Pharmacological properties of the drug Berotek N
Pharmacodynamics. In clinical studies lasting up to 3 months in adults with asthma, COPD and children with asthma, it was found that tetrafluoroethane and freon-containing forms of an aerosol inhaler have the same therapeutic efficacy. Fenoterol hydrobromide is a sympathomimetic agent; in a therapeutic dose, it selectively stimulates β2-adrenergic receptors; when used in higher doses, it loses its selectivity of action and stimulates β1-adrenergic receptors. The binding of the drug to β2-adrenergic receptors leads to the activation of adenylate cyclase by stimulating the Gs protein. When the concentration of cAMP increases, protein kinase A is activated, which ensures phosphorylation of target proteins in smooth muscle cells. This in turn leads to phosphorylation of myosin light chain kinase, inhibition of phosphoinositide hydrolysis and opening of large calcium-dependent potassium channels. There is evidence that large potassium channels can be activated directly by Gs protein. Fenoterol relaxes the smooth muscles of the bronchi and prevents the development of bronchospasm caused by exposure to histamine, methacholine, cold air and allergens (immediate hypersensitivity reactions). Immediately after use, fenoterol blocks the release of mediators of inflammation and bronchial obstruction from mast cells. In addition, after the use of fenoterol in higher doses, an increase in mucociliary clearance is noted. At high concentrations of the drug in the blood plasma, which is usually achieved by oral or intravenous administration, a decrease in the contractile activity of the myometrium is noted. When using the drug in high doses, metabolic effects such as lipolysis, glycogenolysis, hyperglycemia and hypokalemia have been identified; the latter is caused by increased uptake of K+ ion, primarily by skeletal muscles. The β-adrenergic effect of the drug on cardiac activity is an increase in the frequency and strength of heart contractions due to the vascular effect of fenoterol, stimulation of β2-adrenergic receptors, and when used in doses exceeding therapeutic doses, stimulation of cardiac β1-adrenergic receptors. In contrast to the effect on bronchial smooth muscle, the systemic effect of β-agonists causes the development of tolerance. Clinical studies have established the high therapeutic effectiveness of fenoterol in bronchospastic conditions. Fenoterol eliminates bronchospasm caused by various stimulants (for example, cold air), as well as immediate bronchospastic reactions upon contact with an allergen. The therapeutic effect of Berotek N is due to its local effect on the respiratory tract. The pharmacodynamic properties of bronchodilation caused by Berotec N do not relate to the pharmacokinetics of the active substance of the drug. After inhalation of fenoterol hydrobromide for obstructive pulmonary diseases, bronchodilation develops within a few minutes and lasts 3–5 hours. Depending on the method of inhalation and the inhaler used, about 10–30% of the active ingredient reaches the lower respiratory tract, while the remainder of the drug settles in the upper parts of the respiratory tract and in the oral cavity, some of it is swallowed and enters the digestive tract. After inhalation of 1 dose, about 17% of the drug is absorbed; two-phase absorption - 30% of fenoterol is rapidly absorbed with a half-absorption period of 11 minutes, and 70% is slowly absorbed with a half-absorption period of 120 minutes. There is no correlation between plasma concentrations and the pharmacodynamic response time curve after inhalation. The difference in the duration of bronchodilator action after inhalation, compared with intravenous administration, is not confirmed by systemic plasma levels. After oral administration, about 60% of fenoterol hydrobromide is absorbed and undergoes first-pass metabolism, resulting in oral bioavailability of approximately 1.5%. This is why an ingested portion of the active ingredient has virtually no effect on systemic plasma levels after inhalation. With systematic use, the elimination of fenoterol hydrobromide is three-phase with half-lives for successive phases of 0.42 minutes, 14.3 minutes and 3.2 hours. Metabolic transformation of fenoterol hydrobromide occurs almost entirely by sulfation, mainly in the intestinal wall. In unchanged form, fenoterol hydrobromide can cross the placenta and enter breast milk. There is insufficient data regarding the effect of fenoterol hydrobromide on the metabolic state in diabetes mellitus.
Instructions for use BEROTEK N (BEROTEC N)
Suction
Depending on the method of inhalation and the inhalation system used, about 10-30% of the active substance released from the aerosol preparation after inhalation reaches the lower respiratory tract, and the rest is deposited in the upper respiratory tract and in the mouth. As a result, some amount of inhaled fenoterol enters the gastrointestinal tract. The absolute bioavailability of fenoterol after inhalation of one dose of BEROTEKA® N is 18.%. Absorption from the lungs is two-phase:
- 30% of fenoterol hydrobromide is rapidly absorbed with a T1/2 of 11 minutes, and 70% is absorbed slowly with a T1/2 of 120 minutes.
