Nosological classification (ICD-10)
Description of the dosage form
A clear, colorless or almost colorless liquid, free from suspended particles. The smell is almost imperceptible.
The drug Berodual ® contains two components with bronchodilator activity: ipratropium bromide – m-anticholinergic and fenoterol – β2-adrenomimetic. Bronchodilation with inhalation ipratropium bromide is mainly due to local, rather than systemic anticholinergic effects.
Ipratropium bromide is a quaternary ammonium derivative with anticholinergic (parasympatholytic) properties. The drug inhibits the reflexes caused by the vagus nerve, counteracting the effects of acetylcholine, a mediator released from the endings of the vagus nerve. Anticholinergics prevent an increase in the intracellular Ca 2+ concentration, which occurs as a result of the interaction of acetylcholine with the muscarinic receptor located on the smooth muscles of the bronchi. The release of Ca 2+ is mediated by a system of secondary mediators, including inositol triphosphate (ITP) and diacylglycerol (DAG).
In patients with bronchospasm associated with chronic obstructive pulmonary diseases (chronic bronchitis and pulmonary emphysema), a significant improvement in lung function (increase in FEV1 and peak expiratory flow rate by 15% or more) was noted within 15 minutes, the maximum effect was achieved in 1-2 h and continued in most patients until 6 h after administration.
Ipratropium bromide does not adversely affect the secretion of mucus in the respiratory tract, mucociliary clearance and gas exchange.
Fenoterol selectively stimulates β2-adrenoreceptors in a therapeutic dose. Stimulation of β2-adrenoreceptors activates adenylate cyclase through stimulation of the Gs protein. Stimulation of β1-adrenoreceptors occurs when using high doses.
Fenoterol relaxes the smooth muscles of the bronchi and blood vessels and counteracts the development of bronchospastic reactions caused by the effect of histamine, methacholine, cold air and allergens (immediate type hypersensitivity reactions). Immediately after administration, fenoterol blocks the release of inflammatory mediators and bronchial obstruction from mast cells. In addition, when using fenoterol in doses of 0.6 mg, there was an increase in mucociliary clearance.
The β-adrenergic effect of the drug on cardiac activity, such as an increase in the frequency and strength of heart contractions, is due to the vascular action of fenoterol, stimulation of heart β2-adrenoreceptors, and when using doses exceeding therapeutic, stimulation of β1-adrenoreceptors.
As with other β-adrenergic drugs, the QTc interval was lengthened with high doses. When using fenoterol using metered-dose aerosol inhalers (DAI), this effect was not constant and was observed in the case of the use of doses exceeding the recommended ones.
However, after the use of fenoterol using nebulizers (solution for inhalation in vials with a standard dose), systemic exposure may be higher than when using the drug with DAI in 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 the smooth muscles of the bronchi, the systemic effects of β-adrenoreceptor agonists can develop tolerance. The clinical significance of this manifestation is not clear. Tremor is the most common undesirable effect when using β-adrenoreceptor agonists. With the combined use of these two active substances, the bronchodilator effect is achieved by exposing various pharmacological targets. These substances complement each other; as a result, the antispasmodic effect on the muscles of the bronchi is enhanced and a greater breadth of therapeutic action is obtained for bronchopulmonary diseases accompanied by constriction of the respiratory tract. The complementary effect is such that in order to achieve the desired effect a lower dose of the β-adrenergic component is required, which allows an individual to choose an effective dose in the practical absence of side effects of the drug Berodual ®. With acute bronchoconstriction, the effect of the drug Berodual ® develops rapidly, which allows its use in acute attacks of bronchospasm.
The therapeutic effect of the combination of ipratropium bromide and fenoterol is a consequence of its local action in the airways. The development of bronchodilation is not directly proportional to the pharmacokinetic parameters of active substances.
After inhalation, usually 10–39% of the injected dose of the drug is administered to the lungs (depending on the dosage form and method of inhalation). The rest of the dose is deposited on the mouthpiece, in the mouth and oropharynx. Part of the dose deposited in the oropharynx is swallowed and enters the gastrointestinal tract.
Part of the dose that passes into the lungs quickly reaches the systemic circulation (within a few minutes).
There is no evidence that the pharmacokinetics of the combined drug is different from that of each of the individual components.
The ingested portion of the dose is metabolized to sulfate conjugates. Absolute bioavailability when administered orally is low (about 1.5%).
After i / v administration, free and conjugated fenoterol in a 24-hour urine analysis, respectively, 15 and 27% of the injected dose. The overall systemic bioavailability of the inhaled dose of fenoterol is estimated at 7%.
