration method

Nexthaler is a breath-powered inhaler. Patients with moderate to severe asthma and COPD have been shown to generate sufficient inspiratory flow to trigger NEXThaler dose administration (see section 5.1). Administration of the Fostair NEXThaler is independent of flow in the inspiratory flow range that this patient population is able to achieve through the inhaler.

The correct use of the NEXthaler inhaler is essential for the success of the treatment. The patient must be instructed to carefully read the package leaflet and follow the instructions for use contained therein. For the convenience of the prescribing physician, these instructions are provided below.

The dose number displayed in the case window does not decrease when the lid is closed if the patient has not inhaled from the inhaler.

The patient should be instructed to open the inhaler lid only when necessary. If the patient has opened the inhaler but has not inhaled and the lid is closed, the dose returns to the powder reservoir inside the inhaler; the next dose can be safely inhaled.

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

NEXTHALER INHALER INSTRUCTIONS FOR USE

Foster Nexthaler is available in two inhaler sizes:

• an inhaler with 120 puffs

• an inhaler with 180 puffs

A. Package Contents

For information about the contents of the container, see section 6.5.

If the contents of the box do not match what is described in section 6.5, return your inhaler to the person who gave it to you and get a new one.

B. General Warnings and Precautions

•NOTake the inhaler out of the bag if you don't want to use it right away.

• Use your inhaler only as directed.

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

• When you are not using your inhaler, store it in a clean, dry place.

•NOAttempt to disassemble your Nexthaler inhaler for any reason.

C. Key features of your Nexthaler inhaler

Taking a dose with your Nexthaler inhaler requires just three simple steps: open, inhale, close.

D. Before using a new Nexthaler inhaler

1.Open the sachet and take out your inhaler.

ÖNOuse your inhaler if the sachet is opened or broken; Return it to the person who gave it to you and request a new one.

o Use the box label to record the date the sachet was opened.

2.Check your inhaler.

o If your inhaler is cracked or damaged, return it to the person who gave it to you and get a new one.

3.Check the dose counter window. If your inhaler is new, you will see '120' or '180' in the dose counter window.

ÖNOUse a new inhaler if the displayed number is less than '120 or 180'; Return it to the person who gave it to you and request a new one.

E. How to use your Nexthaler inhaler

• If you are not sure you are taking the right dose, talk to your pharmacist or doctor.

• If you are not sure if the dose counter has gone down by one after inhaling, wait until the next scheduled dose and take it as usual. Do not take an extra dose.

E.1. Open

1. Hold the inhaler in an upright position.

2. Check the number of doses remaining: Any number between "1" and "120" or "180" indicates the doses remaining.

o If the dose counter window shows '0', you are out of doses, throw away your inhaler and buy a new one.

3. Fully open the lid.

4. Before inhaling, exhale as much as is comfortable for you.

ÖNOexhale through your inhaler.

E.2. breathe

If possible, stand or sit upright as you inhale.

1. Take the inhaler, put it in your mouth and place your lips around the mouthpiece.

ÖNOCover the vent when holding the inhaler.

ÖNOinhale through the air mouthpiece.

2. Inhale strongly and deeply through your mouth.

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

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

ÖNOinhale through the nose.

ÖNORemove the inhaler from your lips while inhaling.

3. Take the inhaler out of your mouth.

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

5. Breathe out slowly.

ÖNOexhale through your inhaler.

E.3. Nahe

1. Put the inhaler back in an upright position and close the lid completely.

2. Check that the dose counter has decreased by one.

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

f cleaning

• It is not normally necessary to clean the inhaler.

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

ÖNOClean your inhaler with water or another liquid. keep dry

G. Storage and Disposal

Information on storage conditions and disposal instructions, see sections 6.4 and 6.6.

It is recommended to reduce the dose when stopping treatment; Treatment should not be stopped abruptly.

Asthma treatment should normally follow a stepwise plan and the patient's response should be monitored clinically and by pulmonary function tests.

If patients find the treatment ineffective, a physician should be consulted. The increasing use of rescue bronchodilators indicates worsening of the underlying disease and justifies a reassessment of asthma treatment. Sudden and progressive deterioration in asthma control is fatal and the patient should receive urgent medical evaluation. If infection is suspected, consideration should be given to increasing corticosteroid therapy, inhaled or oral, or antibiotic therapy.