Cmax of the drug in blood plasma (Cmax 45.3 pg/ml) was observed 15 minutes after a single inhalation of 100 mcg of fenoterol using a metered-dose inhaler with freon in patients with bronchial asthma. However, in studies involving healthy volunteers, in which blood tests were taken more frequently, it was found that serum Cmax of the drug was achieved earlier: 2 and 3.5 minutes after dosing. Cmax of the drug in serum after inhalation of a single dose of fenoterol 200 mcg using an HFA metered dose inhaler:
- Cmax 66.9 pg/ml, tmax15 minutes.
The therapeutic effect of BEROTEK N is achieved by its local action on the airways. Thus, Cmax in blood plasma is not necessarily related to the bronchodilator effect.
After oral administration, the degree of absorption is 60% of the administered dose of fenoterol hydrobromide. This amount undergoes extensive first-pass metabolism, resulting in a bioavailability of approximately 1.5%. Thus, the ingested portion of the active substance has only a minor effect on Cmax in blood plasma after inhalation.
Distribution
Fenoterol is distributed throughout the body. The volume of distribution at steady state after intravenous administration (Vss) is 1.9-2.7 l/kg. Vd of fenoterol in blood plasma after intravenous administration occurs according to a three-phase pharmacokinetic model. T1/2 are tα= 0.2 minutes, tβ= 14.3 minutes and tγ= 3.2 hours. Plasma protein binding ranges from 40 to 55%.
Metabolism
The biotransformation of fenoterol hydrobromide in humans occurs through conjugation with sulfates. Following oral administration, fentorerol is metabolized primarily through sulfation. This metabolic inactivation of the parent substance begins already in the intestinal walls.
Removal
Biotransformation, including biliary excretion, is due mainly (approximately 85%) to the average total clearance of 1.1-1.8 l/min. after intravenous administration. Renal excretion of fenoterol (0.27 L/min) corresponds to approximately 15% of the average total clearance of the systemically available dose. Considering the part of the drug that binds to plasma proteins, the renal clearance value indicates tubular secretion of fenoterol in addition to glomerular filtration.
After oral and IV administration, the total radioactivity excreted in urine is approximately 39% and 65% of the dose, and the total radioactivity excreted in feces is 40.2% and 14.8% of the dose over 48 hours, respectively. After oral administration, 0.38% of the dose is excreted unchanged into the urine, while with intravenous administration - 15%. After inhalation using a metered dose inhaler, 2% of the dose is excreted unchanged in the urine within 24 hours.
In unchanged form, fenoterol hydrobromide can cross the placental barrier and enter breast milk.
The metabolism of fenoterol hydrobromide in diabetes has not been sufficiently studied.
Use of the drug Berotek N
Attack of asthma. In most cases, 1 dose inhalation is sufficient to relieve an asthma attack; if after 5 minutes the effect is insufficient, inhalation can be repeated. If the attack does not resolve with two doses and there is a need for further inhalation, the patient should immediately seek medical help. Prevention of exercise-induced asthma: 1-2 doses per inhalation, but not more than 8 doses per day. Asthma and other conditions with reversible bronchial obstruction: 1–2 inhalations per dose, if repeated inhalations are necessary, but not more than 8 inhalations per day. Children should use Berotec N 100 mcg metered dose aerosol only as prescribed by a doctor under adult supervision.
BEROTEK N
Directions for use and doses
Doses for adults and adolescents over 12 years of age
Attacks of bronchial asthma and other conditions accompanied by reversible airway obstruction
In most cases, one inhalation dose is sufficient to relieve bronchospasm; If breathing relief does not occur within 5 minutes, inhalation can be repeated.
If there is no effect after two inhalations and additional inhalations are required, you should immediately seek medical help at the nearest hospital. Prevention of asthma by physical effort
1-2 inhalation doses before physical activity, up to 8 inhalations per day.
Doses for children from 6 to 12 years
Attacks of bronchial asthma and other conditions accompanied by reversible airway obstruction
In most cases, one inhalation dose is sufficient to relieve bronchospasm; If breathing relief does not occur within 5 minutes, inhalation can be repeated.
If there is no effect after two inhalations and additional inhalations are required, you should immediately seek medical help at the nearest hospital. Prevention of asthma by physical effort
1-2 inhalation doses before physical activity, up to 8 inhalations per day.
Doses for children from 4 to 6 years
Due to limited experience with children under 6 years of age, the drug should be used only as directed by a physician and under adult supervision.
Attacks of bronchial asthma and other conditions accompanied by reversible airway obstruction
To relieve bronchospasm, one inhalation dose is sufficient.
