Description of the drug IPRATEROL
The patient should be informed that if shortness of breath (difficulty breathing) suddenly increases rapidly, consult a doctor immediately.
Paradoxical bronchospasm
The drug can cause paradoxical bronchospasm, which can be life-threatening. If paradoxical bronchospasm develops, the use of the drug should be stopped immediately and switched to alternative therapy.
Long-term use
In patients with bronchial asthma, the drug 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 beta2-agonists to relieve bronchial obstruction can cause uncontrolled worsening of the disease. In case of increased bronchial obstruction, increasing the dose of beta2-agonists 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 co-administered with the drug only under medical supervision.
Visual disorders
The drug should be prescribed with caution to patients predisposed to the development of angle-closure glaucoma. There are isolated reports of complications from the organ of vision (for example, increased intraocular pressure, mydriasis, angle-closure glaucoma, eye pain) that developed when inhaled ipratropium bromide (or ipratropium bromide in combination with β2-adrenergic receptor agonists) entered 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 is observed, the use of eye drops that reduce intraocular pressure and immediate consultation with a specialist is indicated. Patients should be instructed on the correct use of the inhalation solution. To prevent the solution from getting into the eyes, it is recommended that the solution used with a nebulizer be inhaled through the mouthpiece. If you do not have a mouthpiece, use a mask that fits tightly to your face. Particular care should be taken to protect the eyes of patients predisposed to the development of glaucoma.
Systemic effects
For diseases such as recent myocardial infarction, diabetes mellitus with inadequate glycemic control, severe organic heart and vascular diseases, hyperthyroidism, pheochromocytoma or urinary tract obstruction (for example, prostatic hyperplasia or bladder neck obstruction), the drug should be prescribed only after careful assessment of the risk/benefit ratio, especially when used in doses higher than recommended.
Effect on the cardiovascular system
In post-marketing studies, rare cases of myocardial ischemia have been reported when taking beta-adrenergic agonists. Patients with underlying serious heart disease (eg, coronary artery disease, arrhythmias, or significant heart failure) receiving the drug should be warned to seek medical attention if heart 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
Hypokalemia may occur when using β2-adrenergic agonists.
In athletes, the use of the drug, due to the presence of fenoterol in its composition, can lead to positive doping test results.
Excipients
The drug in the form of an inhalation aerosol contains a preservative, benzalkonium chloride, and a stabilizer, disodium edetate dihydrate. During inhalation, these components may cause bronchospasm in sensitive patients with airway hyperresponsiveness.
Impact on the ability to drive vehicles and machinery
The effect of the drug on the ability to drive vehicles and use machinery has not been specifically studied. However, patients should be informed that during treatment with the drug, the development of such undesirable effects as dizziness, tremor, impaired accommodation, mydriasis, and blurred vision is possible. Therefore, caution should be recommended when driving vehicles or using machinery. If patients experience the above unwanted sensations, they should refrain from potentially dangerous activities such as driving vehicles or operating machinery.
IPRATEROL-NATIV solution for inhalation 0.25+0.5 mg/ml vial-drop. 20 ml
Directions for use and doses
The drug Ipratropium-native is intended only for inhalation administration by inhalation through the mouth using a nebulizer.
Ipratropium-native is not intended for injection or oral administration!
20 drops of the drug Ipratropium-native (about 1 ml) contain 0.250 mg of ipratropium bromide, respectively, 1 drop of the drug contains 0.0125 mg of ipratropium bromide.
The dosage regimen is selected individually.
The drug Ipratropium-native must be used under medical supervision only with the help of a nebulizer of any design, which converts the drug solution into an aerosol for inhalation.
Since many nebulizers operate only with a constant flow of air, it is possible that the nebulized drug will be released into the environment. Taking this into account, the drug Ipratropium-native should be used in well-ventilated areas.
The recommended daily dose should not be exceeded during either acute or maintenance therapy.
If treatment does not lead to significant improvement or if the patient's condition worsens (shortness of breath (difficulty breathing) suddenly or rapidly worsens), a doctor should be consulted immediately.
Unless otherwise prescribed by your doctor, the following dosage regimen is recommended:
Maintenance treatment:
Adults (including the elderly):
2.0 ml of the drug Ipratropium-native (40 drops = 0.5 mg of ipratropium bromide) 3-4 times a day.