Patients should not initiate treatment with Fostair NEXThaler during an exacerbation or when experiencing significantly worsening or acutely worsening asthma. Serious asthma-related side effects and exacerbations may occur during treatment with Fostair NEXThaler. Patients should be asked to continue treatment but to seek medical help if their asthma symptoms are uncontrolled or worsen after starting Fostair NEXThaler.

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

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

For the treatment of acute asthma attacks, patients should be instructed to always have their short-acting bronchodilator, Fostair Nexthaler (for patients using Fostair Nexthaler as maintenance and reliever therapy) or a short-acting bronchodilator (for patients using Fostair Nexthaler). only as maintenance therapy).

Patients should be reminded to take Fostair NEXThaler daily as directed, even if they are asymptomatic. Fostair NEXThaler Relief inhalations should be taken in response to asthma symptoms, but not for regular prophylactic use, e.g. pre-exercise use of a separate rapid-acting bronchodilator should be considered for such use.

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

Pneumonia in patients with COPD

An increased incidence of pneumonia, including pneumonia requiring hospitalization, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid doses, but this has not been conclusively demonstrated in all studies.

There is no conclusive clinical evidence for class differences in the extent of pneumonia risk among inhaled corticosteroids.

Clinicians should be alert to the possible development of pneumonia in patients with COPD, as the clinical features of these infections overlap with the symptoms of COPD exacerbations.

Risk factors for pneumonia in patients with COPD include smoking, older age, low body mass index (BMI), and severe COPD.

Systemic effects of inhaled corticosteroids may occur, especially at high doses prescribed for long periods. These effects are much less common than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataracts, glaucoma, and, more rarely, a variety of psychological or behavioral effects, including psychomotor hyperactivity, sleep, anxiety, depression, or aggression (particularly in children). Therefore, it is important that the dose of inhaled corticosteroids be reduced to the lowest dose at which effective asthma control can be maintained.

Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children and adolescents under 16 years of age who inhale beclomethasone dipropionate in higher than recommended doses may be particularly at risk. Situations that could potentially trigger an acute adrenal crisis include trauma, surgery, infection, or any rapid dose reduction. Symptoms are usually vague and may include anorexia, abdominal pain, weight loss, fatigue, headache, nausea, vomiting, hypotension, decreased consciousness, hypoglycemia, and seizures. Additional treatment with systemic corticosteroids should be considered during periods of stress or elective surgery.

Patients switching from oral to inhaled corticosteroids may remain at risk of impaired adrenal reserve for a significant period of time. Patients who have required rescue treatment with high-dose inhaled corticosteroids in the past or who have received long-term treatment with high-dose inhaled corticosteroids may also be at risk. This possibility of residual deterioration should always be considered in stressful emergency and elective situations, and appropriate treatment with corticosteroids should be considered. The extent of adrenal dysfunction may require specialist consultation prior to elective procedures.

Fostair NEXThaler should be used with caution in patients with active or latent pulmonary tuberculosis, fungal and viral respiratory infections.

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

Caution should be exercised when treating patients with known or suspected congenital or drug-induced QTc prolongation (QTc > 0.44 seconds). Formoterol itself can induce a prolongation of the QTc interval.

Caution should be exercised when administering Fostair Nexthaler to patients with thyrotoxicosis, diabetes mellitus, pheochromocytoma and untreated hypokalemia.

Beta can lead to potentially serious hypokalemia₂-agonist therapy. Special care is needed in severe asthma, as this effect can be exacerbated by hypoxia. Hypokalaemia may also be aggravated by concomitant treatment with other medicinal products that may cause hypokalaemia, e.g. B. xanthine derivatives, steroids and diuretics (see section 4.5). Caution is also needed in unstable asthma, when various "rescue" bronchodilators may be used. In these situations, monitoring of serum potassium is recommended.

Inhaling formoterol can lead to an increase in blood sugar levels. Therefore, blood glucose should be closely monitored in patients with diabetes.