If there is no effect, you should immediately seek medical help at the nearest hospital.
Prevention of asthma by physical effort
1 inhalation dose before physical activity, up to 4 inhalations per day.
Mode of application
To achieve maximum effect, it is necessary to use a dosed aerosol correctly.
Before using metered dose aerosol for the first time, press the bottom of the can twice.
Each time you use a metered dose aerosol, the following rules must be observed:
1. Remove the protective cap.
2. Exhale slowly and completely.
3. Hold the can as shown in Fig. 1 and tightly wrap your lips around the tip. In this case, the arrow and the bottom of the inhaler are facing upward.
4. While inhaling as deeply as possible, simultaneously quickly press the bottom of the can until the inhalation dose is released. Hold your breath for a few seconds, then remove the mouthpiece from your mouth and exhale slowly.
If repeated inhalation is required, repeat the same steps (steps 2-4).
5. Put on the protective cap.
6. If the aerosol can has not been used for more than three days, press the bottom of the can once before use.
The cylinder is designed for 200 inhalations. After this, the cylinder should be replaced. Although some drug may remain in the canister, the amount of drug released during inhalation may be reduced. The cylinder is opaque, so the amount of drug in the cylinder can only be determined in the following way: by removing the protective cap, the cylinder is immersed in a container filled with water. The amount of the drug is determined depending on the position of the cylinder in the water (see Fig. 2).
The inhaler should be washed at least once a week.
It is important to keep the mouthpiece of your inhaler clean so that medication does not accumulate and block the spray.
To clean, first remove the dust cap and remove the container from the inhaler. Rinse the inhaler with warm water to remove any accumulated medication and/or visible dust (see Figure 3).
After cleaning, shake the inhaler and allow it to air dry without using heating devices. When the mouthpiece is dry, return the container and dust cap to their place (see Fig. 4).
WARNING: The plastic mouthpiece is designed specifically for Berotek® N and is used for precise dosing of the drug. The mouthpiece should not be used with other metered dose aerosols. Also, Berotec® N should not be used with any adapters other than the mouthpiece supplied with the drug.
The contents of the cylinder are under pressure. The container must not be opened or heated above 50°C.
Side effects of the drug Berotec N
The most common side effects are skeletal muscle tremor, irritability, headache, dizziness, sinus tachycardia and palpitations. The possibility of developing severe hypokalemia cannot be excluded. As with the use of other inhaled agents, cough, local irritation, and paradoxical bronchospasm are possible. Berotec N, like other β-adrenergic agonists, can cause nausea, vomiting, hyperhidrosis, general weakness, myalgia, and muscle cramps. In some cases, especially after using the drug in high doses, a decrease in diastolic blood pressure, an increase in systolic blood pressure, and arrhythmia were noted. In case of hypersensitivity, allergic skin reactions were rarely observed. Psychiatric agitation has been reported in isolated cases during inhaled therapy with β-mimetics.
Berotek N air 100 mcg 200 doses (Behringer)
Adults and adolescents over 12 years of age Attacks of bronchial asthma and other conditions accompanied by reversible airway obstruction In most cases, 1 inhalation dose is sufficient to relieve bronchospasm; if breathing relief does not occur within 5 minutes, you can repeat the inhalation. If there is no effect after 2 inhalations and additional inhalations are required, you should immediately consult a doctor. Prevention of exercise asthma 1-2 inhalation doses before physical activity, up to 8 inhalations / day .Children from 6 to 12 years old. Attacks of bronchial asthma and other conditions accompanied by reversible obstruction of the airways. In most cases, 1 inhalation dose is sufficient to relieve bronchospasm; if breathing relief does not occur within 5 minutes, you can repeat the inhalation. If there is no effect after 2 inhalations, and additional inhalations are required, you should immediately seek medical help. Prevention of exercise asthma 1-2 inhalation doses before physical activity, up to 8 inhalations/ days. Children from 4 to 6 years old. Due to limited experience in children under 6 years of age, the drug should be used only as prescribed by a doctor and under adult supervision. Attacks of bronchial asthma and other conditions accompanied by reversible obstruction of the airways. To relieve bronchospasm, 1 dose is sufficient. inhalation dose. If there is no effect, you should immediately seek medical help. Prevention of exercise asthma 1 inhalation dose before physical activity, up to 4 inhalations/day. Rules for using the drug To achieve the maximum effect, you must use the metered-dose aerosol correctly. Before using the metered-dose aerosol for the first time, press twice to the bottom of the can. Each time when using a metered aerosol, the following rules must be observed. The can is designed for 200 inhalations. Then the cylinder should be replaced. Although some contents may remain in the canister, the amount of drug released during inhalation is reduced. The inhaler should be rinsed at least once a week. It is important to keep the inhaler mouthpiece clean to ensure that medication does not accumulate and block the nebulization. For cleaning, first remove the dust cap and remove the container from the inhaler. Rinse the inhaler with warm water to remove any accumulated medication and/or visible dust. After cleaning, shake the inhaler and allow it to air dry without using heating devices. When the mouthpiece is dry, return the container and dust cap to its place. The plastic mouthpiece is designed specifically for Berotec® N metered-dose aerosol and serves for precise dosing of the drug. The mouthpiece should not be used with other metered dose aerosols. Berotec® N metered dose aerosol cannot also be used with other adapters.