The kinetic parameters describing the distribution of fenoterol are calculated from the plasma concentration after i.v. administration. After i / v administration, plasma concentration-time profiles can be described by a 3-chamber pharmacokinetic model, according to which T1 / 2 is approximately 3 hours. In this 3-chamber model, the apparent Vss of fenoterol is approximately 189 L (2.7 l / kg) .
About 40% of fenoterol binds to plasma proteins.
Preclinical studies have shown that fenoterol and its metabolites do not penetrate the BBB. The total clearance of fenoterol – 1.8 l / min, renal clearance – 0.27 l / min. The total renal excretion (within 2 days) of the isotope-labeled dose (including the parent compound and all metabolites) was 65% after iv administration. The total isotope-labeled dose excreted through the intestine was 14.8% after intravenous administration, and after oral administration 40.2% within 48 hours. The total isotope-labeled dose excreted through the kidneys was about 39% after oral administration.
The total renal excretion (within 24 hours) of the parent compound is about 46% of the value of the intravenous dose, less than 1% of the dose used orally, and about 3–13% of the inhalation dose of the drug. Based on these data, it is calculated that the total systemic bioavailability of ipratropium bromide, used by mouth and inhalation, is 2 and 7–28%, respectively. Thus, the effect of the part of ipratropium bromide ingested on the systemic effect is insignificant.
The kinetic parameters describing the distribution of ipratropium bromide are calculated on the basis of its concentration in the plasma after i / v administration. A rapid two-phase decrease in plasma concentration is observed. The apparent Vss is approximately 176 liters (2.4 l / kg). The drug binds to plasma proteins to a minimum (less than 20%). Preclinical studies have shown that ipratropium bromide, which is a quaternary derivative of ammonium, does not penetrate the BBB.
T1 / 2 in the final phase is approximately 1.6 hours
The total clearance of ipratropium bromide is 2.3 l / min, and the renal clearance is 0.9 l / min. After i.v. administration, approximately 60% of the dose is metabolized by oxidation, mainly in the liver.
The total renal excretion (within 6 days) of the isotope-labeled dose (including the parent compound and all metabolites) was 72.1% after oral administration, 9.3% after oral administration, and 3.2% after inhalation use. The total isotope-labeled dose excreted through the intestine was 6.3% after IV administration, 88.5% after oral administration, and 69.4% after inhalation use. Thus, the excretion of the isotope-labeled dose after IV injection is carried out mainly through the kidneys.
The T1 / 2 of the parent compound and metabolites is 3.6 h. The major metabolites excreted in the urine are weakly associated with muscarinic receptors and are considered inactive.
Indications drug Berodual ®
Symptomatic treatment of chronic obstructive respiratory diseases with reversible airway obstruction, such as:
chronic obstructive pulmonary disease;
chronic obstructive bronchitis with or without emphysema.
hypersensitivity to ipratropium bromide and fenoterol, atropine-like substances, or any other components of the drug;
hypertrophic obstructive cardiomyopathy;
pregnancy (I term).
With care: angle-closure glaucoma, arterial hypertension, inadequately controlled diabetes mellitus, recent myocardial infarction, severe organic heart and vascular diseases, coronary heart disease, hyperthyroidism, pheochromocytoma, urinary tract obstruction, mucoviscidosis, pregnancy (II and III), adrenal gland, pregnancy (II and III), mucoviscidosis, pregnancy (II and III), adrenal gland, pregnancy (II and III), cystic fibrosis, pregnancy (II and III); feeding.
Use during pregnancy and lactation
The drug is contraindicated in the first trimester of pregnancy.
Existing clinical experience has shown that fenoterol and ipratropium bromide do not have a negative effect on pregnancy. However, when using these drugs during pregnancy should be observed normal precautions (II and III trimesters). The inhibitory effect of fenoterol on uterine contractility should be taken into account.
Preclinical studies have shown that fenoterol can pass into breast milk. With regard to ipratropium bromide, such data are not obtained. A significant effect of ipratropium bromide on the infant, especially in the case of the use of the drug in the form of an aerosol, is unlikely. Nevertheless, given the ability of many drugs to penetrate into breast milk, when prescribing the drug Berodual ® for women who are breastfeeding, caution should be exercised.
Fertility There are no clinical data on the effect of fenoterol, ipratropium bromide, or a combination of these on fertility. Preclinical studies have not shown the effect of ipratropium bromide and fenoterol on fertility.
Many of the listed undesirable effects can be a consequence of anticholinergic and β-adrenergic properties of the drug. Berodual ®, like any inhalation therapy, can cause local irritation. Adverse drug reactions were determined on the basis of data obtained in clinical studies and during pharmacological supervision of the use of the drug after its registration.
