Pharmacy No. 84. Delivery of medicines to your home and office.

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Compound

1 ml of solution for inhalation contains the following pharmaceutical components:

ipratropium bromide – 0.261 mg (0.25 mg when converting the dosage form into a dry residue);
fenoterol hydrobromide – 0.5 mg;
benzalkonium chloride;
disodium edetate dihydrate;
sodium chloride;
1-molar hydrochloric acid;
purified water.

Composition of the 1st injection of metered-dose inhalation aerosol:

ipratropium bromide – 0.021 mg (corresponds to 0.02 mg in the mass part of the anhydrous active substance);
fenoterol hydrobromide – 0.05 mg;
1,1,1,2-tetrafluoroethane (HFA 134a) as propellant;
anhydrous citric acid;
ethanol;
distilled water.

Berodual N aeros. d/inhal. doses 20mcg+50mcg/dose 200doses 10ml No.1

Pharmacological action: bronchodilator. Pharmacodynamics Berodual® N contains two components with bronchodilator activity: ipratropium bromide - an m-anticholinergic blocker and fenoterol hydrobromide - a β2-adrenergic agonist. Bronchodilation following inhaled ipratropium bromide is due primarily to local rather than systemic anticholinergic effects. Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. Ipratropium bromide inhibits reflexes caused by the vagus nerve. Anticholinergics prevent the increase in intracellular Ca2+ concentration, which occurs due to the interaction of acetylcholine with the muscarinic receptor located on the smooth muscles of the bronchi. The release of Ca2+ is mediated by a system of secondary mediators, which include inositol triphosphate (ITP) and diacylglycerol (DAG). In patients with bronchospasm associated with COPD (chronic bronchitis and 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 after 1–2 hours and lasted for most patients within 6 hours after administration. Ipratropium bromide does not have a negative effect on mucus secretion in the respiratory tract, mucociliary clearance and gas exchange. Fenoterol hydrobromide selectively stimulates β2-adrenergic receptors at a therapeutic dose. Stimulation of β2-adrenergic receptors activates adenylate cyclase through stimulation of the Gs protein. Stimulation of β1-adrenergic receptors occurs when high doses are used. Fenoterol hydrobromide relaxes the smooth muscles of the bronchi and blood vessels and counteracts the development of bronchospastic reactions caused by the influence of histamine, methacholine, cold air and allergens (immediate hypersensitivity reactions). Immediately after administration, fenoterol blocks the release of mediators of inflammation and bronchial obstruction from mast cells. In addition, when using fenoterol in doses of 0.6 mg, an increase in mucociliary clearance was observed. 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 effect of fenoterol, stimulation of β2-adrenergic receptors of the heart, and when using doses exceeding therapeutic doses, stimulation of β1-adrenergic receptors. As with the use of other β-adrenergic drugs, prolongation of the QTc interval was observed when using high doses. When fenoterol was used via metered-dose aerosol inhalers (MDIs), the effect was inconsistent and occurred at doses higher than recommended. However, following administration of fenoterol via nebulizers (inhalation solution in unit dose vials), systemic exposure may be higher than when using the drug via a MDI at recommended doses. The clinical significance of these observations has not been established. The most commonly observed effect of β-adrenergic agonists is tremor. In contrast to the effects on bronchial smooth muscle, tolerance may develop to the systemic effects of β-adrenergic agonists; the clinical significance of this manifestation is unclear. Tremor is the most common adverse effect with β-adrenergic agonists. When these two active substances are used together, the bronchodilator effect is achieved by acting on various pharmacological targets. These substances complement each other, as a result, the antispasmodic effect on the bronchial muscles is enhanced and a greater breadth of therapeutic action is provided for bronchopulmonary diseases accompanied by constriction of the airways. The complementary effect is such that to achieve the desired effect, a lower dose of the β-adrenergic component is required, which allows you to individually select an effective dose with virtually no side effects. In acute bronchoconstriction, the effect of the drug Berodual® N develops quickly, which allows its use in acute attacks of bronchospasm.