If anesthesia with halogenated anesthetics is planned, care should be taken not to administer Fostair NEXThaler for at least 12 hours before starting anesthesia due to the risk of cardiac arrhythmia.

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

The medicine contains lactose. Lactose contains small amounts of milk proteins that can 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 disturbances have been reported with the use of systemic and topical corticosteroids. If a patient experiences symptoms such as blurred vision or other visual disturbances, consideration should be given to referring the patient to an ophthalmologist for evaluation of possible causes, which may include cataracts, glaucoma, or rare disorders such as central serous chorioretinopathy (CSCR). . . In English). reported after the use of systemic and topical corticosteroids.

pharmacokinetic interactions

Beclomethasone dipropionate is rapidly metabolized by esterase enzymes.

Beclomethasone is less dependent on CYP3A metabolism than some other corticosteroids and interactions are generally unlikely; However, the possibility of systemic effects cannot be excluded with the concomitant use of strong CYP3A inhibitors (eg ritonavir, cobicistat), therefore caution and adequate monitoring are advised when using these agents.

pharmacodynamic interactions

Beta-blockers (including eye drops) should be avoided in asthmatic patients. If beta-blockers are administered for compelling reasons, the effect of formoterol is reduced or reversed.

The use of other beta-adrenergic drugs can have potentially additive effects, therefore caution should be exercised when theophylline or other beta-adrenergic drugs are prescribed concomitantly with formoterol.

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

In addition, L-dopa, L-thyroxine, oxytocin and alcohol can alter cardiac tolerance to beta.₂- Sympathomimetics.

Concomitant treatment with monoamine oxidase inhibitors, including agents with similar properties to furazolidone and procarbazine, may induce hypertensive reactions.

There is an increased risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons.

Concomitant treatment with xanthine derivatives, steroids or diuretics may potentiate a possible hypokalemic effect of Beta₂-agonists (see section 4.4). Hypokalemia may increase susceptibility to arrhythmias in patients treated with digitalis glycosides.

fertility

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

the pregnancy

There are no relevant clinical data from the use of Fostair NEXThaler in pregnant women. Animal studies with the combination of beclomethasone dipropionate and formoterol have shown evidence of reproductive and fetal toxicity after high systemic exposure (see section 5.3). High doses of corticosteroids given to pregnant animals are known to cause fetal developmental abnormalities, including cleft palate and intrauterine growth retardation. Due to the tocolytic effect of beta₂- Special care is required with sympathomimetics before delivery. The use of formoterol should not be recommended during pregnancy and especially towards the end of pregnancy or during childbirth, unless there is no other established (safer) alternative.

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

breast-feeding

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

Although animal data are not available, it can be assumed that beclomethasone dipropionate is excreted in milk like other corticosteroids.

Although it is not known whether formoterol is excreted in human milk, it has been detected in the milk of lactating animals.

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

The most common side effect is tremor. In a 12-week clinical study of Fostair NEXThaler, tremor was observed only at the highest dose (2 puffs twice daily), was more frequent at initiation of treatment, and was of low intensity. No patient was withdrawn from the study due to tremor.

Clinical trial experience in patients with asthma

The safety of Fostair NEXThaler was evaluated in active, placebo-controlled clinical trials in which 719 patients aged 12 years and older with asthma of varying severity were exposed to the medicine. The frequency of adverse reactions in the table below is for asthmatic patients aged 12 years and older and is based on safety results from two pivotal clinical trials in which Fostair NEXThaler was administered at the doses recommended in this SmPC for periods ranging from 8 to 12 weeks. . Psychiatric disorders were not observed in clinical studies with Fostair NEXThaler, but are included in the table as a possible class effect of inhaled corticosteroids.

Adverse reactions associated with beclomethasone dipropionate and formoterol given as a fixed combination (Fostair Nexthaler) are listed below by system organ class. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000) and very rare (<1/10000), frequency not known (cannot be estimated from available data).

Among the observed side effects typically associated with formoterol are: tremor, headache, tachycardia, sinus bradycardia, angina pectoris, myocardial ischemia, QT interval prolongation.

