Summary of medicine characteristics - FOSTAIR NEXTHALER 200 MICROGRAMS / 12 MICROGRAMS PER ACTUATION INHALATION POWDER
Symptomatic treatment of patients with severe COPD (FEV1 < 50% predicted normal) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodilators.
4.2 Posology and method of administration Asthma
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 dipropionatecontaining non-extrafine products and should be adjusted to the needs of the individual patient. However, patients who are transferred to Fostair NEXThaler inhalation powder from Fostair NEXThaler pressurised inhalation solution do not need dose adjustment.
Dose recommendations for adults 18 years and above:
One inhalation twice daily.
The maximum daily dose is 2 inhalations.
Fostair NEXThaler 200 micrograms/12 micrograms should be used as maintenance therapy only. A different strength Fostair NEXThaler 100 micrograms/6 micrograms is available for maintenance and reliever therapy.
Patients should be regularly reassessed by a doctor, so that the dosage of Fostair NEXThaler remains optimal and is only changed on medical advice. Patients should be advised to take Fostair NEXThaler every day even when asymptomatic.
COPD
Dose recommendations for adults 18 years and above:
One inhalation twice daily.
The maximum daily dose is 2 inhalations.
Special patient groups
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 200/12 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 and COPD patients were shown to be able to produce sufficient inspiratory flow to trigger dose release from Nexthaler (see section 5.1). The delivery of Fostair NEXThaler with Nexthaler is 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 Package Leaflet carefully and follow the instructions for use as given in the leaflet. For the convenience of the prescriber these instructions are provided below.
The number of doses 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 dose is moved back to the powder reservoir within the inhaler; the following 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 pack, 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 “60” in the Dose Counter Window.
o Do not use a new inhaler if the number shown is less than “60” -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 “60” 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 forceful 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 sections 6.4 and 6.6.
4.3 Contraindications
Hypersensitivity to the active substances, milk proteins 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 lifethreatening 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 (a lower strength Fostair NEXThaler 100 /6 micrograms inhalation powder is available, see section 4.2).
Pneumonia in patients with COPD
An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.
There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products.
Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.
Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.
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 medicinal products 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.
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.
The medicinal product contains lactose. Lactose contains small amounts of milk proteins, which may cause allergic reactions.
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-blockers (including eye drops) should be avoided in asthmatic patients. If beta-blockers are administered for compelling reasons, the effect of formoterol will be reduced or abolished.
The use of other beta-adrenergic medicinal products may have potentially additive effects, therefore caution is required when theophylline or other beta-adrenerigic medicinal products 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
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.
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.
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.
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).
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 safety of Fostair NEXThaler inhalation powder has been mainly assessed with the lower strength (100 micrograms/6 micrograms).
The most common adverse reaction is tremor. In a 12-week clinical trial with Fostair NEXThaler 100 micrograms/6 micrograms, tremor was seen only with the highest dose regimen (400 micrograms/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 micrograms/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 medicinal product. 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 NEXThaler100/6 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 | |
| Pneumonia (in COPD patients) | Common | |
| Hypertriglyceridaemia | Uncommon |
| Metabolism and nutrition disorders | ||
| 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 100 micrograms/6 micrograms but typically associated with the inhaled administration of beclometasone dipropionate are other oral fungal infections and pneumonia. 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 micrograms/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 at www.mhra.gov.uk/yellowcard.
4.9
Overdose
The highest recommended dose of Fostair NEXThaler in a single administration is 1 inhalation.
For the pressurised inhalation solution formulation, inhaled doses of up to twelve cumulative actuations of 100 micrograms/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.
Single supra-therapeutic doses up to 800 micrograms of beclometasone dipropionate, 48 micrograms of formoterol, administered via Fostair NEXThaler 100 micrograms/6 micrograms in COPD patients are generally safe and well tolerated.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Adrenergics, inhalants; Adrenergics in combination with corticosteroids or other drugs, excl. anticholinergics.
ATC-code: R03AK08.
Mechanisms of action and pharmacodynamic effects
Fostair NEXThaler contains beclometasone dipropionate and formoterol in a dry powder formulation resulting in an extrafine aerosol with an average mass median aerodynamic diameter (MMAD) of 1.4–1.7 micrometers and codeposition of the two components. The aerosol particles of Fostair NEXThaler are on average much smaller than the particles delivered in non-extrafine formulations.
A radio-labelled drug deposition study in asthmatic adults with Fostair NEXThaler 100/6 micrograms has demonstrated that a high proportion of the drug (estimated 42% of the nominal dose) is deposited in the lung, with a homogenous deposition through the airways. These delivery characteristics support the use of a low corticosteroid dose with enhanced local pharmacodynamic effects, which were shown to be equivalent to the corresponding pressurised inhalation solution.