The maximum daily dose is 8.0 ml of Ipratropium-native (2 mg ipratropium bromide).
Acute bronchospasm
:
Adults (including the elderly)
: 2.0 ml of Ipratropium-native (40 drops = 0.5 mg of ipratropium bromide), repeated inhalations are possible until the patient’s condition stabilizes, the interval between inhalations is determined by the doctor. Ipratropium-native can be used in conjunction with inhaled and 2-adrenergic agonists.
To ensure correct use of the drug, please read these instructions for use carefully.
The recommended dose of Ipratropium-native immediately before use should be diluted with 0.9% sodium chloride solution until the volume of the drug reaches 3-4 ml, pour into a nebulizer and inhale. Do not reuse the solution remaining after inhalation; discard it.
The speed and duration of inhalation may depend on the inhalation method and the type of nebulizer. The duration of inhalation should be monitored by the consumption of the volume of the diluted drug Ipratropium-native. When using a centralized oxygen system, the solution is best used at a flow rate of 6-8 liters per minute. For inhalation, it is recommended to use nebulizers with a mouth tip (mouthpiece). When using a nebulizer with a mask, use an appropriately sized mask.
The nebulizer must be kept clean.
Buy Ipraterol-aeronative aerosol for inhalation 20mcg+50mcg 200 doses in pharmacies
Trade name of the drug:
Ipraterol-aeronative.
International non-proprietary non-proprietary or generic name:
ipratropium bromide + fenoterol.
Composition for 1 dose:
Active ingredients:
Ipratropium bromide 0.021 mg monohydrate (in terms of ipratropium bromide) (0.020 mg) Fenoterol hydrobromide 0.050 mg
Excipients:
Absolute ethanol 15.300 mg Citric acid monohydrate 0.005 mg; Triethyl citrate 0.150 mg; Propellant R 134a (1,1,1,2-tetrafluoroethane) 44.470 mg
Pharmacological properties
Pharmacodynamics
The drug Ipraterol-aeronativ contains two components with bronchodilator activity: ipratropium bromide, an m-anticholinergic blocker, and fenoterol, 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 derivative with anticholinergic (parasympatholytic) properties. Ipratropium bromide inhibits reflexes caused by the vagus nerve. Anticholinergics prevent an increase in the intracellular concentration of calcium ions, which occurs due to the interaction of acetylcholine with muscarinic receptors of bronchial smooth muscles. The release of calcium ions is mediated by a system of secondary mediators, which include inositol triphosphate (ITP) and diacylglycerol (DAG).
In patients with bronchospasm associated with chronic obstructive pulmonary diseases (chronic bronchitis and emphysema), significant improvement in lung function (increase in forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF) by 15% or more) is observed within 15 minutes, the maximum effect is achieved after 1-2 hours and lasts in most patients up to 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 selectively stimulates β2-adrenergic receptors at a therapeutic dose. Stimulation of β1-adrenergic receptors occurs when high doses are used. Fenoterol 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 noted.
The β-adrenergic (stimulating β-adrenergic receptors) 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, a prolongation of the QTc interval is 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 reported 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 receptor agonists; the clinical significance of this manifestation is not clear. 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.
Fenoterol 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 inflammatory and bronchoconstrictive mediators from mast cells. In addition, when using fenoterol in doses of 0.6 mg, an increase in mucociliary clearance is observed.
Tremor is the most common adverse effect with β-adrenergic agonists. In contrast to the effects on bronchial smooth muscle, tolerance may develop to the systemic effects of β-adrenergic agonists, but the clinical significance of this phenomenon has not been identified.
When ipratropium bromide and fenoterol are used together, the bronchodilator (bronchodilator) effect is achieved by acting on various pharmacological targets. These active 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 airway obstruction. 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 a virtually complete absence of adverse reactions.
In acute bronchoconstriction, the effect of the drug develops quickly, which allows its use in acute attacks of bronchospasm.
Pharmacokinetics
There is no evidence that the pharmacokinetics of a combination product containing ipratropium bromide and fenoterol differs from that of each of the individual components.