Pharmacokinetics The therapeutic effect of the combination of ipratropium bromide and fenoterol hydrobromide is a consequence of its local action in the respiratory tract. The development of bronchodilation is not parallel to the pharmacokinetic parameters of the active substances. After inhalation, 10–30% of the administered dose of the drug usually enters the lungs (depending on the dosage form and method of inhalation). The remainder of the dose is deposited on the mouthpiece, in the oral cavity and oropharynx. Part of the dose, deposited in the oropharynx, is swallowed and enters the gastrointestinal tract. Part of the drug dose that enters the lungs quickly reaches the systemic bloodstream (within a few minutes). There is no evidence that the pharmacokinetics of the combination drug differs from that of each of the individual components. Fenoterol hydrobromide The ingested portion of the dose is metabolized to sulfate conjugates. Absolute bioavailability when taken orally is low (about 1.5%). After intravenous administration, free and conjugated fenoterol account for 15 and 27% of the administered dose, respectively, in a 24-hour urine analysis. After inhalation, approximately 1% of the administered dose is excreted as free fenoterol in a 24-hour urinalysis. On this basis, the total systemic bioavailability of an inhaled dose of fenoterol hydrobromide is estimated to be 7%. Kinetic parameters describing the distribution of fenoterol were calculated from plasma concentrations after intravenous administration. After IV administration, plasma concentration-time profiles can be described by a three-compartment model, according to which T1/2 is approximately 3 hours. In this three-compartment model, the apparent Vss of fenoterol is approximately 189 L (≥2.7 L/kg). About 40% of fenoterol is bound to plasma proteins. Preclinical studies have shown that fenoterol and its metabolites do not cross the BBB. The total clearance of fenoterol is 1.8 l/min, renal clearance is 0.27 l/min. Cumulative renal excretion (over 2 days) of the isotope-labeled dose (including parent compound and all metabolites) after IV administration was 65%. The total isotope-labeled dose excreted through the intestines was 14.8% after intravenous administration and 40.2% after oral administration within 48 hours. The total isotope-labeled dose excreted through the kidneys was about 39% after oral administration. Ipratropium bromide Cumulative renal excretion (over 24 hours) of the parent compound is approximately 46% of the IV dose, less than 1% of the oral dose, and approximately 3-13% of the inhalation dose. Based on these data, the total systemic bioavailability of ipratropium bromide administered orally and inhaled is calculated to be 2 and 7–28%, respectively. Therefore, the effect of the ingested portion of ipratropium bromide on systemic exposure is negligible. Kinetic parameters describing the distribution of ipratropium bromide were calculated based on its plasma concentrations after intravenous administration. A rapid two-phase decrease in plasma concentration is observed. The apparent Vss is approximately 176 L (>2.4 L/kg). The drug binds to plasma proteins to a minimal extent (less than 20%). Preclinical studies have shown that ipratropium, a quaternary ammonium compound, does not cross the BBB. T1/2 in the final phase is approximately 1.6 hours. The total clearance of ipratropium is 2.3 l/min, and the renal clearance is 0.9 l/min. After IV administration, approximately 60% of the dose is metabolized by oxidation, mainly in the liver. Cumulative renal excretion (over 6 days) of the isotope-labeled dose (including parent compound and all metabolites) was 72.1% after IV administration, 9.3% after oral administration, and 3.2% after inhalation administration. . The total isotope-labeled dose excreted through the intestines was 6.3% after intravenous administration, 88.5% after oral administration, and 69.4% after inhalation administration. Thus, excretion of the isotope-labeled dose after intravenous administration occurs primarily through the kidneys. T1/2 of the parent compound and metabolites is 3.6 hours. The main metabolites excreted in the urine bind weakly to muscarinic receptors and are considered inactive.