The most common side effects reported in clinical studies were cough, dry mouth, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, feeling of heartbeat, vomiting, increased blood pressure and nervousness.
The frequency of adverse reactions that may occur during therapy is given in the form of the following gradation: very often (≥1 / 10); often (≥1 / 100, ®. Evaluated based on the upper limit of the 95% CI calculated for the total patient population.
Long-term simultaneous use of the drug Berodual ® with other anticholinergic drugs is not recommended due to lack of data.
β-adrenergic and anticholinergic agents, xanthine derivatives (for example, theophylline) can enhance the bronchodilatory effect of the drug Berodual ®. The simultaneous use of other β-adrenomimetics, anticholinergics or xanthine derivatives (for example, theophylline) can lead to increased side effects.
Hypokalemia associated with the use of β-adrenomimetik can be enhanced by the simultaneous appointment of xanthine derivatives, GCS and diuretics. This should be given special attention when treating patients with severe obstructive respiratory diseases.
Hypokalemia can lead to an increased risk of arrhythmias in patients receiving digoxin. In addition, hypoxia can increase the negative impact of hypokalemia on the heart rhythm. In such cases, it is recommended to monitor the level of potassium in the blood serum.
Β2-adrenergic agents should be used with caution in patients receiving MAO inhibitors and tricyclic antidepressants,
Inhalation of halogenated hydrocarbon anesthetics, such as halothane, trichloroethylene or enflurane, can enhance the effect of β-adrenergic agents on CVS.
The combined use of the drug Berodual ® with cromoglicic acid and / or GCS increases the effectiveness of therapy.
Dosage and administration
Treatment must be carried out under medical supervision (for example, in a hospital). Home treatment is possible only after consulting a doctor in cases where a fast-acting β-agonist at a low dose is not effective enough. Also, the solution for inhalation can be recommended to patients in the case when an inhalation aerosol cannot be used or when higher doses are required. The dose should be selected individually, depending on the severity of the attack. Treatment usually must begin with the lowest recommended dose and be discontinued after a sufficient reduction in symptoms has been achieved.
The following doses are recommended.
Adults (including the elderly) and adolescents over 12 years old
Acute bouts of bronchospasm. Depending on the severity of the attack, doses may vary from 1 ml (1 ml = 20 drops) to 2.5 ml (2.5 ml = 50 drops). In severe cases it is possible to use doses reaching 4 ml (4 ml = 80 drops).
Acute attacks of bronchial asthma. Depending on the severity of the attack, doses may vary from 0.5 ml (0.5 ml = 10 drops) to 2 ml (2 ml = 40 drops).
Children under 6 years old (whose body weight is less than 22 kg)
Due to the fact that information on the use of the drug in this age group is limited, the use of the following dose is recommended (only under medical supervision): 0.1 ml (2 drops) / kg body weight, but not more than 0.5 ml (10 drops).
The solution for inhalation should be used only for inhalation (with a suitable nebulizer) and not orally.
Treatment should usually begin with the lowest recommended dose.
The recommended dose should be diluted with 0.9% sodium chloride solution to a final volume of 3-4 ml, and applied (completely) using a nebulizer.
Berodual ® solution for inhalation should not be diluted with distilled water.
Dilution of the solution should be carried out each time before use; remnants of the diluted solution should be destroyed.
The diluted solution should be used immediately after preparation. The duration of inhalation can be controlled by the expenditure of the diluted solution.
Solution Berodual ® for inhalation can be applied using various commercial models of nebulizers. The dose reaching the lungs and the systemic dose depend on the type of nebulizer used and may be higher than the corresponding dose when using the metered-dose aerosol Berodual ® H (which depends on the type of inhaler). When using a centralized oxygen system, the solution is best applied at a flow rate of 6–8 l / min.
You must follow the instructions for use, maintenance and cleaning of the nebulizer.
Symptoms: associated primarily with the action of fenoterol. Possible symptoms associated with excessive stimulation of β-adrenergic receptors. The most likely occurrence of tachycardia, palpitations, tremor, increase in blood pressure, lowering blood pressure, increasing the difference between blood pressure and dad, angina, arrhythmias and hot flashes. Metabolic acidosis and hypokalemia were also observed.
Symptoms of an overdose of ipratropium bromide (such as dry mouth, disturbed accommodation of the eyes), given the greater breadth of the therapeutic effect of the drug and the local route of administration, are usually mild and transient.
Treatment: it is necessary to stop taking the drug. Blood pressure monitoring data should be taken into account. Showing sedatives, tranquilizers, in severe cases – intensive therapy. As a specific antidote, it is possible to use β-blockers, preferably β1-selective blockers. However, you should be aware of the possible increase in bronchial obstruction under the influence of β-blockers and carefully select the dose for patients suffering from bronchial asthma or COPD, due to the danger of severe bronchospasm, which can be fatal.