Suction
When administered via inhalation, ipratropium bromide is characterized by extremely low absorption from the mucous membrane of the respiratory tract. The concentration of ipratropium bromide in blood plasma is at the lower limit of definition, and it can only be measured when using high doses of the active substance. After inhalation, 10-30% of the administered dose of ipratropium bromide usually enters the lungs (depending on the dosage form and method of inhalation). Most of the dose is swallowed and enters the gastrointestinal tract.
The portion of the dose of ipratropium bromide that enters the lungs quickly reaches the systemic circulation (within a few minutes). Total renal excretion (over 24 hours) of the parent compound is approximately 46% of the intravenous dose, less than 1% of the oral dose, and approximately 3-13% of the inhalation dose. Based on these data, it is calculated that the total systemic bioavailability of ipratropium bromide administered by inhalation is 2% and 7-28%, respectively.
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 volume of distribution during steady state (Css) is approximately 176 L (≈ 2.4 L/kg). The drug binds to plasma proteins to a minimal extent (less than 20%). Ipratropium bromide, which is a quaternary amine, does not penetrate the blood-brain barrier. The half-life during the terminal 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 intravenous administration, approximately 60% of the dose is metabolized by oxidation, mainly in the liver. Cumulative renal excretion (over 6 days) of the isotopically labeled dose (including parent compound and all metabolites) was 72.1% after intravenous administration, 9.3% after oral administration, and 3.2% after inhalation administration. The total isotope-labeled dose excreted through the intestine 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. The half-life 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.
Depending on the method of inhalation and the inhalation system used, about 10-30% of fenoterol reaches the lower respiratory tract, and the rest is deposited in the upper respiratory tract and swallowed. As a result, some amount of inhaled fenoterol enters the gastrointestinal tract. Absorption is biphasic - 30% of fenoterol is rapidly absorbed with a half-life (T1/2) of 11 minutes, and 70% is absorbed slowly with a T1/2 of 120 minutes. There is no correlation between fenoterol plasma concentrations achieved after inhalation and the pharmacodynamic time-effect curve. The long-term (3-5 hours) bronchodilator effect of the drug after inhalation, comparable to the corresponding effect achieved after intravenous administration, is not supported by high concentrations of fenoterol in the systemic circulation. After oral administration, about 60% of fenoterol is absorbed. The time to reach maximum concentration in blood plasma is 2 hours.
Distribution
Ipratropium bromide, a quaternary amine, is poorly soluble in fats and poorly penetrates biological membranes. Does not accumulate. Ipratropium bromide binds to plasma proteins to a minimal extent (less than 20%). There is no data on the possibility of ipratropium bromide passing through the placental barrier and into breast milk.
Fenoterol is intensively distributed throughout organs and tissues. The connection with blood plasma proteins is 40-55%. Fenoterol, unchanged, penetrates the placental barrier and is excreted in breast milk.
Metabolism
Ipratropium bromide is metabolized by oxidation primarily in the liver. Up to 8 metabolites of ipratropium bromide are known, which weakly bind to muscarinic receptors and are considered inactive.
Fenoterol is metabolized in the liver. After 24 hours, 60% of the intravenously administered dose and 35% of the oral dose are excreted in the urine. This proportion of fenoterol undergoes biotransformation due to the “first pass” effect through the liver, as a result of which the bioavailability of the drug after oral administration drops to approximately 1.5%. This explains the fact that the ingested amount of the drug has virtually no effect on the concentration of the active substance in the blood plasma achieved after inhalation. The biotransformation of fenoterol in humans occurs primarily through conjugation with sulfates in the intestinal wall.
Removal
Ipratropium bromide is excreted primarily through the intestines and also through the kidneys. About 25% is excreted unchanged, the rest in the form of metabolites.
Fenoterol is excreted by the kidneys and bile in the form of inactive sulfate conjugates. When administered parenterally, fenoterol is excreted according to a three-phase model with half-lives of 0.42 minutes, 14.3 minutes and 3.2 hours.
Pharmacokinetics in selected patient groups
The pharmacokinetics of a combination drug containing ipratropium bromide and fenoterol in patients with diabetes mellitus, elderly and older patients, children, as well as in patients with impaired liver and kidney function.
Indications for use
Chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchial asthma (mild to moderate severity).