The two actives of Fostair NEXThaler have different modes of action. In common with other inhaled corticosteroids and beta2-agonist combinations, additive effects are seen in respect of reduction in asthma exacerbations.
Beclometasone dipropionate
Beclometasone dipropionate given by inhalation at recommended doses has a glucocorticoid antiinflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma with less adverse effects than when corticosteroids are administered systemically.
Formoterol
Formoterol is a selective beta2-adrenergic agonist that produces relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect sets in rapidly, within 1–3 minutes after inhalation, and has a duration of 12 hours after dose administration.
Clinical experience
An open-label placebo study was conducted to verify that the inspiratory flow which could be generated through the Nexthaler inhaler is not influenced by patient’s age, disease and disease severity, and therefore the activation and drug delivery from the device could be achieved in all patients. The primary endpoint was the percentage of patients in each age and disease group able to activate the inhaler. Eighty-nine patients, in the age range 5–84 years, including moderate and severe asthmatics (FEV1 > 60% and < 60% predicted, respectively), and moderate and severe COPD patients (FEV1 > 50% and < 50% predicted, respectively) participated in the trial. All patients, irrespective 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, it was demonstrated by assessing the inspiration profile through the Fostair NEXThaler 100/6 micrograms that mild to severe COPD patients, regardless of their functional limitation, were able to effectively activate and use the device.
5.2 Pharmacokinetic properties
Beclometasone dipropionate
Beclometasone dipropionate is a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclometasone-17-monopropionate which has a more potent topical antiinflammatory activity compared with the pro-drug beclometasone dipropionate.
Absorption, distribution and biotransformation
Inhaled beclometasone dipropionate is rapidly absorbed through the lungs; prior to absorption there is extensive conversion to its active metabolite beclometasone-17-monopropionate via esterase enzymes that are found in most tissues. The systemic availability of the active metabolite arises from lung and from gastrointestinal absorption of the swallowed dose. The bioavailability of swallowed beclometasone dipropionate is negligible however, pre-systemic conversion to beclometasone-17-monopropionate results in part of the dose being absorbed as the active metabolite.
There is an approximately linear increase in systemic exposure with increasing inhaled dose.
The absolute bioavailability following inhalation from a pressurised metered dose inhaler is approximately 2% and 62% of the nominal dose for unchanged beclometasone dipropionate and beclometasone-17-monopropionate respectively.
Following intravenous dosing, the disposition of beclometasone dipropionate and its active metabolite are characterised by high plasma clearance (150 and 120 L/h respectively), with a small volume of distribution at steady state for beclometasone dipropionate (20L) and larger tissue distribution for its active metabolite (424L). Metabolic disposition of beclometasone dipropionate mainly (82%) results in its active metabolite beclometasone-17-monopropionate.
Plasma protein binding is moderately high (87%).
Elimination
Faecal excretion is the major route of beclometasone dipropionate elimination mainly as polar metabolites. The renal excretion of beclometasone dipropionate and its metabolites is negligible. The terminal elimination halflives are 0.5 h and 2.7 h for beclometasone dipropionate and beclometasone-17-monopropionate respectively.
Special populations
The pharmacokinetics of beclometasone dipropionate in patients with renal or hepatic impairment has not been studied; however, as beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes present in intestinal fluid, serum, lungs and liver, to originate the more polar products beclometasone-21-monopropionate, beclometasone-17-monopropionate and beclometasone, hepatic impairment is not expected to modify the pharmacokinetics and safety profile of beclometasone dipropionate.
As beclometasone dipropionate or its metabolites were not traced in the urine, an increase in systemic exposure is not envisaged in patients with renal impairment.
Formoterol
Absorption and distribution
Following inhalation, formoterol is absorbed both from the lung and from the gastrointestinal tract. The fraction of an inhaled dose that is swallowed after administration with a metered dose inhaler (MDI) may range between 60% and 90%. At least 65% of the fraction that is swallowed is absorbed from the gastrointestinal tract. Peak plasma concentrations of unchanged active substance occur within 0.5 to 1 hours after oral administration. Plasma protein binding of formoterol is 61–64% with 34% bound to albumin. There was no saturation of binding in the concentration range attained with therapeutic doses. The elimination half-life determined after oral administration is 2–3 hours. Absorption of formoterol is linear following inhalation of 12 to 96 pg of formoterol fumarate.
Biotransformation
Formoterol is widely metabolised and the prominent pathway involves direct conjugation at the phenolic hydroxyl group. Glucuronide acid conjugate is inactive. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2’-hydroxyl group. Cytochrome P450 isoenzymes CYP2D6, CYP2C19 and CYP2C9 are involved in the O-demethylation of formoterol. Liver appears to be the primary site of metabolism. Formoterol does not inhibit CYP450 enzymes at therapeutically relevant concentrations.
