Berodual, 0.25mg+0.5mg/ml 20 ml

Combined bronchodilator drug. It contains two components with bronchodilator activity: ipratropium bromide – m-cholinoblocker and fenoterol hydrobromide – beta2-adrenomimetic.

The bronchodilation by inhaled administration of ipratropium bromide is mainly due to local rather than systemic anticholinergic action.

Ipratropium bromide is a quaternary ammonium derivative with anticholinergic (parasympatholytic) properties. The drug inhibits vagus nerve reflexes by counteracting the effects of acetylcholine, a mediator released from the vagus nerve endings. Anticholinergic agents prevent an increase in intracellular calcium concentration, which occurs due to the interaction of acetylcholine with the muscarinic receptor located on bronchial smooth muscle. Calcium release is mediated by a system of secondary mediators, including ITP (inositol triphosphate) and DAG (diacylglycerol).

In patients with bronchospasm associated with COPD (chronic bronchitis and pulmonary emphysema), a significant improvement in pulmonary function (increase in forced expiratory volume in 1 second (FEF1) and peak expiratory rate by 15% or more) was noted within 15 minutes, the maximum effect was achieved in 1-2 h and lasted in most patients up to 6 h after administration.

Ipratropium bromide has no adverse effect on airway mucus secretion, mucociliary clearance, and gas exchange.

Phenoterol hydrobromide selectively stimulates β2-adrenoreceptors at therapeutic dose. Stimulation of β1-adrenoreceptors occurs when using high doses (e.g., when prescribed for tocolytic action).

Fenoterol relaxes the smooth muscles of the bronchi and vessels and counteracts the development of bronchospastic reactions due to the effects of histamine, methacholine, cold air and allergens (immediate-type hypersensitivity reactions). Immediately after administration, fenoterol blocks the release of inflammatory mediators and bronchoobstruction from mast cells. In addition, an increase in mucociliary clearance has been observed when using fenoterol at a dose of 600 mcg.

The beta-adrenergic effects of the drug on cardiac activity, such as increase in HR and heart rate, are due to the vascular action of fenoterol, stimulation of β2-adrenoreceptors of the heart, and when used in doses higher than therapeutic, stimulation of β1-adrenoreceptors.

As with other beta-adrenergic drugs, prolongation of the QTc interval was noted with high doses. When fenoterol was used with metered-dose aerosol inhalers (MDIs), this effect was inconsistent and was noted when doses higher than recommended were used. However, after using fenoterol with nebulizers (standard-dose inhalation solution in vials), the systemic effect may be higher than when using the drug with DAIs at the recommended doses. The clinical significance of these observations has not been established.

The most commonly observed effect of β-adrenoreceptor agonists is tremor. In contrast to the effects on bronchial smooth muscles, tolerance may develop to the systemic effects of β-adrenoreceptor agonists The clinical significance of this manifestation is unclear.

When using ipratropium bromide and fenoterol together, the bronchodilator effect is achieved by affecting different pharmacological targets. The mentioned substances complement each other, and as a result the antispasmodic effect on the bronchial muscles increases and a wider therapeutic effect is achieved in bronchopulmonary diseases accompanied with airway constriction.

The complementary action is such that a lower dose of the beta-adrenergic component is required to achieve the desired effect, allowing an individualized effective dose with virtually no side effects.

Indications

Prevention and symptomatic treatment of chronic obstructive airway diseases with reversible bronchospasm, such as bronchial asthma and especially chronic obstructive pulmonary disease (chronic obstructive bronchitis and emphysema).

Active ingredient

How to take, the dosage

The dose must be chosen individually. Medical monitoring is required during therapy (treatment should usually start with the lowest recommended dose).

The following doses are recommended:

In adults (including the elderly) and adolescents over 12 years of age in acute attacks of bronchial asthma, the drug is prescribed in a dose of 1 ml (20 drops). This dose is usually sufficient to quickly relieve bronchospasm attacks of mild to moderate severity. In severe cases, e.g. in patients in intensive care units, if the drug is not effective in doses specified above, it may be required in higher doses – up to 2.5 ml (50 drops). The maximum dose may reach 4.0 ml (80 drops). The maximum daily dose is 8 ml.

In case of moderate bronchospasm or as an aid in ventilation, a lower dose of 0.5 ml (10 drops) is recommended.

