- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyFostair is not intended for the initial management of asthma. The dosage of the components of Fostair 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.Beclometasone dipropionate in Fostair is characterised by an extrafine particle size distribution which results in a more potent effect than formulations of beclometasone dipropionate with a non-extra fine particle size distribution (100 micrograms of beclometasone dipropionate extrafine in Fostair are equivalent to 250 micrograms of beclometasone dipropionate in a non-extrafine formulation). Therefore the total daily dose of beclometasone dipropionate administered in Fostair should be lower than the total daily dose of beclometasone dipropionate administered in a non-extrafine beclometasone dipropionate formulation.This should be taken into consideration when a patient is transferred from a beclometasone dipropionate non-extrafine formulation to Fostair; the dose of beclometasone dipropionate should be lower and will need to be adjusted to the individual needs of the patients.
Dose recommendations for adults 18 years and above:Two inhalations twice daily. The maximum daily dose is 4 inhalations.Fostair 200/6 should be used as maintenance therapy only. A lower strength (Fostair 100/6) is available for maintenance and reliever therapy.Patients should be advised to have their separate short-acting bronchodilator available for rescue use at all times.Patients should be regularly reassessed by a doctor, so that the dosage of Fostair 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 long term control of symptoms is maintained with the lowest recommended dosage, then the next step could include a test of inhaled corticosteroid alone. Fostair 200/6 should not be used for step-down treatment but a lower strength of the beclometasone dipropionate component in the same inhaler is available for step-down treatment (Fostair 100/6 micrograms). Patients should be advised to take Fostair every day even when asymptomatic.
Special patient groups:There is no need to adjust the dose in elderly patients. There are no data available for use of Fostair in patients with hepatic or renal impairment (see section 5.2).
Dose recommendations for children and adolescents under 18 years:
Fostair 200/6 should not be used in children and adolescents less than 18 years.
Method of administrationFostair is for inhalation use.To ensure proper administration of the drug, the patient should be shown how to use the inhaler correctly by a physician or other health professional. Correct use of the pressurised metered dose inhaler is essential in order that treatment is successful. The patient should be advised to read the Patient Information Leaflet carefully and follow the instructions for use as given in the Leaflet. Fostair inhaler is provided with a counter on the back of the actuator, which shows how many doses are left. For the 120 doses presentation each time the patient press the canister, a puff of medicine is released and the counter counts down by one. For the 180 presentation, each time the patient press the canister the counter rotates by a small amount and the number of puffs remaining is displayed in intervals of 20. Patients should be advised not to drop the inhaler as this may cause the counter to count down. Testing the inhaler Before using the inhaler for the first time or if the inhaler has not been used for 14 days or more, the patient should release one actuation into the air in order to ensure that the inhaler is working properly. After testing the inhaler for the first time, the counter should read 120 or 180. Use of the inhaler: If the inhaler has been exposed to severe cold, patients should warm it with their hands for a few minutes before using it. They should never warm it by artificial means. Whenever possible patients should stand or sit in an upright position when inhaling from their inhaler. 1. Patients should remove the protective cap from the mouthpiece and check that the mouthpiece is clean and free from dust and dirt or any other foreign objects.2. Patients should breathe out as slowly and deeply as possible.3. Patients should hold the canister vertically with its body upwards and put the lips around the mouthpiece without biting the mouthpiece.4. At the same time, patients should breathe in slowly and deeply through the mouth. After starting to breathe in, they should press down on the top of the inhaler to release one puff.5. Patients should hold the breath for as long as possible and, finally, they should remove the inhaler from the mouth and breathe out slowly. Patients should not breathe out into the inhaler.To inhale a further puff, patients should keep the inhaler in a vertical position for about half a minute and repeat steps 2 to 5. IMPORTANT: patients should not perform steps 2 to 5 too quickly. After use, patients should close the inhaler with protective cap and check the dose counter. Patients should be advised to get a new inhaler when the dose counter or indicator shows the number 20. They should stop using the inhaler when the counter shows 0 as any puffs left in the device may not be enough to release a full dose If mist appears following inhalation, either from the inhaler or from the sides of the mouth, the procedure should be repeated from step 2.For patients with weak hands it may be easier to hold the inhaler with both hands. Therefore the index fingers should be placed on the top of the inhaler canister and both thumbs on the base of the inhaler. Patients should rinse their mouth or gargle with water or brush the teeth after inhaling (see section 4.4).The canister contains a pressurised liquid. Patients should be advised not to expose to temperatures higher than 50°C and not to pierce the canister.Cleaning Patients should be advised to read the Patient Information Leaflet carefully for cleaning instructions. For the regular cleaning of the inhaler, patients should remove the cap from the mouthpiece and wipe the outside and inside of the mouthpiece with a dry cloth. They should not remove the canister from the actuator and should not use water or other liquids to clean the mouthpiece. Patients who find it difficult to synchronise aerosol actuation with inspiration of breath, may use the AeroChamber Plus spacer device. They should be advised by their doctor, pharmacist or a nurse in the proper use and care of their inhaler and spacer and their technique checked to ensure optimum delivery of the inhaled drug to the lungs. This may be obtained by the patients using the AeroChamber Plus by one continuous slow and deep breath through the spacer, without any delay between actuation and inhalation.
Beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes.
Beclometasone 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 should therefore not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons.On the other hand, concomitant use of other beta-adrenergic drugs can 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, antihistamines, 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. Fostair contains a small amount of ethanol. There is a theoretical potential for interaction in particularly sensitive patients taking disulfiram or metronidazole.
|System Organ Class||Adverse Reaction||Frequency|
|Infections and Infestations||Pharyngitis, oral candidiasis||Common|
|Influenza, oral fungal infection, oropharyngeal candidiasis, oesophageal candidiasis, vulvovaginal candidiasis, gastroenteritis, sinusitis, rhinitis, pneumonia*||Uncommon|
|Blood and lymphatic system disorders||Granulocytopenia||Uncommon|
|Immune system disorders||Dermatitis allergic||Uncommon|
|Hypersensitivity reactions, including erythema, lips, face, eye and pharyngeal oedema||Very rare|
|Endocrine disorders||Adrenal suppression||Very rare|
|Metabolism and nutrition disorders||Hypokalaemia, hyperglycaemia||Uncommon|
|Psychomotor hyperactivity, sleep disorders, anxiety, depression, aggression, behavioural changes (predominantly in children)||Unknown|
|Nervous system disorders||Headache||Common|
|Eye disorders||Glaucoma, cataract||Very rare|
|Ear and labyrinth disorders||Otosalpingitis||Uncommon|
|Cardiac disorders||Palpitations, electrocardiogram QT corrected interval prolonged, electrocardiogram change, tachycardia, tachyarrhythmia, atrial fibrillation*||Uncommon|
|Ventricular extrasystoles, angina pectoris||Rare|
|Vascular disorders||Hyperaemia, flushing||Uncommon|
|Respiratory, thoracic and mediastinal disorders||Dysphonia||Common|
|Cough, productive cough, throat irritation, asthmatic crisis, pharyngeal erythema||Uncommon|
|Dyspnoea, exacerbation of asthma||Very rare|
|Gastrointestinal disorders||Diarrhoea, dry mouth, dyspepsia, dysphagia, burning sensation of the lips, nausea, dysgeusia||Uncommon|
|Skin and subcutaneous tissue disorders||Pruritus, rash, hyperhidrosis, urticaria||Uncommon|
|Musculoskeletal and connective tissue disorders||Muscle spasms, myalgia||Uncommon|
|Growth retardation in children and adolescents||Very rare|
|Renal and urinary disorders||Nephritis||Rare|
|General disorders and administration site conditions||Oedema peripheral||Very rare|
|Investigations||C-reactive protein increased, platelet count increased, free fatty acids increased, blood insulin increased, blood ketone body increased, blood cortisol decrease*||Uncommon|
|Blood pressure increased||Uncommon|
|Blood pressure decreased||Rare|
|Bone density decreased||Very rare|
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: R03 AK08.
Mechanisms of action and pharmacodynamic effectsFostair contains beclometasone dipropionate and formoterol. These two actives 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 a single dose. Clinical efficacy and safety for FostairIn clinical trials in adults, the addition of formoterol to beclometasone dipropionate improved asthma symptoms and lung function and reduced exacerbations. In a 24-week study the effect on lung function of Fostair 100/6 HFA was at least equal to that of the free combination of beclometasone dipropionate and formoterol, and exceeded that of beclometasone dipropionate alone. The efficacy of Fostair 200/6 HFA, 2 puffs twice a day, was evaluated in a 12 week pivotal trial comparing the effect on lung function versus treatment with beclometasone dipropionate monotherapy in asthmatic patients not adequately controlled with previous treatment (high dose ICS or medium dose-ICS+LABAs combinations). The study demonstrated the superiority of Fostair 200/6 HFA compared to BDP HFA in terms of change from baseline in the average pre-dose morning PEF (adjusted mean difference 18.53 L). In a 24 week pivotal trial the safety profile of Fostair 200/6 HFA, 2 puffs twice a day, was comparable to that of an approved fixed dose combination (fluticasone/salmeterol 500/50, 1 puff twice daily). No clinically relevant effect was observed with Fostair 200/6 HFA on the HPA axis after 6 months of treatment. The study showed that both Fostair 200/6 µg and the approved fixed dose combination were not superior to non extrafine beclometasone dipropionate monotherapy (2000 µg/day) on the change in pre-dose morning FEV1 and percentage of complete days without asthma symptoms.
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 (36 %) 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 41% 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 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 120L/h respectively), with a small volume of distribution at steady state for beclometasone dipropionate (20L) and larger tissue distribution for its active metabolite (424L).Plasma protein binding is moderately high.
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.
FormoterolAbsorption 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
After dispensing:Do not store above 25°C (for a maximum of 5 months).
Chiesi Limited, 333 Styal Road, Manchester, M22 5LG
0800 009 2329
+44 (0) 161 488 5555