Special instructions for the use of the drug Berotek N
During pregnancy and breastfeeding. No negative effects have been identified when using the drug during pregnancy. However, special care must be taken when taking it in the first trimester of pregnancy. It is necessary to take into account the inhibitory effect of fenoterol on uterine contractility. Fenoterol passes into breast milk; The safety of using the drug during breastfeeding has not been established. The need for simultaneous anti-inflammatory therapy in patients with asthma and patients with steroid-dependent COPD should be considered. When using the new Berotec N metered-dose aerosol for the first time, some patients may note that its taste is slightly different from the previous aerosol containing freon. Patients should be informed about this when prescribing the new Berotec N metered dose aerosol, and also that both dosage forms of the aerosol are interchangeable and identical in their properties, and the difference in taste does not affect the effectiveness and safety of the drug. Concomitant use with other sympathomimetic bronchodilators should only be done under medical supervision. Anticholinergic bronchodilators can be used for inhalation simultaneously with Berotec N. In some situations, especially at doses higher than recommended, Berotec N should be used only after a careful assessment of the risk/benefit ratio. Such situations include poorly controlled diabetes mellitus, recent myocardial infarction, severe organic lesions of the heart or blood vessels, hyperthyroidism, and pheochromocytoma. In case of sudden development and rapid progression of shortness of breath, the patient should immediately consult a doctor. With long-term use of the drug, “as needed” administration is more preferable than regular use. The use of the drug does not exclude the simultaneous use of basic anti-inflammatory therapy (for example, inhaled corticosteroids) for asthma and COPD to prevent the progression of pathological changes in the lungs. With increasing bronchial obstruction, exceeding the recommended dose of a drug containing β2-agonists, such as Berotec N, may lead to further deterioration of the patient's condition. Use of β2-agonists such as Berotec N in high doses over a long period of time may lead to worse control of symptoms of bronchial obstruction. In this situation, to prevent a potentially life-threatening condition, it is necessary to review the treatment regimen and especially the adequacy of anti-inflammatory therapy. Severe hypokalemia may occur during therapy with β2-adrenergic agonists. Particular attention is necessary in severe forms of asthma, since in this case hypokalemia can be potentiated by the simultaneous administration of xanthine derivatives, corticosteroids, and diuretics. In addition, hypoxia as a symptom of asthma can enhance the negative effect of hypokalemia on heart rate. In such situations, monitoring serum potassium levels is recommended. Warning. The cylinder is designed for 200 inhalations. After using 200 doses, it must be replaced, even if it contains a residual amount of the drug. The plastic tip is specially designed for Berotek N metered aerosol and serves for precise dosing. The tip is not recommended for use with other metered aerosols. The inhalation tip should be kept clean and, if necessary, can be washed with warm water. After using soap or detergent, rinse the handpiece thoroughly with clean water.