In children aged 6-12 years old in acute attacks of bronchial asthma for quick relief of symptoms it is recommended to administer the drug in a dose of 0.5-1 ml (10-20 drops); in severe cases – up to 2 ml (40 drops); in particularly severe cases the drug may be used (with medical supervision) in a maximum dose of 3 ml (60 drops). Maximum daily dose is 4 ml.

In cases of moderate bronchospasm or to assist in ventilation, the recommended dose is 0.5 ml (10 drops).

In children less than 6 years of age (body weight less than 22 kg), due to the fact that information about the use of the drug in this age group is limited, the following dose is recommended (subject to medical supervision only): 25 µg ipratropium bromide and 50 µg fenoterol hydrobromide = 0.1 ml (2 drops) per kg body weight (per dose), but no more than 0.5 ml (10 drops) (per dose). The maximum daily dose is 1.5 ml.

The rules for use of the drug

The inhalation solution should only be used for inhalation (with a suitable nebulizer) and should not be used orally.

The treatment should usually be started with the lowest recommended dose.

The recommended dose should be diluted with saline to a final volume of 3 to 4 ml and administered (completely) with a nebulizer. The inhalation solution should not be diluted with distilled water.

The dilution must be done each time before use; any leftover diluted solution must be discarded.

The diluted solution should be used immediately after preparation.

The duration of inhalation can be controlled by how much of the diluted amount is used.

The inhalation solution can be used with a variety of commercial nebulizer models. The dose reaching the lungs and the system dose depend on the type of nebulizer used and may be higher than the corresponding doses when using Berodual HFA and CFC aerosol (which depends on the type of inhaler). Where wall oxygen is available, the solution is best administered at a flow rate of 6-8 L/min.

The instructions for use, maintenance and cleaning of the nebulizer must be followed.

Interaction

Beta-adrenomimetics and anticholinergic agents, xanthine derivatives (including theophylline) may increase the bronchodilator effect of Berodual.

Concomitant use of other beta-adrenomimetics, anticholinergic agents of systemic action, xanthine derivatives (e.g., theophylline) may increase the side effects. A significant weakening of the bronchodilator effect of Berodual with concomitant use of beta-adrenoblockers is possible.

Hypokalemia associated with the use of beta-adrenomimetics may be enhanced by concomitant use of xanthine derivatives, corticosteroids and diuretics. This fact should be paid special attention when treating patients with severe forms of obstructive airway disease.

Hypokalemia may increase the risk of arrhythmias in patients receiving digoxin. In addition, hypoxia may increase the negative effect of hypokalemia on heart rhythm. Monitoring of serum potassium levels is recommended in such cases.

Beta-adrenergic agents should be used with caution in patients who have received MAOI inhibitors and tricyclic antidepressants, because these drugs can increase the effect of beta-adrenergic agents.

The use of inhaled halogenated anesthetics, such as halothane, trichloroethylene, or enflurane, may increase the cardiovascular effects of beta-adrenergic agents.

The co-administration of Berodual with cromoglycic acid and/or GCS increases the effectiveness of therapy.

Special Instructions

The patient should be informed that if there is a sudden rapid increase in breathlessness (difficulty in breathing), a physician should be consulted immediately.

It should be noted that in patients with bronchial asthma Berodual® should be used only as needed. In patients with mild forms of chronic obstructive pulmonary disease, symptomatic treatment may be preferable to regular use.

In patients with bronchial asthma, remember to provide or increase anti-inflammatory therapy to control airway inflammation and the course of the disease.

The regular use of increasing doses of drugs containing beta2-adrenomimetics, such as Berodual®, to relieve bronchial obstruction may cause uncontrolled worsening of the disease course. If bronchial obstruction worsens, simply increasing the dose of beta2-adrenomimetics (including Berodual®) beyond what is recommended for the long term is not only unwarranted, but also dangerous. A review of the patient’s treatment plan and adequate anti-inflammatory therapy with inhaled GCS should be considered to prevent a life-threatening worsening of the disease course.

In patients with a history of cystic fibrosis, gastrointestinal motility may be impaired.

Other sympathomimetic bronchodilators should be prescribed concomitantly with Berodual only under medical supervision.

Patients should be instructed on the proper use of Berodual inhaled solution. It is recommended that the solution used with a nebulizer be inhaled through a mouthpiece to prevent eye contact with the solution. If a mouthpiece is not available, a mask that fits snugly over the face should be used. Patients with a predisposition to glaucoma should be especially careful to protect their eyes.