Among the observed side effects typically associated with beclomethasone dipropionate are: nasopharyngitis, oral thrush, hoarseness, throat irritation, irritability, decreased urinary free cortisol, decreased blood cortisol, increased blood sugar.

Other adverse reactions not seen in clinical experience with Fostair NEXThaler but typically associated with inhaled administration of beclomethasone dipropionate include other oral fungal infections and pneumonia. Taste disturbances have occasionally been reported during therapy with inhaled corticosteroids.

See Section 4.4 for measures to minimize the occurrence of oral yeast infections, oral thrush and hoarseness.

Systemic effects of inhaled corticosteroids (eg, beclomethasone dipropionate) may occur, particularly when given at prescribed high doses for prolonged periods. These may include Cushing's syndrome, Cushingoid features, adrenal suppression, decreased bone mineral density, growth retardation in children and adolescents, cataracts and glaucoma cataracts (see also section 4.4).

Additional side effects not seen in clinical experience with therapeutic doses of Fostair NEXThaler, but usually associated with beta administration₂-Agonists such as formoterol are palpitations, atrial fibrillation, ventricular extrasystoles, tachyarrhythmia, possibly severe hypokalemia and increase/decrease in blood pressure. Insomnia, dizziness, restlessness and anxiety have been reported infrequently during therapy with inhaled formoterol. Formoterol can also cause muscle spasms and myalgia.

Hypersensitivity reactions including rash, hives, itching and erythema and swelling of the eyes, face, lips and throat (angioedema) have been reported.

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

pediatric population

Available pharmacokinetic data do not support the safety of Fostair NEXThaler in children aged 5 to 11 years. There are limited clinical data in adolescents aged 12 to 17 years (see sections 4.2, 5.1 and 5.2). In a 12-week randomized clinical trial in adults and adolescents, 162 adolescents aged 12 to 17 years with moderate to severe asthma were given Fostair NEXThaler or its pressurized inhalation formulation 1 or 2 puffs twice daily; The frequency, type and severity of side effects were not different in adolescents than in adults.

Report suspected side effects

It is important to report suspected adverse drug reactions after approval. Allows continuous monitoring of the benefit-risk ratio of the drug. Healthcare professionals are encouraged to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

The maximum recommended single dose of Fostair NEXThaler is 2 puffs. Four cumulative inhalations of Fostair NEXThaler (a total of 400 micrograms of beclomethasone dipropionate, 24 micrograms of formoterol, administered as a single dose) were studied in asthmatic patients. Cumulative treatment did not cause clinically relevant abnormal effects on vital signs and no serious or serious adverse reactions were observed (see also section 4.8).

For the formulation of the pressurized gas inhalation solution, inhalation doses of up to twelve cumulative applications (a total of beclomethasone dipropionate 1200 micrograms, formoterol 72 micrograms) were investigated in patients with asthma. Cumulative treatments did not cause abnormal effects on vital signs and no serious or serious adverse events were observed.

Excessive doses of formoterol can cause typical beta effects.₂-adrenergic agonists: nausea, vomiting, headache, tremor, drowsiness, palpitations, tachycardia, ventricular arrhythmias, QTc interval prolongation, metabolic acidosis, hypokalemia, hyperglycemia.

In case of overdose with formoterol, supportive and symptomatic treatment is indicated. Severe cases require hospitalization. The use of cardioselective beta-blockers may be considered, but only with extreme caution, as the use of beta-blockers may cause bronchospasm. Serum potassium should be monitored.

Acute inhalation of beclomethasone dipropionate in higher than recommended doses may result in transient adrenal suppression. This does not require emergency measures, as adrenal function recovers within a few days, as confirmed by plasma cortisol measurements. In these patients, treatment should be continued at a dose sufficient to control asthma.

Chronic overdose of inhaled beclomethasone 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.

Supratherapeutic single doses of up to 800 micrograms of beclomethasone dipropionate, 48 micrograms of formoterol administered through the Fostair Nexthaler are generally safe and well tolerated.

Pharmacotherapeutic group: adrenergics, inhalants: formoterol and other drugs for obstructive airway diseases.

ATC code: R03AK08.