Berotec N aerosol dosed for inhalation 100 µg/dose 10 ml (200 doses) No. 1
Name
Berotek N aer.dose.d/ing.100mcg/dose in vial. 10ml (200 doses) per pack. No. 1
Description
10 ml in a metal can with a dosing valve. Spray can with instructions for use in a cardboard box
Main active ingredient
Ipratropium bromide + fenoterol
Release form
Aerosol
Dosage
20mcg+50mcg/dose
Pharmacological properties
Pharmacodynamics
BERODUAL N contains two components with bronchodilator activity: ipratropium bromide (m-anticholinergic blocker) and fenoterol hydrobromide (beta-adrenergic agonist). Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. Preclinical studies have shown that it inhibits reflexes mediated by the vagus nerve by counteracting the effect of acetylcholine, a neurotransmitter released from this nerve. Anticholinergics prevent the increase in intracellular calcium concentration, which is caused by the interaction of acetylcholine with the muscarinic receptor of bronchial smooth muscle. The release of calcium is mediated by a system of second messengers consisting of IPG (inositol triphosphate) and DAG (diacylglycerol). Bronchodilation that occurs after inhalation of ipratropium bromide is a local and lung-specific effect that is not systemic. Fenoterol hydrobromide is a direct-acting sympathomimetic, a selective stimulator of beta2-adrenergic receptors when taken in therapeutic doses. Stimulation of beta1-adrenergic receptors occurs when the drug is used in higher doses (for example, during tocolytic therapy). Binding of beta2-adrenergic receptors activates adenylate cyclase through the stimulatory Gs protein with a subsequent increase in the formation of cAMP, which in turn activates protein kinase A. The latter phosphorylates target proteins in smooth muscle cells. This results in phosphorylation of myosin light chain kinase, inhibition of phosphoinosine hydrolysis, and opening of calcium-dependent fast potassium channels. Fenoterol hydrobromide relaxes the smooth muscles of the bronchi and blood vessels, and also prevents the development of bronchospasm caused by the effects of bronchoconstrictor factors such as histamine, methacholine, cold air and allergens (immediate reaction). After taking the drug, the release of inflammatory mediators from mast cells is inhibited. In addition, after taking 0.6 mg of fenoterol, an increase in mucociliary transport is observed. Higher plasma concentrations of the drug, achieved after oral or, more often, intravenous administration, inhibit uterine contractility. When taking high doses of the drug, effects are observed at the metabolic level: lipolysis, glycogenolysis, hyperglycemia and hypokalemia (the latter is due to increased absorption of K+ by skeletal muscles). The beta-adrenergic effects of the drug at the level of the heart muscle, such as an increase in heart rate and increased myocardial contractility, are explained by the effect of fenoterol on blood vessels, stimulation of beta2-adrenergic receptors of the heart, and when taking the drug in doses exceeding therapeutic doses, stimulation of beta1-adrenergic receptors. As with other beta-adrenergic agents, prolongation of the QTc interval has been reported. For fenoterol administered by metered dose inhaler, these events were discrete and occurred at doses higher than recommended. However, systemic exposure after administration of the drug using nebulizers (inhalation solution) was higher than when administering recommended doses using a metered dose inhaler. Clinical significance has not been established. The most commonly observed effect of beta-agonists is tremor. In contrast to the effects on bronchial smooth muscle, the systemic effects of beta-adrenergic agonists are associated with the development of tolerance. 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 narrowing of the airways. The complementary effect is such that to achieve the desired effect, a lower dose of beta-agonist is required, which allows you to individually select an effective dose with virtually no side effects.
Pharmacokinetics
The therapeutic effect of the combination of ipratropium bromide and fenoterol hydrobromide is created by local action on the respiratory tract. Therefore, the pharmacodynamics of bronchodilation is not related to the pharmacokinetics of the active substances. After inhalation, 10-39% of the dose, depending on the dosage form, inhalation method and the device used for inhalation, is deposited in the lungs. The rest of the dose remains in the mouthpiece, mouth, and upper respiratory tract (oropharynx). The same amount of dose is deposited in the respiratory tract after inhalation of a metered dose aerosol. After inhalation of an aqueous solution through the Respimat inhaler, the amount entering the lungs was 2 times higher compared to inhalation with a metered-dose aerosol, while when inhaled through the Respimat inhaler, a much smaller amount of the active substance settles in the oropharynx. A portion of the dose that reaches the lungs quickly enters the circulatory system (within minutes). The active substance, deposited in the oropharynx, is slowly swallowed and passes through the gastrointestinal tract. Therefore, systemic exposure results from bioavailability from the lungs and gastrointestinal tract. There is no data indicating that the pharmacokinetics of both ingredients in combination differs from the pharmacokinetics of the active substances individually. Fenoterol hydrobromide The ingested portion is metabolized primarily to complex sulfate compounds. The absolute bioavailability of the drug when administered orally is low (about 1.5%). After intravenous administration of fenoterol in the urine for 24 hours, about 15% and 27% of the administered dose, respectively, are found in the free and conjugated state. After inhalation of BERODUAL N using a metered dose inhaler, about 1% of the dose is excreted as free fenoterol in the urine within 24 hours. Based on this information, the calculated total systemic bioavailability of fenoterol hydrobromide after inhalation administration is approximately 7%. The distribution of fenoterol in blood plasma after intravenous administration occurs according to a three-phase pharmacokinetic model, the final half-life is about 3 hours. In this three-phase pharmacokinetic model, the apparent volume of distribution at steady state (Vdss) is approximately 189 L (? 2.7 L/kg). About 40% of the substance binds to blood plasma proteins. Fenoterol and its metabolites do not penetrate the blood-brain barrier. The total clearance of fenoterol is 1.8 l/min, renal clearance is 0.27 l/min. Ipratropium bromide Cumulative renal excretion (0-24 hours) of ipratropium (parent compound) approaches 46% of the intravenous dose, less than 1% of the oral dose, and approximately 3-13% of the BERODUAL N dose administered by metered dose inhaler. Based on these data, the overall systemic bioavailability of ipratropium bromide for oral and inhaled administration is 2% and 7 to 28%, respectively. The ingested portion of the dose of ipratropium bromide does not have a significant systemic effect. Kinetic parameters characterizing the distribution of ipratropium were calculated based on plasma concentrations of the drug after intravenous administration. A rapid two-phase decrease in plasma concentrations is observed. The apparent volume of distribution at equilibrium (Vdss) is approximately 176 L (“2.4 L/kg). The drug minimally (less than 20%) binds to blood plasma proteins. Preclinical studies conducted on mice and dogs showed that ipratropium, being a quaternary amine; does not penetrate the blood-brain barrier. The half-life of the final elimination 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 intravenous administration, approximately 60% of the dose is metabolized in the liver by oxidation.