Berodual® should be used with caution in patients predisposed to acute glaucoma or in patients with concomitant urinary tract obstruction (e.g., prostatic hyperplasia or bladder cervical obstruction).

In athletes, the use of Berodual due to its phenoterol content may lead to positive doping tests.

The drug contains a preservative – benzalkonium chloride and a stabilizer – diethionate dihydrate. During inhalation, these components may cause bronchospasm in sensitive patients with airway hyperresponsiveness.

Influence on driving and operating machinery

There have been no studies of the effect of the drug on the ability to drive vehicles and operate mechanisms. However, patients should be cautioned that during treatment with Berodual they may experience adverse events such as dizziness, tremor, impaired eye accommodation, mydriasis, and blurred vision. Therefore, caution should be advised when driving motor vehicles or using machinery. If patients experience the above mentioned undesirable effects, such potentially dangerous activities as driving or operating machinery should be avoided.

Contraindications

Hypertrophic obstructive cardiomyopathy, tachyarrhythmia, I and III trimesters of pregnancy. Hypersensitivity to phenoterol or atropine-like drugs or other components of this drug.

With caution: closed-angle glaucoma, arterial hypertension, diabetes mellitus, recent myocardial infarction (within the last 3 months), heart and vascular diseases, such as chronic heart failure, coronary heart disease, heart defects, aortic stenosis, marked lesions of the cerebral and peripheral arteries.

Hyperthyroidism, pheochromocytoma, prostatic hyperplasia, bladder cervical obstruction, cystic fibrosis, II trimester of pregnancy, breastfeeding.

Side effects

Many of the listed undesired effects may result from the anticholinergic and beta-adrenergic properties of Berodual. As with any inhalation therapy, the use of Berodual may cause local irritation. Adverse reactions of the drug have been determined based on data obtained in clinical studies and in pharmacological surveillance of the use of the drug after its registration.

The most common adverse effects reported in clinical trials were cough, dry mouth, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, palpitations, vomiting, increased systolic BP, and nervousness.

Immune system disorders: anaphylactic reaction, hypersensitivity.

Metabolism disorders: hypokalemia.

Nervous system and mental disorders: nervousness, agitation, mental disorders, headache, tremor, dizziness.

VIocular system disorders: glaucoma, increased intraocular pressure, accommodation disorders, mydriasis, blurred vision, eye pain, corneal edema, conjunctival hyperemia, appearance of a halo around objects.

Cardiovascular system disorders: tachycardia, palpitations, arrhythmias, atrial fibrillation, supraventricular tachycardia, myocardial ischemia, increased systolic BP, increased diastolic BP.

Respiratory system: cough, pharyngitis, dysphonia, bronchospasm, pharyngeal irritation, pharyngeal edema, laryngospasm, paradoxical bronchospasm, dry pharynx.

Digestive system disorders: vomiting, nausea, dry mouth, stomatitis, glossitis, GI motility disorders, diarrhea, constipation, swelling of the mouth.

Skin and subcutaneous tissue disorders: urticaria, pruritus, angioedema, hyperhidrosis.

Muscular system disorders: muscle weakness, muscle spasm, myalgia.

Urinary system disorders: urinary retention.

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Overdose

Symptoms: symptoms of overdose are usually associated mainly with the action of fenoterol (appearance of symptoms associated with overstimulation of β-adrenoreceptors). Tachycardia, palpitations, tremors, increased or decreased BP, increased difference between systolic and diastolic BP, angina pectoris, arrhythmias, a feeling of blood rush to the face, a feeling of heaviness behind the chest, increased bronchoobstruction, metabolic acidosis are the most likely to occur.

Possible symptoms of overdose caused by ipratropium bromide (such as dry mouth, impaired eye accommodation) are mild and transient, due to the wide therapeutic range of doses of the drug and its topical use.

Treatment: the use of sedatives, tranquilizers is recommended; in severe cases – intensive therapy. As a specific antidote, β-adrenoreceptor blockers may be used, preferably selective beta1-adrenoblockers. However, in patients with bronchial asthma or chronic obstructive pulmonary disease the possibility of increasing bronchial obstruction under the influence of beta-adrenoblockers should be taken into account and their dose should be chosen carefully.

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