1 metered dose (actuation) contains: 1-(3,5-dihydroxy-phenyl)-2-[[1-(4-hydroxy-benzyl)-ethyl]-amino]-ethanol hydrobromide (= fenoterol hydrobromide) 100 mcg.
Propellant: 1,1,1,2-Tetrafluoroethane (HFA 134a).
Excipients/Inactive Ingredients: citric acid anhydrous, purified water, ethanol absolute.
Pharmacotherapeutic group: Adrenergics for inhalative use in obstructive airway diseases, selective beta-2-adrenoreceptor agonists. ATC code: R03AC04.
Pharmacology: BEROTEC is an effective bronchodilator for use in acute asthma in other conditions with reversible airway narrowing such as chronic obstructive bronchitis with or without pulmonary emphysema.
Following inhalation of fenoterol hydrobromide in obstructive lung diseases, bronchodilatation occurs within a few minutes. The bronchodilator effect lasts 3-5 hours.
Mode of Action: Fenoterol hydrobromide is a direct acting sympathomimetic agent, selectively stimulating beta2-receptors in the therapeutic dose range. The stimulation of beta1-receptors comes into effect at a higher dose range. Occupation of beta2-receptors activates adenyl cyclase via a stimulatory Gs-protein. The increase in cyclic AMP activates protein kinase A which then phosphorylates target proteins in smooth muscle cells. This in turn leads to the phosphorylation of myosin light chain kinase, inhibition of phosphoinositide hydrolysis, and the opening of large-conductance calcium-activated potassium channels. There is some evidence that the "maxi-K channel" can be directly activated via the Gs-protein.
Pharmacodynamics: Fenoterol relaxes bronchial and vascular smooth muscle and protects against bronchoconstricting stimuli such as histamine, methacholine, cold air, and allergen (early response). After acute administration the release of bronchoconstricting and pro-inflammatory mediators from mast cells is inhibited. Further, an increase in mucociliary clearance has been demonstrated after administration of doses of fenoterol (0.6mg).
Higher plasma concentrations, which are more frequently achieved with oral, or even more so, with intravenous administration inhibit uterine motility. Also at higher doses, metabolic effects are observed: Lipolysis, glycogenolysis, hyperglycaemia and hypokalaemia, the latter caused by increased K+-uptake primarily into skeletal muscle. Beta-adrenergic effects on the heart such as increase in heart rate and contractility are caused by the vascular effects of fenoterol, cardiac beta2-receptor stimulation, and at supratherapeutic doses, by beta1-receptor stimulation. As with other beta-adrenergic agents, QTc prolongation has been reported. For fenoterol pressurised inhalation, solution these events were discrete and observed at doses higher than recommended. However, systemic exposure after administration with the nebulizer solution might be higher than with recommended pressurised inhalation, solution doses (refer to Dosage & Administration). The clinical significance has not been established. Tremor is a more frequently observed effect of beta-agonists.
In clinical studies fenoterol was shown to be highly efficacious in manifest bronchospasm. It prevents bronchoconstriction following exposure to various stimuli such as exercise cold air, and the early response following allergen exposure.
Pharmacokinetics: The pharmacokinetics of fenoterol were studied after intravenous, inhaled and oral dosing. The therapeutic effect of BEROTEC is produced by local action in the airway. Thus, drug concentrations in plasma are not necessarily correlated with a bronchodilatory effect.
Following inhalation, 10 - 30% of the active ingredient released from the aerosol preparation reaches the lower respiratory tract, depending on the method of inhalation and the system used. The remainder is deposited in the upper respiratory tract and the mouth and is subsequently swallowed.
Absorption: The absolute bioavailability of fenoterol following inhalation from BEROTEC pressurised inhalation, solution is 18.7%. Absorption from the lung follows a biphasic course. 30% of the fenoterol hydrobromide dose is rapidly absorbed with a half-life of 11 minutes, and 70% is slowly absorbed with a half-life of 120 minutes.