Carefully
The drug Ipraterol-aeronativ should be used with caution in patients with diseases such as angle-closure 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 , arrhythmias, aortic stenosis, severe lesions of the cerebral and peripheral arteries, hyperthyroidism, pheochromocytoma, prostatic hyperplasia, bladder neck obstruction, cystic fibrosis, II and III trimesters of pregnancy, breastfeeding period. The drug Ipraterol-aeronativ should be used with caution in children and adolescents aged 6 to 18 years.
Use during pregnancy and breastfeeding
Data from preclinical studies and existing clinical experience with the use of a combination of fenoterol and ipratropium bromide have shown that the active ingredients included in the combination drug do not have a negative effect during pregnancy. The possibility of an inhibitory effect of fenoterol on uterine contractility should be taken into account. The drug Ipraterol-aeronativ is contraindicated in the first trimester of pregnancy (possible weakening of labor). The drug Ipraterol-aeronativ should be used with caution in the second and third trimesters of pregnancy.
Fenoterol passes into breast milk. Data confirming that ipratropium bromide passes into breast milk have not been obtained. The safety of the drug during breastfeeding has not been established. In this regard, the use of the drug Ipraterol-aeronativ during breastfeeding is possible only if the potential benefit to the mother outweighs the potential risk to the child.
Directions for use and doses
The dose should be selected individually.
Unless otherwise directed by a physician, the following doses are recommended:
Adults and children over 6 years old
Treatment of attacks
In most cases, two inhalation doses of the aerosol are sufficient to relieve symptoms. If breathing relief does not occur within 5 minutes, you can use an additional 2 inhalation doses.
If there is no effect after 4 inhalation doses and additional inhalations are required, seek immediate medical attention.
Intermittent and long-term therapy
1-2 inhalations per dose, up to 8 inhalations per day (on average 1-2 inhalations 3 times a day). For bronchial asthma, the drug should be used only as needed.
The drug Ipraterol-aeronativ should be used in children only as prescribed by a doctor and under the supervision of adults (see section “Special instructions”).
Instructions for inhalation
Patients should be instructed on the correct use of the metered dose aerosol.
The drug Ipraterol-aeronativ is intended for inhalation use only.
Before using the inhaler for the first time or if the inhaler has not been used for a week or longer, check its operation. To do this, remove the protective cap from the mouthpiece of the inhaler, shake the inhaler well and press the balloon, releasing one stream of the drug into the air.
Carrying out inhalation
Step 1. Remove the protective cap from the inhaler mouthpiece as shown in Figure 1. Step 2. Shake the inhaler vigorously. Step 3: Exhale slowly and completely. Do not exhale into the inhaler! Step 4: Hold the balloon as shown in Figure 2 and wrap your lips tightly around the mouthpiece. The cylinder must be pointing upside down! Step 5. Inhale as deeply as possible, while quickly pressing the bottom of the balloon until one inhalation dose is released. Step 6: Hold your breath for a few seconds, then remove the mouthpiece from your mouth and exhale slowly through your nose. Step 7. Place the protective cap on the inhaler mouthpiece.
Repeat steps 2–6 for a second inhalation dose, if necessary.
Cleaning the inhaler
The inhaler mouthpiece should be cleaned regularly (once a week).
Remove the metal can from the plastic case and rinse the case and cap with warm water. Do not use hot water. Dry thoroughly, but do not use heating devices. Place the can back into the case and put on the cap. Do not immerse the metal can in water.
The cylinder is designed for 200 inhalations. After this, the cylinder should be replaced.
The use of the drug in children should be supervised by adults.
It is recommended to pinch the child's nostrils to prevent inhalation through the nose during inhalation.
Warning: the plastic mouthpiece is designed specifically for the drug Ipraterol-aeronativ and serves for precise dosing of the drug. The mouthpiece should not be used with other metered dose aerosols. Also, you cannot use the drug Ipraterol-aeronativ with any other adapters, except for the mouthpiece supplied with the drug.
The contents of the cylinder are under pressure. The cylinder must not be opened and heated above 50 °C!
Side effect
Many of the listed adverse reactions may be a consequence of the anticholinergic and β-adrenergic properties of the drug Ipraterol-aeronativ. The use of the drug Ipraterol-aeronativ, like any inhalation therapy, can cause local irritation.
The most common adverse reactions are cough, dry mouth, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, palpitations, vomiting, increased systolic blood pressure and nervousness.
