Berodual

Contents	Ipratropium Br 20 mcg, fenoterol HBr 50 mcg
Indications	Prevention and treatment of symptoms in chronic obstructive airway disorders with reversible bronchospasm eg, bronchial asthma and especially chronic bronchitis with or without emphysema. Concomitant anti-inflammatory therapy should be considered for patients with bronchial asthma and steroid responsive chronic obstructive pulmonary disease (COPD).
Dosage	The dosage should be adapted to the individual requirements. Unless otherwise prescribed, the following dosages are recommended: Adults and Children >6 years: Acute Asthma Episodes: 2 puffs are sufficient for prompt symptom relief in many cases. In more severe cases, if breathing has not noticeably improved after 5 min, 2 further puffs may be taken. If an attack has not been relieved by 4 puffs, further puffs may be required. In these cases, patients should consult the physician or the nearest hospital immediately. Intermittent and Long-Term Treatment: 1-2 puffs for each administration, up to a maximum of 8 puffs/day (average 1-2 puffs 3 times daily). In children, Berodual N metered aerosol should only be used on medical advice and under the supervision of an adult. Administration: Instructions for Use: Patients should be instructed in the correct administration of the metered aerosol to ensure successful therapy. Depress the valve twice before the apparatus is used for the 1st time. Before each use, the following rules should be observed: Remove protective cap. Breathe-out deeply. Hold the metered aerosol and close lips over the mouthpiece. The arrow and the base of the container should be pointing upwards. Breathe-in as deeply as possible, pressing the base of the container firmly at the same time, this releases 1 metered dose. Hold breath for a few seconds, then remove the mouthpiece from the mouth and breathe-out. The same action should be repeated for a 2nd inhalation. Replace the protective cap after use. If the metered aerosol has not been used for >3 days, the valve has to be actuated once. The container is not transparent. It is not therefore possible to see when it is empty. The aerosol will deliver 200 doses (puffs). When these have all been used, the aerosol may still appear to contain a small amount of fluid. The aerosol should, however, be replaced because the patient may not get the right amount of treatment. The amount of treatment in the aerosol can be checked as follows: Remove the aerosol from the plastic mouthpiece and put the aerosol into a container of water. The contents of the aerosol can be estimated by observing its position in the water. The mouthpiece should always be kept clean and can be washed with warm water. If soap or detergent is used, the mouthpiece should be thoroughly rinsed in clear water.
Overdosage	Symptoms: The effects of overdosage are expected to be primarily related to fenoterol. The expected symptoms with overdosage are those of excessive β-adrenergic stimulation, the most prominent being tachycardia, palpitation, tremor, hypertension, hypotension, widening of the pulse pressure, anginal pain, arrhythmias and flushing. Expected symptoms of overdosage with ipratropium bromide (eg, dry mouth, visual accommodation disturbances) are mild because the systemic availability of inhaled ipratropium is very low. Treatment: Administration of sedatives, tranquillisers, in severe cases intensive therapy. Beta-receptor blockers, preferably β1-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 or COPD because of the risk of precipitating severe bronchospasm, which may be fatal.
Contraindications	Hypertrophic obstructive cardiomyopathy, tachyarrhythmia. Hypersensitivity to fenoterol HBr, sympathomimetic amines or atropine-like substances or to any of the excipients of Berodual N.