Maximum plasma concentration (geometric mean) following inhalation of a single dose of 200μg fenoterol via pressurised inhalation, solution (HFA-MDI) was 66.9pg/mL with a tmax-value of 15 minutes.
After oral administration, approximately 60% of the fenoterol hydrobromide dose is absorbed. The amount absorbed undergoes extensive first-pass metabolism resulting in an oral bioavailability of about 1.5%. Thus, the contribution of the swallowed portion of the active ingredient to the plasma concentration following inhalation is minor.
Distribution: Fenoterol distributes widely throughout the body. The volume of distribution at steady state following intravenous administration (Vss) is 1.9 - 2.7 L/kg. The disposition of fenoterol in plasma following intravenous administration is adequately described by a 3-compartment pharmacokinetic model. The half-lives are tα = 0.42 minutes, tβ = 14.3 minutes, and tγ = 3.2 hours. The plasma protein binding is 40 to 55%.
Biotransformation: Fenoterol undergoes extensive metabolism by conjugation to glucuronides and sulphates in humans. Following oral administration, fenoterol is metabolized predominantly by sulphation. This metabolic inactivation of the parent compound starts already in the intestinal wall.
Excretion: The renal clearance of fenoterol (0.27 L/min) corresponds to about 15% of the mean total clearance of a systematically available dose. Taking into account the fraction of drug bound of plasma protein, the value of renal clearance suggest tubular secretion of fenoterol in addition to glomerular filtration.
Total radioactivity excreted in urine following oral administration is approximately 39% of the dose, and total radioactivity excreted in faeces is 40.2% and 14.8% of the dose within 48 hours. 0.38% of the dose is excreted as parent compound in urine after oral administration. Following inhalation from a metered dose inhaler, 2% of the dose is excreted renally unchanged within 24 hours.
In its non-metabolised state, fenoterol hydrobromide can pass through the placenta and enter the maternal milk. There is insufficient data on the effects of fenoterol hydrobromide in the diabetic metabolic state.
a) Symptomatic treatment of acute asthma attacks.
b) Prophylaxis of exercise induced asthma.
c) Symptomatic treatment of bronchial asthma and other conditions with reversible airway narrowing e.g. chronic obstructive bronchitis. Concomitant anti-inflammatory therapy should be considered for patients with bronchial asthma and steroid responsive chronic obstructive pulmonary disease (COPD).
a) Acute asthma episodes and other conditions with reversible airway narrowing: 1 actuation is sufficient for prompt symptom relief in most cases, if breathing has not noticeably improved after 5 minutes, a second actuation may be taken, up to a maximum of 8 actuations per day.
If an attack has not been relieved by 2 actuations, further actuations may be required.
In this situation, patients should be advised to consult the physician or to go to the nearest hospital immediately (see Precautions).
b) Prophylaxis of exercise induced asthma: 1 - 2 actuations prior to exercise up to a maximum of 8 actuations per day.
In children BEROTEC 100 mcg pressurised inhalation, solution should only be used on medical advice and under the supervision of an adult.
c) Bronchial asthma and other conditions with reversible airways narrowing: If repeated dosing is required, 1 - 2 puffs for each administration, up to a maximum of 8 puffs per day.
Instruction for use: The correct administration of the pressurised inhalation, solution is essential for successful therapy.
Depress the valve twice before the apparatus is used for the first time.
Before each use the following rules should be observed: 1. Remove protective cap.
2. Breathe out deeply.
3. Hold the inhaler and close lips over the mouthpiece. The arrow and the base of the container should be pointing upwards.
4. Breathe in as deeply as possible, pressing the base of the container firmly at the same time, this releases one metered dose. Hold the breath for a few seconds, then remove the mouthpiece and breathe out. If a second inhalation is required, the same action (steps 2-4) should be repeated.