Indications for use
Prevention and treatment of shortness of breath in chronic obstructive disorders of the respiratory tract: allergic and non-allergic (endogenous) bronchial asthma, physical exertion asthma, chronic obstructive bronchitis, complicated or uncomplicated by emphysema. To prepare (“open the lungs”) and maintain aerosol therapy with corticosteroids, mucolytics, saline solutions, cromoglycic acid and antibiotics. Long-term treatment should be accompanied by appropriate anti-inflammatory therapy.
Directions for use and doses
The dosage depends on the nature and severity of the disease. For adults and children over 6 years of age, the following doses are recommended: To relieve a sudden spasm of bronchial smooth muscles with an attack of shortness of breath, inhalation of one therapeutic dose (100 mcg of fenoterol hydrobromide and 40 mcg of ipratropium bromide), which corresponds to 2 inhalation doses, is recommended. As a rule, one inhalation dose is sufficient to provide a significant improvement in bronchial patency. If there is no noticeable improvement within 5 minutes after the first 1-2 inhalation doses, another 1-2 inhalation doses may be used. Severe dyspnea and failure of the second therapeutic dose may indicate the need for additional doses. In these cases, patients should seek medical attention immediately. If long-term treatment with the BERODUAL N metered dose inhaler is necessary, the recommended dose is 1-2 inhalation doses 3-4 times a day. For the treatment of bronchial asthma, the BERODUAL N metered dose inhaler should be used only as needed. In general, the time and dose of each administration should be adjusted according to the symptoms. It is necessary to ensure at least a 3-hour interval between drug administration. The daily dose should not exceed 12 inhalation doses, since higher doses usually do not provide additional therapeutic effect, but may lead to the development of potentially serious side effects. For targeted prevention of asthma attacks during physical exertion or when contact with an allergen is expected, it is recommended to take 2 inhalation doses of the drug 10-15 minutes before the expected physical activity/contact with the allergen. To achieve successful therapy, patients must be instructed on how to properly use the metered dose inhaler
Use during pregnancy and lactation
Pregnancy Data from preclinical studies, combined with existing experience with the drug in humans, have not revealed any side effects of fenoterol or ipratropium during pregnancy. However, normal precautions should be taken when using medications during pregnancy. It is necessary to take into account the ability of fenoterol to have a suppressive effect on uterine contractility. The use of betag-agonists at the end of pregnancy or in high doses can cause negative effects in newborns (tremor, tachycardia, fluctuations in blood glucose levels, hypokalemia). Breastfeeding period Preclinical studies have shown the ability of fenoterol to be excreted in breast milk. There is no data confirming the excretion of ipratropium bromide in breast milk. The appearance of ipratropium after inhalation administration in breast milk in a concentration that can affect the infant is unlikely. When using BERODUAL N in a woman during breastfeeding, caution should be exercised. Fertility There are no clinical data on the effect of the combination of ipratropium bromide and fenoterol hydrobromide on fertility. Preclinical studies conducted with ipratropium bromide and fenoterol hydrobromide individually did not demonstrate a negative effect on fertility.