Special Precautions	When using the new formulation of Berodual N metered aerosol for the 1st time, some patients may notice that the taste is slightly different from that of the CFC-containing formulation. Patients should be made aware of this when changing from 1 formulation to the other. They should also be told that the formulations have been shown to be interchangeable for all practical purposes and that the difference in taste has no consequences in terms of the safety or the efficacy of the new formulation. In the case of acute, rapidly worsening dyspnoea (difficulty in breathing), a physician should be consulted immediately. Prolonged Use: In patients with bronchial asthma and mild COPD on demand (symptom-oriented) treatment may be preferable to regular use. The addition or the increase of anti-inflammatory therapy to control airway inflammation and to prevent deterioration of disease control should be considered for patients with bronchial asthma and with steroid-responsive COPD. The use of increasing amounts of β2-agonists containing products eg, Berodual N on a regular basis to control symptoms of bronchial obstruction may suggest declining disease control. If bronchial obstruction deteriorates, it is inappropriate and possibly hazardous to simply increase the use of β2-agonist containing products eg, Berodual N beyond the recommended dose over extended periods of time. In this situation, the patient's therapy plan and in particular, the adequacy of anti-inflammatory therapy with inhaled corticosteroids, should be reviewed to prevent potentially life-threatening deterioration of disease control. Other sympathomimetic bronchodilators should only be used with Berodual N under medical supervision. In the following conditions, Berodual N should only be used after careful risk/benefit assessment, especially when doses higher than recommended are used: Insufficiently controlled diabetes mellitus, recent myocardial infarction, severe organic heart or vascular disorders, hyperthyroidism, phaeochromocytoma. Cardiovascular effects may be seen with sympathicomimetic drugs, including Berodual. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischaemia associated with β-agonists. Patients with underlying severe heart disease (eg, ischaemic heart disease, arrhythmia or severe heart failure) who are receiving Berodual N, 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 eg, dyspnoea and chest pain, as they may be of either respiratory or cardiac origin. Potentially serious hypokalaemia may result from β2-agonist therapy. Berodual N should be used with caution in patients with prostatic hyperplasia or bladder-neck obstruction or predisposed to narrow-angle glaucoma. There have been isolated reports of ocular complications (ie, mydriasis, increased intraocular pressure, narrow-angle glaucoma, eye pain) when aerosolised ipratropium bromide either alone or in combination with an adrenergic β2-agonist, was sprayed into the eyes. Thus, patients must be instructed in the correct administration of Berodual N metered aerosol. Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately. Patients with cystic fibrosis may be more prone to GI motility disturbances. Immediate hypersensitivity reactions may occur after administration of Berodual N, as demonstrated by rare cases of urticaria, angio-oedema, rash, bronchospasm, oropharyngeal oedema and anaphylaxis. Use in pregnancy & lactation: Preclinical data, combined with available experience in humans have shown no evidence of ill effects in pregnancy of fenoterol or ipratropium. Nonetheless, the usual precautions regarding the use of drugs during pregnancy, especially during the 1st trimester should be exercised. The inhibitory effect of Berodual N on uterine contraction should be taken into account when used before childbirth. Preclinical studies have shown that fenoterol HBr is excreted into breast milk. It is not known whether ipratropium is excreted into breast milk. But it is unlikely that ipratropium would reach the infant to an important extent, especially when administered as an aerosol. However, because many drugs are excreted in breast milk, caution should be exercised when Berodual N is administered to a nursing woman.