Mechanisms of action and pharmacodynamic effects

Fostair Nexthaler contains beclomethasone dipropionate and formoterol in a dry powder formulation, resulting in an extra fine aerosol with a mass median aerodynamic diameter (MMAD) of 1.4-1.5 microns and co-deposition of the two components. Foster Nexthaler aerosol particles are, on average, much smaller than particles provided in non-extra fine formulations.

A study of deposition of radiolabeled drugs in adult asthmatics showed that a high proportion of the drug (estimated at 42% of the nominal dose) is deposited in the lungs, with homogeneous deposition in the airways. These administration characteristics support the use of a low-dose corticosteroid with enhanced local pharmacodynamic effects that have been shown to be equivalent to the corresponding pressurized inhalation solution (seeclinical experience).

The two active substances in Fostair Nexthaler have different modes of action. Common with other inhaled and beta corticosteroids₂Additive effects in reducing asthma exacerbations are seen with combinations of agonists.

Beclometasondipropionato

Beclomethasone dipropionate, given by inhalation at recommended doses, has anti-inflammatory glucocorticoid effects in the lungs, resulting in reduced symptoms and exacerbations of asthma with fewer side effects than systemic administration of corticosteroids.

formoterol

Formoterol is a beta selective₂-Adrenergic agonist that causes relaxation of bronchial smooth muscle in patients with reversible airway obstruction. The bronchodilator effect has a rapid onset, between 1 and 3 minutes after inhalation, and lasts for 12 hours after ingestion.

clinical experience

The efficacy of the two components of Fostair NEXThaler inhalation powder was evaluated in three separate studies compared to the 100 micrograms/6 micrograms pressurized inhalation formulation in patients with moderate to severe persistent asthma. In general, the efficacy of the two inhalers is expected to be equivalent in clinical practice with 1 and 2 puffs twice daily.

In one study, the primary objective was to evaluate the efficacy of the inhaled corticosteroid component, measured as bronchodilation (pre-dose FEV).₁). A clinically significant improvement in pre-dose FEV₁was observed in 696 patients with moderate to severe symptomatic asthma at the end of a 3-month treatment period compared to baseline with 1 inhalation twice daily and 2 inhalations twice daily of both formulations. A mean increase of at least 250 mL was observed. There were no clinically relevant differences in pre-dose FEV₁between Foster Nexthaler inhalation powder and pressurized inhalation solution in both strengths. A significant dose-response relationship was observed for morning PEF. Statistical significance for dose-response relationship in pre-dose FEV₁was not hit. Measures of asthma control, such as assessment of morning and evening asthma symptoms and percentage of symptom-free days, improved significantly from the beginning to the end of the treatment period, particularly for the two high doses of both formulations.

In the second study, the primary objective was to evaluate the effectiveness of long-acting beta.₂- agonistic component of Foster Nexthaler. In this study, bronchodilation was measured by serial spirometric measurements of FEV at baseline and up to 12 hours after administration of a single dose.₁(FEV₁AUC for at least 80% of the duration of action of formoterol). Compared to placebo, Foster NEXthaler, one puff and four puffs of both drugs significantly improved FEV₁abc_0-12. Both doses of Fostair NEXThaler inhalation powder were not less than the corresponding dose of the pressurized inhalation solution formulation. A statistically significant dose-response relationship was found between low and high doses for both formulations.

In the third study, after an initial 4-week period on a fixed combination of beclomethasone dipropionate/formoterol pressurized inhalation solution, 1 puff twice daily, 755 controlled asthmatic patients were randomized to 8-week treatment with the same inhaler with inhalation of Foster NEXthaler powder. or with beclomethasone dipropionate 100 micrograms per dose of snuff powder, each given as 1 puff twice daily. The primary endpoint was the change from baseline in mean morning expiratory flow (PEF) over the treatment period. After 8 weeks of treatment, there was no difference in the primary outcome between the two combination inhalers, both were significantly better than beclomethasone dipropionate monotherapy. No differences were found between the two combination inhalers in terms of symptom measures such as asthma control questionnaire scores and number of rescue-free days.