Precautionary measures
If shortness of breath (difficulty breathing) suddenly increases rapidly, you should consult a doctor immediately. 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. BERODUAL N should be used only after a careful assessment of the risk/benefit ratio, especially when using doses higher than recommended in the following diseases: diabetes mellitus with inadequate glycemic control, recent myocardial infarction, myocarditis, severe organic diseases of the heart or blood vessels (in particular, in the presence of tachycardia), hyperthyroidism, pheochromocytoma. When using sympathomimetic drugs, including BERODUAL N, effects on the cardiovascular system may occur. Post-marketing studies and published literature have reported rare cases of myocardial ischemia with beta-agonists. Patients with underlying serious heart disease (eg, coronary artery disease, arrhythmias, or severe heart failure) receiving BERODUAL N should be warned to seek medical attention if they experience heart pain or other symptoms indicating worsening of their heart disease. It is necessary to pay attention to symptoms such as shortness of breath and chest pain, as they can be of either pulmonary or cardiac etiology. There are isolated reports of complications from the organ of vision (for example, mydriasis, increased intraocular pressure, angle-closure glaucoma and eye pain) that developed when inhaled ipratropium bromide or ipratropium bromide in combination with beta-adrenergic agonists came into contact with the eyes. Attention! Patients should be instructed on the correct use of BERODUAL N metered dose aerosol. Care must be taken to prevent contact of the drug with the eyes. Symptoms of acute angle-closure glaucoma may include pain or discomfort in the eyes, blurred vision, halo, colored spots in front of the eyes, redness of the eyes due to injection of conjunctival vessels and corneal edema. If any of these symptoms appear, immediate consultation with a specialist is necessary and the use of miotic agents is indicated. In patients with a history of cystic fibrosis, gastrointestinal motility disorders may occur when treated with inhaled anticholinergic drugs. This effect is reversible and disappears after stopping treatment. Long-term use of the drug In patients with bronchial asthma, BERODUAL N should be used only as needed. In patients with mild chronic obstructive pulmonary disease, on-demand symptomatic treatment may be preferable to regular use of the drug. In patients with bronchial asthma or chronic obstructive pulmonary disease responding to steroid therapy, the need for or intensification of anti-inflammatory therapy should be remembered to control airway inflammation and the course of the disease. In patients with bronchial asthma, regular use of increasing doses of drugs containing betag-agonists, such as BERODUAL N, to relieve bronchial obstruction, can cause an uncontrolled worsening of the disease. In case of increased bronchial obstruction, increasing the dose of beta-adrenergic agonists, including 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, or adjusting the dose of anti-inflammatory therapy. An increased risk of serious complications of bronchial asthma, including fatal ones, has been reported when using high and very high doses of inhaled beta2-agonists for a long period of time without adequate anti-inflammatory therapy. The cause-and-effect relationship has not been clearly established. Inadequacy of anti-inflammatory therapy may be of vital importance. Other sympathomimetic bronchodilators should be prescribed simultaneously with BERODUAL N only under medical supervision. Potentially severe hypokalemia may occur when high doses of beta2-agonists are used. It is recommended to monitor the concentration of potassium in the blood if its level is initially low. Blood glucose levels may increase. In this regard, it is recommended to monitor blood glucose levels in patients with diabetes mellitus. After using BERODUAL N, in rare cases, immediate hypersensitivity reactions may occur: urticaria, angioedema, rash, bronchospasm; swelling of the oropharynx and allergic reactions. This medicine contains 99% ethanol (alcohol; less than 100 mg/dose). The use of BERODUAL N may lead to positive doping test results.
Interaction with other drugs
Long-term co-administration of BERODUAL N with other anticholinergic drugs has not been studied and is therefore not recommended. The simultaneous use of the following drugs/groups of drugs may affect the action of BERODUAL N. They enhance the effect and/or increase the risk of adverse reactions: other beta-adrenergic agonists (any method of administration); other anticholinergic drugs (any route of administration); xanthine derivatives (for example, theophylline); anti-inflammatory drugs (corticosteroids); monoamine oxidase inhibitors; tricyclic antidepressants; halogenated hydrocarbon anesthetics (for example, halothane, trichlorethylene or enflurane), because they may increase the effects on the cardiovascular system. Reduces the effectiveness of BERODUAL N: simultaneous use of beta-blockers. Other possible reactions: Hypokalemia caused by the use of a beta2-agonist can be enhanced by the simultaneous use of xanthine derivatives, glucocorticosteroids and diuretics. This should especially be taken into account when treating patients with severe forms of obstructive airway disease. Hypokalemia may lead to an increased risk of arrhythmias in patients taking digoxin. In addition, the negative effect of hypokalemia on heart rate can be enhanced by hypoxia. In such cases, it is recommended to monitor serum potassium levels. The risk of developing an acute attack of glaucoma increases if nebulized ipratropium bromide alone or in combination with a betag agonist comes into contact with the eye.