Side effects Many of the listed undesirable effects may be a consequence of the anticholinergic and β-adrenergic properties of the drug. Berodual® N, like any inhalation therapy, may cause local irritation. Adverse reactions to the drug were determined based on data obtained in clinical trials and during pharmacological surveillance 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, palpitations, vomiting, increased systolic blood pressure and nervousness. The frequency of adverse reactions that may occur during therapy is given in the following gradation: very often (≥1/10); often (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); unspecified frequency (frequency cannot be estimated from available data). From the immune system: rarely* - anaphylactic reaction, hypersensitivity. Metabolism and nutrition: rarely* - hypokalemia. Mental disorders: infrequently - nervousness; rarely - agitation, mental disturbances. From the nervous system: infrequently - headache, tremor, dizziness. From the organ of vision: rarely* - glaucoma, increased IOP, accommodation disturbances, mydriasis, blurred vision, eye pain, corneal edema, conjunctival hyperemia, the appearance of a halo around objects. From the cardiovascular system: infrequently - increased heart rate, tachycardia, palpitations; rarely - arrhythmia, atrial fibrillation, supraventricular tachycardia*, myocardial ischemia*. From the respiratory system, chest and mediastinum: often - cough; infrequently - pharyngitis, dysphonia; rarely - bronchospasm, pharyngeal irritation, pharyngeal edema, laryngospasm*, paradoxical bronchospasm*, dry throat*. From the gastrointestinal tract: infrequently - vomiting, nausea, dry mouth; rarely - stomatitis, glossitis, gastrointestinal motility disorders, diarrhea, constipation*, oral edema*. From the skin and subcutaneous tissues: rarely - urticaria, itching, rash, angioedema, hyperhidrosis*. From the musculoskeletal system and connective tissue: rarely - muscle weakness, muscle spasm, myalgia. From the kidneys and urinary tract: rarely - urinary retention. Laboratory and instrumental data: infrequently - increased systolic blood pressure; rarely - increased blood pressure. * These adverse reactions were not identified during clinical trials of the drug Berodual® N. The assessment was made based on the upper limit of the 95% CI calculated for the general patient population.

Interaction Long-term simultaneous use of Berodual® N with other anticholinergic drugs is not recommended due to the lack of data. β-adrenergic and anticholinergic drugs, xanthine derivatives (for example, theophylline) can enhance the bronchodilator effect of the drug Berodual® N. Simultaneous administration of other β-adrenergic agonists that enter the systemic circulation of anticholinergic drugs or xanthine derivatives (for example, theophylline) may lead to increased side effects effects. A significant weakening of the bronchodilator effect of the drug Berodual® N is possible with the simultaneous administration of β-blockers. Hypokalemia associated with the use of β-adrenergic agonists can be enhanced by the simultaneous administration of xanthine derivatives, corticosteroids and diuretics. This should be given special attention when treating patients with severe forms of obstructive airway disease. Hypokalemia may lead to an increased risk of arrhythmias in patients receiving digoxin. In addition, hypoxia may enhance the negative effects of hypokalemia on heart rate. In such cases, it is recommended to monitor serum potassium concentrations. Beta2-adrenergic agents should be prescribed with caution to patients receiving MAO inhibitors and tricyclic antidepressants, because these drugs can enhance the effect of β-adrenergic drugs. Inhalation of halogenated hydrocarbon anesthetics, such as halothane, trichlorethylene or enflurane, may increase the adverse effects of beta-adrenergic agents on the cardiovascular system.

Overdose Symptoms: usually associated primarily with the action of fenoterol. Symptoms associated with excessive stimulation of β-adrenergic receptors may occur. The most likely occurrence is tachycardia, palpitations, tremor, arterial hypertension or hypotension, increased pulse pressure, angina pain, arrhythmias and hot flashes, metabolic acidosis, and hypokalemia. Symptoms of an overdose of ipratropium bromide (such as dry mouth, impaired eye accommodation), given the wide breadth of the therapeutic effect of the drug and the local method of administration, are usually mild and transient. Treatment: you must stop taking the drug. Data from monitoring the acid-base balance of the blood should be taken into account. Sedatives and tranquilizers are indicated, and in severe cases, intensive care. As a specific antidote, it is possible to use β-blockers, preferably β1-selective blockers. However, one should be aware of the possible increase in bronchial obstruction under the influence of beta-blockers and carefully select the dose for patients suffering from bronchial asthma or COPD due to the risk of severe bronchospasm, which can be fatal.

