- beclometasone dipropionate
- formoterol fumarate dihydrate
POM: Prescription only medicine
This information is intended for use by health professionals
PosologyThe 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 aboveTwo 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 populationsThere 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 populationFostair NEXThaler 200/6 micrograms should not be used in children and adolescents below 18 years.
Method of administrationFostair 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 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 Patient Information Leaflet carefully and follow the instructions for use as given in the leaflet. For instructions for use, see section 6.6.Whenever possible patients should stand or sit in an upright position when inhaling from their inhaler. With Nexthaler, an inhalation is made available only when the cover is fully opened. Opening the cover, inhaling and closing the cover in sequence drives the dose counter mechanism. The patient should be instructed to close the cover fully at all times. 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. Optimal lung delivery is obtained if the patient inhales by breathing in quickly and deeply through the inhaler. A breath holding period of 5-10 seconds (or as long as comfortable for the patient) is suggested before breathing out.The patient must be made aware that exhaling through the Nexthaler, before or after the inhalation, must be avoided as this would affect its performance.Patients should rinse their mouth or gargle with water or brush their teeth after inhaling (see section 4.4).
Pharmacokinetic interactionsBeclometasone 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 interactionsBeta-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.
FertilityThere 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).
PregnancyThere 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-feedingThere 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.
Clinical Trials Experience in asthma patientsThe 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|
|Metabolism and nutrition disorders||Hypertriglyceridaemia||Uncommon|
|Psychiatric disorders||Psychomotor hyperactivity, sleep disorders, anxiety, depression, aggression, behavioural changes (predominantly in children)||Frequency not known|
|Nervous system disorders||Tremor||Common|
|Respiratory, thoracic and mediastinal disorders||Throat irritation, exacerbation of asthma||Uncommon|
|General disorders and administration site conditions||Fatigue||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|
Reporting of suspected adverse reactionsReporting 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.
ATC code: R03AK08.
Mechanisms of action and pharmacodynamic effectsFostair 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 co-deposition 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 dipropionateBeclometasone 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.
FormoterolFormoterol 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 experienceThe efficacy of the two components of Fostair NEXThaler inhalation powder has been assessed for the lower strength (100 micrograms/6 micrograms) in three separate studies in comparison with the 100 micrograms/6 micrograms pressurised inhalation solution formulation in moderate to severe patients with persistent asthma. Overall, the efficacy of the two inhalers is expected to be equivalent in clinical practice at both 1 and 2 inhalations bid.In one study the primary objective was the efficacy evaluation of the inhaled corticosteroid component measured on bronchodilation (pre-dose FEV1). A clinically significant improvement in pre-dose FEV1 was seen in 696 patients with moderate to severe symptomatic asthma at the end of a 3 months treatment period in comparison with baseline values, with 1 inhalation bid and 2 inhalations bid of both formulations. A mean increase of at least 250 mL was observed. There was no clinically relevant difference in pre-dose FEV1 between Fostair NEXThaler inhalation powder and the pressurised inhalation solution at either dosage. A significant dose-response was observed for morning PEF. Statistical significance for the dose-response in pre-dose FEV1 was not reached. Measurements of control of asthma such as morning and evening asthma symptoms scores and percentage of days without symptoms improved significantly from baseline through to the end of the treatment period, particularly for the two high doses of both formulations. In the second study the primary aim was the efficacy evaluation on the long-acting beta2-agonist component of Fostair NEXThaler. In this study bronchodilation at the onset and up to 12 hrs after single doses administration was measured by serial spirometric evaluations of FEV1 (FEV1 AUC over at least 80% of formoterol duration of action). Compared with placebo, Fostair NEXThaler, one inhalation and four inhalations of both actives significantly improved the FEV1 AUC0-12. Both doses of Fostair NEXThaler inhalation powder were non-inferior to the corresponding dose of the pressurised inhalation solution formulation. A statistically significant dose-response was found with both formulations between the low and high dose. In the third study, after a 4-week run-in period with beclometasone dipropionate/formoterol pressurised inhalation solution fixed combination, 1 inhalation bid, 755 controlled asthmatic patients were randomised to 8 weeks of treatment with the same inhaler, with Fostair NEXThaler inhalation powder or with beclometasone dipropionate 100 micrograms per dose inhalation powder, all given at 1 inhalation bid. The primary objective was the change from baseline over the entire treatment period in mean morning expiratory flow (PEF). After 8 weeks of treatment there was no difference in the primary endpoint between the two combination inhalers, both being significantly better than beclometasone dipropionate monotherapy. No differences were found between the two combination inhalers in measures of symptoms such as the asthma control questionnaire score and the number of rescue-free days.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 a double blind, randomised, 5-way crossover, placebo controlled study in 60 partially controlled or uncontrolled adult asthmatic patients with two different single doses (1 or 4 inhalations) of Fostair NEXThaler 100 micrograms/6 micrograms and Fostair NEXThaler 200 micrograms/6 micrograms, or placebo, the bronchodilator effect (FEV1 AUC0-12h normalised by time) was investigated. The adjusted mean difference (95% CI) for Fostair NEXThaler 200 micrograms /6 micrograms vs Fostair NEXThaler 100 micrograms/6 micrograms was 0.029 (-0.018; 0.076) L for the lower formoterol dose level (1 inhalation 6 μg) and 0.027 (-0.020; 0.073) L for the higher formoterol dose level (4 inhalations 24 μg). The results showed that the lower limits of the two-sided 95% CIs for the adjusted mean difference between treatments were well above the pre-specified non-inferiority limit (-0.12 L) thus demonstrating the predefined non-inferiority (0.12 L) of Fostair NEXThaler 200 micrograms/6 micrograms compared to the lower strength in terms of FEV1 AUC0-12h normalised by time at both formoterol dose levels (6 and 24 micrograms).