Adverse Drug Reactions	Adverse reactions of Berodual N are nervousness, dryness of the mouth, headache, dizziness and fine tremor of skeletal muscles. Tachycardia, increased heart rate and palpitations may occur. GI motility disturbances (eg, vomiting, constipation, diarrhoea) and urinary retention albeit reversible have been reported. Ocular side effects (including accommodation disturbances and glaucoma) may occur (see Precautions). Skin reactions or allergic-type reactions eg, skin rash, angio-oedema of the tongue, lips and face, urticaria, laryngospasm and anaphylactic reactions have been reported. Potentially serious hypokalaemia may result from β2-agonist therapy. As with other β-agonist containing products, nausea, vomiting, sweating, weakness and myalgia/muscle cramps may occur. Decrease in diastolic blood pressure and increase in systolic blood pressure have been observed. Arrhythmias (particularly after higher doses), atrial fibrillation, supraventricular tachycardia and myocardial ischaemia may occur. In individual cases, psychological alterations have been reported under inhalational therapy with β-agonist containing products. As with use of other inhalation therapy, cough, local irritation (eg, pharyngitis, throat irritation) and inhalation-induced bronchospasm have been reported. Click to view ADR Monitoring Form
Drug Interactions	Other β-adrenergics, anticholinergics and xanthine derivatives (eg, theophylline) may enhance the bronchodilatatory effect. The concurrent administration of other β-mimetics, systemically available anticholinergics and xanthine derivatives (eg, theophylline) may increase the adverse reactions. A potentially serious reduction in bronchodilatation may occur during concurrent administration of β-blockers. Hypokalaemia induced by β2-agonist 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. Hypokalaemia may result in an increased susceptibility to arrhythmias in patients receiving digoxin. Additionally, hypoxia may aggravate the effects of hypokalaemia on cardiac rhythm. It is recommended that serum potassium levels are monitored in such situations. Beta2-agonist-containing medicinal products should be administered with caution to patients being treated with MAOIs, tricyclic antidepressants or other sympathomimetic agents, since the action of β-adrenergic agonists may be enhanced, particularly to the cardiovascular system. Inhalation of halogenated hydrocarbon anaesthetics eg, halothane, trichloroethylene and enflurane may increase the susceptibility on the cardiovascular effects of β-agonists. View more drug interactions with Berodual N
Caution For Usage	The plastic mouthpiece has been specially designed for use with Berodual N to ensure that the patient always gets the right amount of the medicine. The mouthpiece must never be used with any other metered aerosol nor must the Berodual N metered aerosol be used with any mouthpiece other than the 1 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.
Storage	Store below 30°C.
Description	Each metered dose contains ipratropium bromide 21 mcg (corresponding to anhydrous ipratropium bromide 20 mcg) and fenoterol HBr 50 mcg. Ipratropium bromide is (8r)-3α-hydroxy-8-isopropyl-1αH,5αH-tropanium bromide (±)-tropate monohydrate. Fenoterol HBr is 1-(3,5-dihydroxy-phenyl)-2-[[1-(4-hydroxy-benzyl)-ethyl]-amino]-ethanol hydrobromide. Berodual is a clear, colourless liquid, free from suspended particles.
Mechanism of Action	Pharmacology: Trials with a treatment duration of up to 3 months involving adult asthmatics and COPD patients, and asthmatic children, in which the HFA formulation and the CFC formulation have been compared, have shown the 2 formulations to be therapeutically equivalent. Berodual N contains 2 active bronchodilating ingredients: Ipratropium bromide, exhibiting an anticholinergic effect and fenoterol HBr, a β-adrenergic agent. Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In preclinical studies, it inhibits vagally-mediated reflexes by antagonising the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increase in intracellular concentration of cyclic guanosine monophosphate (cyclic-GMP) caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle. The bronchodilatation following inhalation of ipratropium bromide is primarily a local, site-specific effect, not a systemic one. In controlled up to 90-day studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (chronic bronchitis and emphysema), significant improvements in pulmonary function (FEV1 and FEF25-75% increases of ≥15%) occurred within 15 min, reached a peak in 1-2 hrs and persisted in the majority of patients up to 6 hrs. In controlled up to 90-day studies in patients with bronchospasm associated with asthma, significant improvements in pulmonary function (FEV1 increases of ≥15%) occurred in 40% of the patients. Preclinical and clinical evidence suggest no deleterious effect of ipratropium bromide on airway mucous secretion, mucociliary clearance or gas exchange. Fenoterol HBr is a direct acting sympathomimetic