The adverse reactions presented below are listed according to the damage to organs and organ systems and the frequency of occurrence. The incidence of adverse reactions is estimated as follows:
very common - ≥ 1/10, common - ≥ 1/100 and uncommon - ≥ 1/1,000 and rare - ≥ 1/10,000 and very rare - unspecified frequency (cannot be calculated from the available data). occurring “very often” – > 10%; “often” – > 1% and 0.1% and 0.01% and
Immune system disorders: rarely - hypersensitivity reactions, anaphylactic reactions. Metabolic and nutritional disorders: rarely – hypokalemia, metabolic acidosis. Mental disorders: infrequently – nervousness; rarely – anxiety, mental disturbances. Nervous system disorders: uncommon – headache, dizziness, tremor. Visual disorders: rarely - glaucoma, increased intraocular pressure, impaired accommodation, mydriasis, blurred vision, eye pain, corneal edema, conjunctival hyperemia, the appearance of a halo around objects and colored spots before the eyes. Cardiac disorders: uncommon – tachycardia, palpitations; rarely - arrhythmias, atrial fibrillation, supraventricular tachycardia, myocardial ischemia. Disorders of the respiratory system, chest and mediastinal organs: often – cough; uncommon – pharyngitis, dysphonia; rarely - bronchospasm, pharyngeal irritation, pharyngeal edema, laryngospasm, paradoxical bronchospasm, dry throat. Gastrointestinal disorders: uncommon – vomiting, dry mouth, nausea; rarely - stomatitis, glossitis, gastrointestinal motility disorders, diarrhea, constipation, swelling of the oral cavity. Disorders of the skin and subcutaneous tissues: rarely - urticaria, skin rash, itching, angioedema, increased sweating. Musculoskeletal and connective tissue disorders: rarely - muscle weakness, myalgia, muscle spasm. Renal and urinary tract disorders: rarely – urinary retention. Laboratory and instrumental data: infrequently - increased systolic blood pressure; rarely – increased diastolic blood pressure.
Overdose
Symptoms
Symptoms of overdose are usually related to the effects of fenoterol. Symptoms may appear due to excessive stimulation of β-adrenergic receptors. The most likely occurrence is tachycardia, palpitations, tremor, arterial hypertension or hypotension, an increase in the difference between systolic and diastolic blood pressure, an increase in pulse pressure, increased angina pain, arrhythmias to the face, metabolic acidosis, hypokalemia, a feeling of heaviness in the chest, increased bronchial obstruction . Possible 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 in nature.
Treatment
It is necessary to stop taking the drug Ipraterol-aeronativ. Data from monitoring the acid-base balance of the blood should be taken into account. It is recommended to prescribe sedatives, anxiolytic drugs (tranquilizers), and in severe cases, intensive therapy.
As a specific antidote, it is possible to use β-blockers, preferably selective β1-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 with bronchial asthma or chronic obstructive pulmonary disease due to the risk of developing severe bronchospasm, which can be fatal.
Interaction with other drugs
Long-term simultaneous use of the drug Ipraterol-aeronativ with other anticholinergic drugs is not recommended due to the lack of data.
Concomitant use of other β-adrenomimetic and anticholinergic drugs, incl. systemic action, and xanthine derivatives (for example, theophylline) can enhance the bronchodilator effect of the drug Ipraterol-aeronativ and lead to increased adverse reactions.
It is possible to significantly weaken the bronchodilator effect of the drug Ipraterol-aeronativ 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, glucocorticosteroids and diuretics. This fact should be given special attention when treating patients with severe forms of obstructive airway diseases. 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 the concentration of potassium in the blood plasma.
Beta2-adrenergic drugs should be prescribed with caution to patients receiving monoamine oxidase inhibitors and tricyclic antidepressants, as these drugs can enhance the effect of beta-adrenergic drugs.
Inhalation of general anesthetics such as halogenated hydrocarbon anesthetics (halothane, trichlorethylene, enflurane) may increase the adverse cardiovascular effects of beta-adrenergic agents.
Combined use of the drug with cromoglycic acid and/or glucocorticosteroids increases the effectiveness of therapy.