Dyspnea. In the case of an unexpected rapid increase in shortness of breath (difficulty breathing), you should immediately consult a doctor.
Hypersensitivity. After use of the drug Berodual ®, immediate hypersensitivity reactions may occur, signs in which in rare cases can be urticaria, angioedema, rash, bronchospasm, oropharyngeal edema, anaphylactic shock.
Paradoxical bronchospasm. The drug Berodual ®, like other inhalants, can cause paradoxical bronchospasm, which can be life-threatening. In the event of the development of paradoxical bronchospasm, the use of the drug Berodual ® should be immediately stopped and switched to alternative therapy.
Long-term use. In patients with asthma, Berodual ® should be used only as needed. In patients with a mild form of COPD, symptomatic treatment may be preferable to regular use. Patients with asthma should be aware of the need to conduct or enhance anti-inflammatory therapy to control the inflammatory process of the respiratory tract and the course of the disease.
Regular use of increasing doses of drugs containing β2-adrenomimetics, such as Berodual ®, for the relief of bronchial obstruction can cause an uncontrolled deterioration in the course of the disease. In the case of increased bronchial obstruction, an increase in the dose of β2-agonists, in
Other sympathomimetic bronchodilators should be administered simultaneously with the drug Berodual ® only under medical supervision.
Violations of the gastrointestinal tract. Patients with a history of cystic fibrosis may have gastrointestinal motility disorders.
Violations by the organs of sight. Avoid contact with eyes. Berodual ® should be used with caution in patients prone to acute glaucoma. There are separate reports of complications from the organ of vision (eg, increased IOP, mydriasis, angle-closure glaucoma, eye pain) developed when inhalation ipratropium bromide (or ipratropium bromide in combination with β2-adrenoreceptor agonists) hit the eyes. Symptoms of acute angle-closure glaucoma can be pain or discomfort in the eyes, blurred vision, appearance of aureole in objects and colored spots before the eyes, combined with corneal edema and redness of the eye, due to conjunctival vascular injection. If any composition of these symptoms develops, the use of IOP eye drops is shown, and an immediate consultation with a specialist is indicated. To prevent the solution from getting into the eyes, it is recommended that the solution used with a nebulizer be inhaled through the mouthpiece. In the absence of a mouthpiece, a mask should be used tightly to the face. Particular care should be taken to protect the eyes of patients prone to the development of glaucoma.
System effects For the following diseases: recent myocardial infarction, poorly controlled diabetes mellitus, severe organic heart and vascular diseases, hyperthyroidism, pheochromocytoma, urinary tract obstruction (for example, prostatic hyperplasia or bladder neck obstruction) benefit, especially when using doses higher than recommended.
Impact on the CAS. In postmarketing studies, there were rare cases of myocardial ischemia when taking β-agonists. Patients with concomitant serious heart disease, such as coronary artery disease, arrhythmias, or severe heart failure, who are receiving Berodual ® should consult a doctor if there is pain in the heart or other symptoms that indicate worsening heart disease. You need to pay attention to symptoms such as shortness of breath and chest pain,
Hypokalemia. When using β2-agonists, hypokalemia may occur (see “Overdose”).
In athletes, the use of the drug Berodual ® due to the presence of fenoterol in its composition can lead to positive results of doping tests.
Excipients. The drug contains benzalkonium chloride preservative and disodium edetate dihydrate stabilizer. During inhalation, these components can cause bronchospasm in sensitive patients with airway hyperresponsiveness.
Impact on the ability to drive vehicles and mechanisms. Studies on the effect of the drug on the ability to drive vehicles and mechanisms have not been conducted. Care should be taken when performing these activities,
Solution for inhalation, 0.25 mg + 0.5 mg / ml. On 20 ml in a glass bottle of amber color with a PE-dropper and a screw-in polypropylene cover with control of the first opening. The bottle is placed in a carton box.
Institute de Angeli
The legal entity in whose name the registration certificate is issued. Beringer Ingelheim International GmbH. Binger Strasse 173, 55216 Ingelheim am Rhein, Germany.
You can get more information about the drug, as well as send your claims and information about adverse events at the following address in Russia. Beringer Ingelheim, LLC, 125171 Moscow, Leningradskoye Shosse, 16A, p. 3.
Tel: (495) 544-50-44; fax: (495) 544-56-20.
Pharmacy sales terms
Storage conditions of the drug Berodual ®
Keep out of the reach of children.
The shelf life of the drug Berodual ®
Do not use after the expiration date printed on the package.