Contraindications
BERODUAL N is contraindicated in patients with known hypersensitivity to fenoterol hydrobromide and/or ipratropium bromide, atropine-like substances, or any of the excipients. BERODUAL N is also contraindicated in patients with hypertrophic obstructive cardiomyopathy and tachyarrhythmia. Overdose Symptoms Depending on the degree of overdose, the following side effects, typical for betag-agonists, may occur: a feeling of a rush of blood to the face, delirium, headache, tachycardia, palpitations, arrhythmia, arterial hypotension up to shock, increased blood pressure, anxiety, pain in the chest, agitation, possible appearance of extrasystoles and There have been cases of the development of metabolic acidosis, as well as hypokalemia, when using fenoterol in doses exceeding the recommended ones approved for indications for BERODUAL N. Symptoms of an overdose of ipratropium bromide (such as dry mouth, impaired accommodation) are usually weakly expressed due to the low systemic bioavailability of inhaled ipratropium. Therapy Treatment with BERODUAL N should be discontinued. It is necessary to monitor acid-base balance and blood electrolytes. The administration of sedatives and tranquilizers is indicated; in severe cases, intensive supportive care, including hospitalization, may be required. Beta-blockers (preferably beta-blockers) can be used as an antidote for fenoterol; however, it is necessary to take into account the possibility of deterioration of bronchial obstruction, which requires careful selection of the dose of the drug in patients suffering from bronchial asthma or COPD, due to the risk of provoking severe bronchospasm, which can be fatal.
Compound
One inhalation dose contains the active ingredients: ipratropium bromide monohydrate 21 mcg (0.021 mg), which corresponds to 20 mcg (0.020 mg) of ipratropium bromide, and fenoterol hydrobromide 50 mcg (0.050 mg); excipients: anhydrous citric acid, purified water, absolute ethanol, tetrafluoroethane (HFA 134a).
Overdose
Symptoms Depending on the degree of overdose, the following side effects typical of betag-adrenergic agonists may occur: a feeling of a rush of blood to the face, delirium, headache, tachycardia, a feeling of palpitations, arrhythmia, arterial hypotension up to shock, increased blood pressure, anxiety, pain in chest, agitation, possible appearance of extrasystoles and There have been cases of the development of metabolic acidosis, as well as hypokalemia, when using fenoterol in doses exceeding the recommended ones approved for indications for BERODUAL N. Symptoms of an overdose of ipratropium bromide (such as dry mouth, impaired accommodation) are usually mild due to the low systemic bioavailability of inhaled ipratropium. Therapy Treatment with BERODUAL N should be discontinued. It is necessary to monitor acid-base balance and blood electrolytes. The administration of sedatives and tranquilizers is indicated; in severe cases, intensive supportive care, including hospitalization, may be required. Beta-blockers (preferably beta-blockers) can be used as an antidote for fenoterol; however, it is necessary to take into account the possibility of deterioration of bronchial obstruction, which requires careful selection of the dose of the drug in patients suffering from bronchial asthma or COPD, due to the risk of provoking severe bronchospasm, which can be fatal.
Side effect
Many of the following side effects can be attributed to the anticholinergic and beta-adrenergic properties of BERODUAL N. Like other drugs used by inhalation, BERODUAL N may cause symptoms of local irritation. The most commonly reported side effects include: cough, dry mouth, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, palpitations, vomiting, increased systolic blood pressure and nervousness. The incidence of side effects is indicated as: very often (? 1/10); often (from ?1/100 to
Storage conditions
Store in a place protected from direct sunlight at temperatures below 25°C. Do not expose to high temperatures or freeze. Keep out of the reach of children.
Interactions of the drug Berotec N
β-adrenergic agonists, anticholinergics and xanthine derivatives (such as theophylline) may enhance the effects of fenoterol. Simultaneous administration of other β-adrenergic agonists, systematic use of anticholinergics and xanthine derivatives (for example, theophylline) may increase side effects. With simultaneous use of beta-adrenergic blockers, there is a potential for a serious reduction in bronchodilation. β-adrenergic agonists should be administered with caution to patients taking MAO inhibitors or tricyclic antidepressants, as the effects of β-adrenergic agents may be enhanced. Inhalation of halogenated hydrocarbon anesthetics (halothane, trichlorethylene, enflurane) can increase the severity of the effect of β-adrenergic drugs on the cardiovascular system.
Overdose of the drug Berotec N
Possible symptoms of overdose are excessive β-adrenergic stimulation, including tachycardia, palpitations, tremor, hypertension (arterial hypertension), hypotension, increased pulse blood pressure, angina pectoris, arrhythmia, and flushing. Treatment: sedatives, tranquilizers; β-adrenergic receptor blockers, preferably β1-selective, are used as specific antidotes. The possibility of increased bronchospasm should be taken into account, so patients with asthma must carefully set the dose.