Special instructions Shortness of breath. If shortness of breath (difficulty breathing) suddenly increases rapidly, you should consult a doctor immediately. Hypersensitivity. After using the drug Berodual® N, immediate hypersensitivity reactions may occur, signs of which in rare cases may include urticaria, angioedema, rash, bronchospasm, oropharyngeal edema, anaphylactic shock. Paradoxical bronchospasm. Berodual® N, like other inhaled drugs, can cause paradoxical bronchospasm, which can be life-threatening. If paradoxical bronchospasm develops, the use of Berodual® N should be stopped immediately and switched to alternative therapy. Long-term use. In patients suffering from bronchial asthma, Berodual® N should be used only as needed. In patients with mild COPD, symptomatic treatment may be preferable to regular use. In patients with bronchial asthma, one should remember the need to carry out or intensify 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-adrenergic agonists, such as Berodual® N, to relieve bronchial obstruction can cause uncontrolled worsening of the disease. In case of increased bronchial obstruction, increase the dose of β2-agonists, incl. Berodual® N, more than recommended for a long time is not only not justified, but also dangerous. To prevent life-threatening worsening of the disease, consideration should be given to reviewing the patient's treatment plan and adequate anti-inflammatory therapy with inhaled corticosteroids. Other sympathomimetic bronchodilators should be prescribed simultaneously with Berodual® N only under medical supervision. Gastrointestinal disorders. In patients with a history of cystic fibrosis, gastrointestinal motility disorders are possible. Visual disorders. Avoid contact of the drug with the eyes. Berodual® N should be used with caution in patients predisposed to acute-angle glaucoma. There are isolated reports of complications from the organ of vision (for example, increased IOP, mydriasis, angle-closure glaucoma, eye pain) that developed when inhaled ipratropium bromide (or ipratropium bromide in combination with β2-adrenergic receptor agonists) came into contact with the eyes. Symptoms of acute angle-closure glaucoma may include pain or discomfort in the eyes, blurred vision, the appearance of a halo on objects and colored spots in front of the eyes in combination with corneal edema and redness of the eyes due to conjunctival vascular injection. If any combination of these symptoms develops, the use of eye drops that lower IOP and immediate consultation with a specialist is indicated. Systemic effects. For the following diseases: recent myocardial infarction, diabetes mellitus with inadequate glycemic control, severe organic diseases of the heart and blood vessels, hyperthyroidism, pheochromocytoma or urinary tract obstruction (for example, prostatic hyperplasia or bladder neck obstruction), Berodual® N should be used only after careful risk/benefit assessment, especially when using doses higher than recommended. Impact on cardiovascular system. In post-marketing studies, rare cases of myocardial ischemia have been reported when taking beta-agonists. Patients with concomitant serious heart disease, such as coronary artery disease, arrhythmias or severe heart failure, receiving Berodual® N should consult a doctor if chest pain or other symptoms indicating worsening of heart disease occur. It is necessary to pay attention to symptoms such as shortness of breath and chest pain, because... they can be of both cardiac and pulmonary etiology. Hypokalemia. When using β2-agonists, hypokalemia may occur (see "Overdose"). In athletes, the use of the drug Berodual® N due to the presence of fenoterol in its composition can lead to positive results of doping tests. Please note that the drug contains a small amount of ethanol (13.313 mg per dose). Impact on the ability to drive vehicles and machinery. Studies have not been conducted to study the effect of the drug on the ability to drive vehicles and operate machinery. Care should be taken when performing these activities as... possible development of dizziness, tremor, impaired eye accommodation, mydriasis and blurred vision. If the above undesirable sensations occur, you should refrain from such potentially dangerous actions as driving vehicles and machinery.