An open-label placebo study was conducted to verify that the inspiratory flow that can be produced by the NEXThaler inhaler is not affected by the age, disease and disease severity of the patient and therefore activation and delivery of the NEXthaler drug from the device could be achieved in all the patients. . The primary endpoint was the percentage of patients in each age and disease group who were able to activate their inhaler. Eighty-nine patients aged 5 to 84 years, including moderate and severe asthmatics (FEV₁> 60% or ≤ 60% predicted) and patients with moderate and severe COPD (FEV₁≥ 50% or < 50% prognosis) participated in the study. All patients, regardless of age, disease and disease severity, were able to generate sufficient inspiratory flow to activate the NEXThaler inhaler.

In an additional open-label placebo study, assessment of the inspiratory profile provided by the Foster NEXThaler showed that patients with mild to severe COPD were able to activate and use the device effectively, regardless of their functional impairment.

pediatric population

There are very limited clinical data on the use of Fostair NEXThaler in children aged 5 to 11 years. Compared to an equivalent dose of unlicensed combination products containing beclomethasone dipropionate (BDP) and anhydrous formoterol (FF), administration of a single dose of an experimental fixed-dose formulation containing the same extra-fine active ingredients as Fostair Nexthaler, but in a lower dose (50 µg BDP and 6 µg FF) led to significantly higher systemic bioavailability for both components (see section 5.2).

This increased systemic availability was associated with a statistically significant decrease in plasma potassium (point estimate 0.94, 95% CI [0.92, 0.96]) and a mean time increase in heart rate (point estimate 1.06 , 95% CI [1, 01, 1.10]). Furthermore, a tendency towards cortisol suppression and elevated urinary glucose levels was observed in children in the test group compared to the reference treatment.

Only limited information was collected from adolescents.

In a 3-month randomized clinical trial, 162 subjects aged 12 to 17 years diagnosed with moderate to severe asthma received Fostair's Nexthaler or the appropriate pressurized inhalation solution formulation as 1 or 2 puffs twice daily. Change in FEV before dosing₁at the end of treatment was higher in adolescents than in adults.

See also sections 4.2, 4.8 and 5.2 for information on pediatric use.

Beclometasondipropionato

Beclomethasone dipropionate is a prodrug with weak glucocorticoid receptor binding affinity that is hydrolyzed by esterase enzymes to an active metabolite, beclomethasone-17-monopropionate, which exhibits potent topical anti-inflammatory activity compared to the prodrug beclomethasone dipropionate.

Absorption, distribution and metabolism

Inhaled beclomethasone dipropionate is rapidly absorbed from the lungs; Prior to absorption, extensive conversion to its active metabolite, beclomethasone-17-monopropionate, occurs by esterase enzymes found in most tissues. Systemic availability of the active metabolite results from pulmonary and gastrointestinal absorption of the absorbed dose. The bioavailability of ingested beclomethasone dipropionate is negligible; However, presystemic conversion to beclomethasone-17 monopropionate results in part of the dose being absorbed as the active metabolite.

Systemic exposure increases almost linearly with increasing inhaled dose.

The absolute bioavailability after inhalation with a pressurized metered-dose inhaler is approximately 2% and 62% of the nominal dose for unchanged beclomethasone dipropionate and beclomethasone monopropionate-17, respectively.

After intravenous administration, the distribution of beclomethasone dipropionate and its active metabolite is characterized by high plasma clearance (150 and 120 L/h, respectively) with a small volume of distribution at steady state for beclomethasone dipropionate (20 L) and a greater distribution of its active metabolite (424L) . The metabolic disposition of beclomethasone dipropionate leads mainly (82%) to its active metabolite, beclomethasone-17-monopropionate.

Plasma protein binding is moderately high (87%).

excretion

Beclomethasone dipropionate is mainly excreted in the faeces, mainly as polar metabolites. Renal excretion of beclomethasone dipropionate and its metabolites is negligible. The terminal elimination half-lives are 0.5 h and 2.7 h for beclomethasone dipropionate and beclomethasone monopropionate-17, respectively.

special populations

The pharmacokinetics of beclomethasone dipropionate in patients withkidney or liver failurehas not been studied; However, as beclomethasone dipropionate is metabolized very rapidly via esterase enzymes in intestinal fluid, serum, lungs and liver to the more polar products beclomethasone 21-monopropionate, beclomethasone 17-monopropionate and beclomethasone, hepatic dysfunction is not expected to alter the pharmacokinetics and safety profile of beclomethasone dipropionate.