Elimination
The cumulative urinary excretion of formoterol after single inhalation from a dry powder inhaler increased linearly in the 12 – 96 pg dose range. On average, 8% and 25% of the dose was excreted as unchanged and total formoterol, respectively. Based on plasma concentrations measured following inhalation of a single 120 pg dose by 12 healthy subjects, the mean terminal elimination half-life was determined to be 10 hours. The (R,R)- and (S,S)-enantiomers represented about 40% and 60% of unchanged active substance excreted in the urine, respectively. The relative proportion of the two enantiomers remained constant over the dose range studied and there was no evidence of relative accumulation of one enantiomer over the other after repeated dosing.
After oral administration (40 to 80 pg), 6% to 10% of the dose was recovered in urine as unchanged active substance in healthy subjects; up to 8% of the dose was recovered as the glucuronide.
A total 67% of an oral dose of formoterol is excreted in urine (mainly as metabolites) and the remainder in the faeces. The renal clearance of formoterol is 150 ml/min.
Special populations
Hepatic/Renal impairment: the pharmacokinetics of formoterol has not been studied in patients with hepatic or renal impairment.
Clinical experience
The systemic exposure to beclometasone dipropionate and formoterol in the combination has been compared to the single components. There was no evidence of pharmacokinetic or pharmacodynamic (systemic) interactions between beclometasone dipropionate and formoterol.
A single dose pharmacokinetic study in healthy subjects evaluated the lung availability (using charcoal block technique) and total systemic exposure (without charcoal block) of Fostair NEXThaler 200/12 micrograms DPI formulation versus a beclomethasone dipropionate/ formoterol fumarate dihydrate 100/6 micrograms DPI formulation.
Results from this study indicate that that the total systemic exposure and lung availability of formoterol, BDP and B17MP are essentially the same after administration of CHF 1535 200/12 DPI (2 inhalations) vs. CHF 1535 100/6 DPI (4 inhalations): the 90% CIs of the treatment ratios (200/12 vs. 100/6) for all primary PK variables (AUC0-t and Cmax for FF, BDP and B17MP with and without charcoal block) were entirely contained within the 80–125% acceptance range for bioequivalence.
5.3 Preclinical safety data
The toxicity observed in animal studies with beclometasone dipropionate and formoterol, given in combination or separately, consisted mainly of effects associated with exaggerated pharmacological activity. They are related to the immuno-suppressive activity of beclometasone dipropionate and to the known cardiovascular effects of formoterol evident mainly in dogs. Neither increase in toxicity nor occurrence of unexpected findings were observed upon administration of the combination.
Reproduction studies in rats showed dose-dependent effects. The presence of beclometasone dipropionate at high doses was associated with reduced female fertility, decrease in the number of implantations and embryofetal toxicity. High doses of corticosteroids given to pregnant animals are known to cause abnormalities of fetal development including cleft palate and intra-uterine growth retardation, and it is likely that the effects seen with the beclometasone dipropionate/formoterol combination were due to beclometasone dipropionate. These effects were noted only with high systemic exposure to the active metabolite beclometasone-17-monopropionate (more than 200 fold the expected plasma levels in patients). Additionally, increased duration of gestation and parturition, an effect attributable to the known tocolytic effects of beta2-sympathomimetics, was seen in animal studies. These effects were already noted for maternal plasma formoterol levels below the levels expected in patients treated with Fostair NEXThaler.
Genotoxicity studies performed with a beclometasone dipropionate/formoterol combination do not indicate a mutagenic potential. No carcinogenicity studies have been performed with the proposed combination. However animal data reported for the individual constituents do not suggest any potential risk of carcinogenicity in man.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate (which contains small amounts of milk proteins) magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
After first opening the pouch, the medicinal product should be used within 6 months.
6.4 Special precautions for storage
Store in the original package in order to protect from moisture.
Only remove the inhaler from its foil package immediately before first use.
Before first opening the pouch:
This medicinal product does not require any special temperature storage conditions.
After first opening the pouch:
Do not store above 25°C.
6.5 Nature and contents of container
Each carton contains 1, 2 or 3 Nexthaler inhalers which provide 60 inhalations each. Each inhaler is contained in a heat sealed protective pouch (foil package) made of PET/Al/PE (Polyethylene Terephtalate/Aluminium/ Polyethylene) or PA/Al/PE (Polyamide/Aluminium/Polyethylene).
Not all pack sizes may be marketed.
Fostair NEXThaler is a multi-dose inhalation device. The device consists of a casework comprising a lower shell with window to display number of doses left and an integral cover. When opened, the cover, which also drives the dose counter mechanism, reveals a mouthpiece through which the medicinal product is inhaled. The lower shell and mouthpiece are made from acrylonitrile butadiene styrene and the cover is made from polypropylene.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Chiesi Limited
333 Styal Road
Manchester
M22 5LG
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 08829/0181
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
31/03/2020