- 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
ASTHMAFostair 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-extrafine 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.
There are two treatment approaches:A. Maintenance therapy: Fostair is taken as regular maintenance treatment with a separate as needed rapid-acting bronchodilator.B. Maintenance and reliever therapy: Fostair is taken as regular maintenance treatment and as needed in response to asthma symptoms.
A.Maintenance therapyPatients should be advised to have their separate rapid-acting bronchodilator available for rescue use at all times.
Dose recommendations for adults 18 years and above:One or two inhalations twice daily. The maximum daily dose is 4 inhalations.
B. Maintenance and reliever therapyPatients take their daily maintenance dose of Fostair and in addition take Fostair as needed in response to asthma symptoms. Patients should be advised to always have Fostair available for rescue use. Fostair maintenance and reliever therapy should especially be considered for patients with : not fully controlled asthma and in need of reliever medication asthma exacerbations in the past requiring medical intervention Close monitoring for dose-related adverse effects is needed in patients who frequently take high numbers of Fostair as-needed inhalations.
Dose recommendations for adults 18 years and above:The recommended maintenance dose is 1 inhalation twice daily (one inhalation in the morning and one inhalation in the evening). Patients should take 1 additional inhalation as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. The maximum daily dose is 8 inhalations.Patients requiring frequent use of rescue inhalations daily, should be strongly recommended to seek medical advice. Their asthma should be reassessed and their maintenance therapy should be reconsidered.
Dose recommendations for children and adolescents under 18 years:The safety and efficacy of Fostair in children and adolescents under 18 years of age have not been established yet. No data are available with Fostair in children under 12 years of age. Only limited data are available in adolescents between 12 and 17 years of age. Therefore Fostair is not recommended for children and adolescents under 18 years until further data become available.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 control of symptoms is maintained with the lowest recommended dosage, then the next step could include a test of inhaled corticosteroid alone. Patients should be advised to take Fostair every day even when asymptomatic.
Dose recommendations for adults 18 years and above:Two inhalations twice daily.
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).
Method of administrationTo 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 to drop the inhaler as this may cause the counter to count down.
Testing the inhalerBefore 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 dose counter should read 120 or 180.Whenever possible patients should stand or sit in an upright position when inhaling from their inhaler. Use of the 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 mouthpiece4. 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).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.
Pneumonia in patients with COPDAn 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.Patients should be advised that Fostair contains a small amount of ethanol (approximately 7 mg per actuation); however at normal doses the amount of ethanol is negligible and does not pose a risk to patients. 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 candida infection.
Pharmacokinetic interactionsBeclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes without involvement of cytochrome P450 system.
Pharmacodynamic interactionsBeta-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.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, pneumonia (in COPD patients)||Common|
|Influenza, oral fungal infection, oropharyngeal candidiasis oesophageal candidiasis, vulvovaginal candidiasis, gastroenteritis, sinusitis, rhinitis||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||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, 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 at 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 for Fostair maintenance therapyIn 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 was at least equal to that of the free combination of beclometasone dipropionate and formoterol, and exceeded that of beclometasone dipropionate alone.
Clinical efficacy for Fostair maintenance and reliever therapyIn a 48-week parallel group study involving 1701 asthma patients, the efficacy of Fostair administered as maintenance (1 inhalation BID) and reliever therapy (up to a total of 8 puffs per day) was compared to Fostair administered as maintenance therapy (1 inhalation BID) plus as needed salbutamol, in adult patients with un-controlled moderate to severe asthma.The results demonstrated that Fostair used as maintenance and reliever therapy significantly prolonged the time to first severe exacerbation (*) when compared with Fostair used as maintenance plus as needed salbutamol (p< 0.001 for both ITT and PP population). The rate of severe asthma exacerbations per patients/year, was significantly reduced in the maintenance and reliever therapy group compared to salbutamol group: 0,1476 vs 0,2239 respectively (statistically significant reduction: p<0.001). Patients in the Fostair maintenance and reliever group achieved a clinically meaningful improvement in asthma control. The mean number of inhalations/day of reliever medication and the proportion of patients using reliever medication decreased similarly in both groups. Note* :severe exacerbations were defined as deterioration in asthma resulting in hospitalisation or emergency room treatment, or resulting in the need for systemic steroids for more than 3 daysIn another clinical study, a single dose of Fostair 100/6 mcg provided a quick bronchodilation effect and a rapid relief from dyspnea symptoms similar to that of salbutamol 200 mcg/dose in asthmatic patients when metacholine challenge is used to induce bronchoconstriction.
COPDIn two 48-weeks studies, the effects on lung function and the rate of exacerbation (defined as courses of oral steroids and/or course of antibiotics and/or hospitalisations) in patients with severe COPD (30% <FEV1%<50%) was evaluated. One pivotal trial showed a significant improvement in lung function (primary endpoint: pre-dose FEV1) compared to formoterol after 12 weeks of treatment (adjusted mean difference between Fostair and formoterol: 69 ml) as well as at each clinic visit during the whole treatment period (48 weeks). The study demonstrated that the mean number of exacerbations per patient/year (exacerbation rate, co-primary endpoint) was statistically significantly reduced with Fostair as compared with formoterol treatment (adjusted mean rate 0.80 compared with 1.12 in the formoterol group, adjusted ratio 0.72, p<0.001) over 48 weeks treatment period in a total of 1199 patients with severe COPD. In addition, Fostair statistically significantly prolonged the time to first severe exacerbation compared to formoterol. The superiority of Fostair versus formoterol was also confirmed in terms of exacerbation rate in subgroups of patients taking (around 50% in each treatment arm) or not Tiotropium Bromide as concomitant medication.The other pivotal study, which was a three arm, randomised, parallel group study in 718 patients, confirmed the superiority of Fostair versus formoterol treatment in terms of change in pre-dose FEV1 at the end of treatment (48 weeks) and demonstrated the non-inferiority of Fostair compared to budesonide/formoterol fixed dose combination on the same parameter.
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.
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.
After dispensing:Do not store above 25°C (for a maximum of 5 months).The canister contains a pressurised liquid. Do not expose to temperatures higher than 50°C. Do not pierce the canister.
Chiesi Limited, 333 Styal Road, Manchester, M22 5LG
0800 009 2329
+44 (0) 161 488 5555