Since beclomethasone dipropionate or its metabolites were not detected in urine, no increase in systemic exposure is expected in patients with renal impairment.

formoterol

Recording and Distribution

After inhalation, formoterol is absorbed both through the lungs and the gastrointestinal tract. The fraction of an inhaled dose that is swallowed after administration with a metered dose inhaler (MDI) can range from 60% to 90%. At least 65% of the ingested fraction is absorbed from the gastrointestinal tract. Peak plasma concentrations of unchanged drug occur between 0.5 and 1 hour after oral administration. Formoterol binding to plasma proteins is 61-64%, with 34% bound to albumin. No binding saturation occurred in the concentration range achieved with therapeutic doses. The elimination half-life determined after oral administration is 2 to 3 hours. Absorption of formoterol is linear after inhalation of 12 to 96 µg of formoterol fumarate.

metabolism

Formoterol is extensively metabolised, with the main pathway involving direct conjugation at the phenolic hydroxyl group. The glucuronic acid conjugate is inactive. The second major pathway involves O-demethylation followed by conjugation at the 2'-hydroxyl phenolic group. The cytochrome P450 isoenzymes CYP2D6, CYP2C19 and CYP2C9 are involved in the O-demethylation of formoterol. The liver appears to be the main site of metabolism. Formoterol does not inhibit CYP450 enzymes at therapeutically relevant concentrations.

excretion

Cumulative urinary excretion of formoterol after a single inhalation with a dry powder inhaler increased linearly over the dose range 12 to 96 μg. On average, 8% and 25% of the dose was excreted as unchanged and total formoterol, respectively. Based on measured plasma concentrations following inhalation of a single 120 μg dose in 12 healthy volunteers, the mean terminal elimination half-life was determined to be 10 hours. The (R,R) and (S,S) enantiomers represented approximately 40% and 60% of the drug excreted unchanged in the urine, respectively. The relative ratio of the two enantiomers remained constant over the studied dose range and there was no evidence of relative accumulation of one enantiomer over the other after repeated dosing.

After oral administration (40 to 80 µg) in healthy volunteers, 6% to 10% of the dose was recovered as unchanged drug in the urine; up to 8% of the dose was recovered as the glucuronide.

A total of 67% of an oral dose of formoterol is excreted in the urine (mainly as metabolites) and the remainder in the faeces. The renal clearance of formoterol is 150 ml/min.

special populations

liver/kidney failure: The pharmacokinetics of formoterol in patients with hepatic or renal impairment has not been studied.

pediatric population

In single-dose pharmacokinetic studies in asthmatic children aged 5 to 11 years, two experimental fixed-dose pediatric formulations containing the same extra-fine active ingredients as Fostair Nexthaler, but at lower dosage concentrations (A: 50 µg BDP and 6 µg FF = 50/6; B: 35 µg BDP and 4 µg FF = 35/4) were compared with equivalent doses of unlicensed combination products containing BDP and FF. Due to the lack of a carbon block, only systemic exposure was determined as a safety precaution. Compared with the free combination, BDP/FF 50/6 resulted in higher systemic exposure (AUC0_T) and maximum concentrations (C_maximum) of the three analytes, the parent compound BDP, the active metabolite beclomethasone 17-monopropionate (B17MP) and formoterol. Subsequent dose concentration reduction by approximately 30% to BDP/FF 35/4 still resulted in a significantly higher AUC0_Tof B17MP (point estimator 152.5, 90% CI [141.1 164.8]) and the parent compound BDP (point estimator 188.6, 90% CI [163.8 217.1]). ABC₀of formoterol was in and C_maximumslightly exceeded the 80-125% bioequivalence range.

clinical experience

Systemic exposure to beclomethasone dipropionate and formoterol in combination was compared with the individual components. There was no evidence of pharmacokinetic or pharmacodynamic (systemic) interactions between beclomethasone dipropionate and formoterol.