Beclometasone dipropionateBeclometasone 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 anti-inflammatory activity compared with the pro-drug beclometasone dipropionate.
Absorption, distribution and biotransformationInhaled 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%).
EliminationFaecal 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 half-lives are 0.5 h and 2.7 h for beclometasone dipropionate and beclometasone-17-monopropionate respectively.
Special populationsThe 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.
Linearity/non-linearityA clinical pharmacology study was conducted to evaluate the lung bioavailability and total systemic exposure of the two components across two different dose strengths of the inhalation powder (Fostair NEXThaler 100/6 micrograms and Fostair NEXThaler 200/6 micrograms). These parameters were assessed after a single dose (4 inhalations) of each formulation, both with and without activated charcoal block. The study had an open-label, 6-way cross-over, single-dose design. A total of 30 adult asthmatic patients with an FEV1 ≥70% of the predicted values were enrolled and treated with low daily doses of inhaled corticosteroids (e.g., budesonide or equivalent ≤400 µg/day) or low dose of inhaled corticosteroids/long-acting β2-agonists fixed combinations. The lung bioavailability of B17MP (active metabolite of beclometasone dipropionate) and the total systemic exposure of B17MP were dose-proportional between the 200/6 and the approved 100/6 strength in both study conditions (with and without activated charcoal). Formoterol bioequivalence in terms of lung bioavailability and total systemic exposure was not fully demonstrated in this study as the lower 90% CI of Cmax and AUCt were below the 80% lower bioequivalence limit when the two dose strengths were compared. This reduced systemic exposure (which amounts to 20-14% in Cmax and AUCt) does not raise concerns in terms of safety since no differences in systemic effects (including glucose, potassium and cardiovascular parameters) have been observed thus showing that Fostair NEXThaler 200/6 micrograms is at least as safe as Fostair NEXThaler 100/6 micrograms. In terms of lung deposition the difference was 20% and 22% for Cmax and AUCt respectively. The equivalent efficacy in terms of bronchodilation of the two dose strengths (100/6 micrograms and 200/6 micrograms) has been demonstrated in a specific pharmacodynamics study (see section 5.1).
Absorption and distributionFollowing 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 drug 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 μg of formoterol fumarate.
BiotransformationFormoterol 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.
EliminationThe cumulative urinary excretion of formoterol after single inhalation from a dry powder inhaler increased linearly in the 12 96 μg 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 μg 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 drug 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 μg), 6% to 10% of the dose was recovered in urine as unchanged drug 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 populationsHepatic/Renal impairment: the pharmacokinetics of formoterol has not been studied in patients with hepatic or renal impairment; however, as formoterol is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver cirrhosis.
Clinical experienceThe 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.
INSTRUCTIONS FOR USE OF NEXTHALER INHALERA. Contents of the PackageThis package contains:• 1 instruction leaflet• 1 Nexthaler inhaler inside the sealed protective sachet.
If the package contents are not the same as this, 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 sachet if you do not intend to use it immediately.• Only use your inhaler as indicated.• 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.• 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.• Do not use your Nexthaler inhaler:o after its expiry dateo if it is more than 6 months since you opened the sacheto if it is brokeno if the dose counter window shows 0o if you cannot read the dose counter window.In these cases, dispose of your inhaler, or return it to the person who supplied it, and get a new one. Ask your pharmacist how to dispose of inhalers no longer required.C. Key features of your Nexthaler inhaler Taking a dose from your Nexthaler inhaler requires just three simple steps: Open, Inhale, CloseD. Before using a new Nexthaler inhaler1. Open the sachet and take out your inhaler. o Do not use your inhaler if the sachet is not sealed or it is damaged return it to the person who supplied it and get a new one.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 inhalerE.1. Visual Check
1. 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.
2. Make sure the cover is fully closed before you use it.E.2. Open
1. Hold your inhaler firmly in the upright position.
2. Open the cover fully.
3. Before inhaling breathe out as far as is comfortable.o Do not breathe out through your inhaler.E.3. 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.4. 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.4.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• When you are not using your inhaler keep it in a clean dry place. You may put it back in the sachet after use.o Do not expose your inhaler to heat or direct sunlight.o Do not expose your inhaler to a humid or wet environment. • Keep out of the sight and reach of children.• If your inhaler has been stored for over 6 months since you opened the sachet, dispose of it and get a new one.H. Disposal• Dispose of your Nexthaler inhaler if the number shown in the dose counter window is 0.• Ask your pharmacist what to do with medicines you have finished or do not need.o Do not dispose of medicines with your regular household waste.