5. Replace the protective cap after use.
6. After not using the inhaler for three days the valve has to be actuated once.
The container is not transparent. It is therefore not possible to see when it is empty. The inhaler will deliver 200 puffs. When the labelled number of doses have been used the canister may still appear to contain a small amount of fluid. The inhaler should, however, be replaced so that patient can be certain in getting the right amount of medicine in each actuation.
Clean the mouthpiece at least once a week.
It is important to keep the mouthpiece of the inhaler clean to ensure that medicine does not build up and block the spray.
For cleaning, first take off the dust cap and remove the canister from the mouthpiece. Rinse warm water through the mouthpiece until no medication build-up and/or dirt is visible.
After cleaning shake out the mouthpiece and let it air-dry without using any heating system. Once the mouthpiece is dry, replace the canister and the dust cap.
WARNING: The plastic mouthpiece has been specially designed for use with BEROTEC 100 mcg pressurised inhalation, solution to ensure that patient always get the right amount of the medicine. The mouthpiece must never be used with any other metered aerosol nor must the BEROTEC 100 mcg pressurised inhalation, solution be used with any mouthpiece other than the one supplied with the product.
The container is under pressure and should by no account be opened by force or exposed to temperatures above 50°C.
Symptoms: The expected symptoms with overdosage are those of excessive beta-adrenergic-stimulation, the most prominent being tachycardia, palpitation, tremor, hypertension, hypotension, widening of the pulse pressure, anginal pain, arrhythmias and flushing.
Metabolic acidosis and hypokalaemia have also been observed with fenoterol when applied in doses higher than recommended for the approved indications of BEROTEC.
Therapy: Treatment with BEROTEC should be discontinued. Acid base and electrolyte monitoring should be considered.
Administration of sedatives and, in severe cases, intensive therapy may be needed.
Beta-receptor blockers, preferably beta1-selective, are suitable as specific antidotes; however, a possible increase in bronchial obstruction must be taken into account and the dose should be adjusted carefully in patients suffering from bronchial asthma.
BEROTEC is contraindicated in patients with: hypertrophic obstructive cardiomyopathy; tachyarrhythmia; hypersensitivity to fenoterol hydrobromide or to any of the excipients of the products.
In the following conditions BEROTEC should only be used after careful risk-benefit assessment, especially when highest recommended doses are utilized: insufficiently controlled diabetes mellitus; recent myocardial infarction; severe organic heart or vascular disorders; hyperthyroidism; phaeochromocytoma.
Paradoxical bronchospasm: As with other inhaled medicines BEROTEC may result in paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs BEROTEC should be discontinued immediately and substituted with an alternative therapy.
Cardiovascular effects: Cardiovascular effects may be seen with sympathomimetic drugs, including BEROTEC. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischaemia associated with beta agonists.
Patients with underlying severe heart disease (e.g. ischaemic heart disease, arrhythmia or severe heart failure) who are receiving BEROTEC should be warned to seek medical advice if they experience chest pain or other symptoms of worsening heart disease.
Attention should be paid to assessment of symptoms as dyspnoea and chest pain, as they may be of either respiratory or cardiac origin.
Hypokalaemia: Potentially serious hypokalaemia may result from beta2-agonist therapy. Particular caution is advised in severe asthma, as hypokalaemia this effect may be potentiated by concomitant treatment with xanthine derivatives, glucocorticosteroids and diuretics. Additionally, hypoxia may aggravate the effects of hypokalaemia on cardiac rhythm. Hypokalaemia may result in an increased susceptibility to arrhythmias in patients receiving digoxin.
It is recommended that serum potassium levels are monitored in such situations.
Acute progressive dyspnoea: The patient should be advised to consult a physician immediately in the case of acute, rapidly worsening dyspnea.
Particular warning for regular use: On demand (symptom-oriented) treatment is preferable to regular use.
Patients must be evaluated for the addition or the increase of anti-inflammatory therapy (e.g. inhaled corticosteroids) to control airway inflammation and to prevent long-term lung damage.