The pharmacokinetics of the Fostair NEXThaler inhalation powder were compared with the corresponding pressurized inhalation formulation. The analysis of steroid components focused on beclomethasone-17-monopropionate, the major active metabolite of beclomethasone dipropionate.

Systemic absorption and metabolism of beclomethasone dipropionate was rapid and C_maximumwas reached 5 minutes after dosing for both treatments, but was greater with Fostair Nexthaler inhalation powder (+68%). The AUCt after Fostair NEXThaler inhalation was approximately 3-fold greater than after pressurized inhalation. W_maximumFor beclomethasone-17-monopropionate, the major active metabolite, which accounts for about 82% of the total blood level, was achieved on average after 30 minutes and 15 minutes with NEXThaler and pressurized inhalation solution, respectively. The plasma concentration of beclomethasone-17-monopropionate was lower (Cmax_maximum-49% e ABC_T- 29%), after inhaling the inhalation dust than through the pressurized inhalation solution. After inhalation of Fostair Nexthaler, the maximum concentration (C_maximum) of formoterol was reached within 5 minutes and was higher (+47%) for the inhalation powder, while total exposure (AUC_T) was comparable for both treatments.

One study examined relative lung clearance using a carbon block to exclude drug absorption from the GI tract and using an approved spacer, the AeroChamber Plus.^®for the reference medicine (the pressurized inhalation solution). In this context, Nexthaler and pressurized inhalation solution have been shown to be equivalent in terms of AUC._Tbeclomethasone 17-monopropionate and formoterol (inhalation powder/pressurized inhalation solution ratio and 90% confidence interval were within 80-125%); however C_maximumof beclomethasone 17-monopropionate was lower (-38%) after inhalation with NEXThaler.

Non-clinical data on the individual components of Fostair NEXThaler reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity. The toxicity profile of the combination mirrored that of the individual components, with no increased toxicity or unexpected findings.

Reproductive studies in rats have shown dose-dependent effects. The presence of high doses of beclomethasone dipropionate has been associated with reduced female fertility, reduced number of implantations and embryofoetal toxicity. High doses of corticosteroids in pregnant animals are known to cause fetal developmental abnormalities such as cleft palate and intrauterine growth retardation, and the effects seen with the beclomethasone dipropionate/formoterol combination are likely due to beclomethasone dipropionate. These effects were seen only at high systemic exposures to the active metabolite beclomethasone 17-monopropionate (more than 200 times the expected plasma levels in patients). Furthermore, the prolonged duration of pregnancy and childbirth is an effect attributed to the well-known tocolytic effects of beta.₂-Sympathomimetics observed in animal studies. These effects were observed when maternal plasma levels of formoterol were below expected levels in patients treated with Fostair NEXThaler.

Genotoxicity studies performed with a beclomethasone dipropionate/formoterol combination do not indicate any mutagenic potential. No carcinogenicity studies have been performed with the proposed combination. However, animal data reported for the individual components do not indicate a potential carcinogenicity risk in humans.

Lactose monohydrate (contains small amounts of milk protein)

Magnesium stearate.

3 years.

After first opening the sachet, the medicine should be used within 6 months.

Store in the original container in order to protect from moisture.

Do not remove the inhaler from its foil packaging until you are ready to use it for the first time.

Before opening the bag for the first time:

This medicine does not require any special storage temperature conditions.

After opening the bag for the first time:

Do not store above 25°C.

Each pack contains 1, 2 or 3 NEXthaler inhalers filled with 1.50 g or 2.22 g of inhalation powder to deliver 120 puffs or 180 puffs respectively. Each inhaler is contained in a heat-sealed protective pouch (aluminium pouch) made of PET/Al/PE (polyethylene terephthalate/aluminium/polyethylene) or PA/Al/PE (polyamide/aluminum/polyethylene).

Not all pack sizes can be marketed.

Fostair Nexthaler is a multidose inhaler. The device consists of a case consisting of a tiny box with a window to display the number of doses remaining and an integrated lid. When opened, the lid, which also operates the dose counting mechanism, reveals a mouthpiece through which the medicine is inhaled. The bottom shell and mouthpiece are made of acrylonitrile butadiene styrene and the cap is made of polypropylene.

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Manchester

M22 5LG

Great Britain