agent, selectively stimulating β2-receptors in the therapeutic dose range. The stimulation of β1-receptors comes into effect at a higher dose range. Occupation of β2-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. Fenoterol relaxes bronchial and vascular smooth muscle and protects against bronchoconstricting stimuli eg, 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 higher doses of fenoterol. Higher plasma concentrations, which are more frequently achieved with oral, or even more so, with IV 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. β-Adrenergic effects on the heart eg, increase in heart rate and contractility are caused by the vascular effects of fenoterol, cardiac β2-receptor stimulation and at supratherapeutic doses by β1-receptor stimulation. As with other β-adrenergic agents including fenoterol, QTc prolongations have been reported. The clinical significance has not been established. Tremor is a more frequently observed effect of β-agonists. Unlike the effects on the bronchial smooth muscle, the systemic effects of β-agonists are subject to the development of tolerance. In clinical studies, fenoterol was shown to be highly efficacious in manifest bronchospasm. It prevents bronchoconstriction following exposure to various stimuli eg, exercise, cold air and the early response following allergen exposure. Concurrent use of these 2 active ingredients dilates the bronchi by affecting different pharmacological sites of action. The 2 active substances thus complement each other in their spasmolytic action on the bronchial muscles and allow a broad therapeutic use in the field of bronchopulmonary disorders associated with constriction of the respiratory tract. The complementary action is such that only a very low proportion of the β-adrenergic component is needed to obtain the desired effect, facilitating individual dosage suited to each patient with a minimum of adverse reactions. In patients with asthma and with COPD, studies with the metered aerosol have shown that a combination of ipratropium and fenoterol is as efficacious as double the dose of fenoterol administered without ipratropium. Cumulative-dose studies have also showed that the combination is better tolerated. In adequately sized studies in patients with asthma and COPD, the combination demonstrated better efficacy than each of its components. In acute bronchoconstriction, Berodual N is effective shortly after administration and is therefore also suitable for treating acute attacks of asthma. Pharmacokinetics: The therapeutic effect of Berodual N is produced by a topical action in the airway. The pharmacodynamics of the bronchodilation produced by Berodual N are therefore not relevant to the pharmacokinetics of the active constituents of the preparation. Pharmacokinetic investigation has shown, however, that the HFA formulation and the conventional CFC formulation can be considered equivalent. About 16% of the dose are deposited in the respiratory tract following inhalation by metered aerosol. The remaining portion is being swallowed. The active ingredients (fenoterol HBr and ipratropium bromide) are absorbed very quickly from the respiratory tract. The peak plasma concentrations are reached only minutes after inhalation. There is no evidence that the pharmacokinetics of both ingredients in the combination differ from those of the monosubstance. Fenoterol HBr: The swallowed portion is mainly metabolised to sulphate conjugates. The absolute bioavailability following oral administration is low (approximately 1.5%). Following IV administration, 3 phases were observed, whereby the terminal t½ was approximately 3 hrs. Fenoterol and its conjugates are rapidly excreted renally (renal clearance: 267 mL/min). About 40% of the drug are bound to plasma proteins. In its nonmetabolised state, fenoterol HBr can slowly pass through the placenta and enter the maternal milk. Ipratropium Bromide: The absolute bioavailability after oral administration is low (approximately 2%). Following IV administration, a rapid biphasic decline in plasma is noted for ipratropium. The terminal t½ was about 1.6 hrs. The total clearance of ipratropium bromide is 2.3 L/min. Approximately 40% of the clearance is renal (0.9 L/min) and 60% nonrenal ie, mainly hepato-metabolic. The main metabolites found in urine bind poorly to the muscarinic receptor. Forty-six percent (46%) of ipratropium bromide are excreted renally after IV administration, 4.4-13.1% after inhalation from a metered dose inhaler are excreted as unchanged compound in urine. Ipratropium bromide is minimally (<20%) bound to plasma proteins. The ipratropium ion does not cross the blood-brain barrier. It is not known if placental barrier is crossed.
MIMS Class	Antiasthmatic & COPD Preparations
ATC Classification	R03AK03 - fenoterol and other drugs for obstructive airway diseases ; Belongs to the class of adrenergics and other inhalants used in the treatment of obstructive airway diseases.
Poison Schedule [?]	POM
Presentation/Packing	Metered-dose inhaler 200 puffs/10 mL.