If bronchial obstruction deteriorates it is inappropriate and possibly hazardous to simply increase the use of beta2-agonist containing drugs such as BEROTEC beyond the recommended dose over extended periods of time. The use of increasing amounts of beta2-agonist containing products like BEROTEC on a regular basis to control symptoms of bronchial obstruction may suggest declining disease control. In this situation, the patient's therapy plan, and in particular the adequacy of the anti-inflammatory therapy, should be reviewed to prevent potentially life threatening deterioration of disease control.
Concomitant use with sympathomimetic and anticholinergic bronchodilators: Other sympathomimetic bronchodilators should only be used with BEROTEC under medical supervision (see Interactions). Anticholinergic bronchodilators may however be inhaled at the same time.
Interference with laboratory tests or other diagnostic measures: The use of BEROTEC may lead to positive results on fenoterol in tests for nonclinical substance abuse, e.g. in the context of athletic performance enhancement (doping).
Driving and Using Machines: No studies on the effect on the ability to drive and use machines have been performed.
However, patients should be advised that symptoms such as dizziness have been reported in clinical trials.
Therefore, caution should be recommended when driving a car or operating machinery.
Pregnancy: Nonclinical data, combined with available experience in humans have shown no evidence of adverse effects of BEROTEC in pregnancy. Nonetheless, the usual precautions regarding the use of drugs during pregnancy, especially during the first trimester, should be exercised.
The inhibitory effect of fenoterol on uterine contraction should be taken into account.
Lactation: Nonclinical studies have shown that fenoterol is excreted into breastmilk. Safety during breastfeeding has not been established. Caution should be exercised when BEROTEC is administered to a nursing woman.
Fertility: Clinical data on fertility are not available for fenoterol. Nonclinical studies performed with fenoterol showed no adverse effect on fertility.
As with all inhalation therapy BEROTEC may show symptoms of local irritation.
The following adverse reactions have been reported during use of BEROTEC in clinical trials and during the post-marketing experience.
Immune system disorders: hypersensitivity.
Metabolism and nutrition disorders: hypokalaemia including serious hypokalaemia.
Psychiatric disorders: agitation, nervousness.
Nervous system disorders: tremor, headache, dizziness.
Cardiac disorders: myocardial ischaemia, arrhythmia, tachycardia, palpitations.
Respiratory, thoracic and mediastinal disorders (only applicable to inhalative use): bronchospasm paradoxical, cough, throat irritation.
Gastrointestinal disorders: nausea, vomiting.
Skin and subcutaneous tissue disorders: hyperhidrosis, skin reaction such as rash, pruritus, urticaria.
Musculoskeletal, connective tissue and bone disorders: muscle spasm, myalgia, muscular weakness.
Investigations: blood pressure systolic increased, blood pressure diastolic decreased.
Beta-adrenergics, anticholinergics, and xanthine derivatives (such as theophylline) may enhance the effects of fenoterol. The concurrent administration of other beta-mimetics, systemically available anticholinergics and xanthine derivatives (e.g. theophylline) may increase the side effects.
Hypokalaemia induced by beta2-agonists may be increased by concomitant treatment with xanthine derivatives, corticosteroids, and diuretics. This should be taken into account particularly in patients with severe airway obstruction (see Precautions).
A potentially serious reduction in bronchodilatation may occur during concurrent administration of beta-blockers.
Beta-adrenergic agonists should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of beta adrenergic agonists may be enhanced. Inhalation of halogenated hydrocarbon anaesthetics such as halothane, trichloroethylene and enflurane may increase the susceptibility to the cardiovascular effects of beta-agonists.
R03AC04 - fenoterol ; Belongs to the class of adrenergic inhalants, selective beta-2-adrenoreceptor agonists. Used in the treatment of obstructive airway diseases.
MDI 100 mcg/puff (clear, colourless liquid, free from suspended particles) x 200 puffs.