Long-term simultaneous use of the drug Ipraterol-aeronativ with other anticholinergic drugs is not recommended due to the lack of data. Concomitant use of other β-adrenomimetic anticholinergics that enter the systemic circulation or xanthine derivatives (for example, theophylline) may lead to increased side effects. and anticholinergic drugs, incl. systemic action, and xanthine derivatives (for example, theophylline) can enhance the bronchodilator effect of the drug Ipraterol-aeronativ and lead to increased adverse reactions.
It is possible to significantly weaken the bronchodilator effect of the drug Ipraterol-aeronativ 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, glucocorticosteroids and diuretics. This fact should be given special attention when treating patients with severe forms of obstructive airway diseases. 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 the potassium concentration in blood serum.
Beta2-adrenergic drugs should be prescribed with caution to patients receiving monoamine oxidase inhibitors and tricyclic antidepressants, as these drugs can enhance the effect of beta-adrenergic drugs.
Inhalation of general anesthetics such as halogenated hydrocarbon anesthetics and anesthetics. for example (halothane, trichlorethylene, enflurane) may increase the adverse effects of β-adrenergic drugs on the cardiovascular system.
Combined use of the drug with cromoglycic acid and/or glucocorticosteroids increases the effectiveness of therapy.
special instructions
If shortness of breath (difficulty breathing) suddenly increases rapidly, you should consult a doctor immediately.
In children, the drug Ipraterol-aeronativ should be used only as prescribed by a doctor and under the supervision of adults. Use in children under 6 years of age is contraindicated due to lack of experience with use.
Hypersensitivity
After using the drug Ipraterol-aeronativ, immediate hypersensitivity reactions may occur, signs of which in rare cases may include: urticaria, angioedema, rash, bronchospasm, oropharyngeal edema, anaphylactic shock.
Paradoxical bronchospasm
The drug Ipraterol-aeronativ, like other inhaled drugs, can cause paradoxical bronchospasm, which can be life-threatening. In case of development of paradoxical bronchospasm, the use of the drug Ipraterol-aeronativ should be stopped immediately and switched to alternative therapy.
Long-term use
- in patients with bronchial asthma, the drug Ipraterol-aeronativ should be used only as needed; in patients with mild COPD, symptomatic treatment may be preferable to regular use; - in patients suffering from 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 the drug Ipraterol-aeronativ, to relieve bronchial obstruction can cause uncontrolled worsening of the disease. In case of increased bronchial obstruction, increasing the dose of β2-adrenergic agonists, including the drug Ipraterol-aeronativ, more than recommended for a long period of time is not only not justified, but also dangerous. To prevent life-threatening worsening of the disease, a review of the patient's treatment plan and adequate anti-inflammatory therapy with inhaled glucocorticosteroids should be considered.
Other sympathomimetic bronchodilators should be prescribed concomitantly with Ipraterol-Aeronativ only under medical supervision.
Gastrointestinal disorders
In patients with a history of cystic fibrosis, gastrointestinal motility disorders are possible.
Visual disorders
The drug Ipraterol-aeronativ should be used with caution in patients predisposed to angle-closure glaucoma. There are isolated reports of complications from the organ of vision (for example, increased intraocular pressure, mydriasis, angle-closure glaucoma, eye pain) that developed when inhaled ipratropium bromide (or ipratropium bromide in combination with β2-adrenergic agonists) entered the eyes. Symptoms of acute angle-closure glaucoma may include pain or discomfort in the eyes, blurred vision, the appearance of a halo around objects and colored spots in front of the eyes, combined with swelling of the cornea and redness of the eyes due to conjunctival hyperemia. If any combination of these symptoms develops, the use of eye drops that reduce intraocular pressure and immediate consultation with a specialist is indicated. Patients should be instructed on the correct use of the inhaled drug Ipraterol-aeronativ. To prevent the solution from getting into the eyes, it is recommended that the solution used with a nebulizer be inhaled through the mouthpiece. If there is no mouthpiece, a mask that fits tightly to the face should be used. Patients predisposed to developing glaucoma should take special care to protect their eyes.
Systemic effects
For diseases such as 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, with prostatic hyperplasia or bladder neck obstruction), Ipraterol-aeronative should Use only after a careful risk/benefit assessment, especially when using doses higher than recommended.
Effect on the cardiovascular system
There have been rare cases of myocardial ischemia when taking β2-adrenergic agonists. Patients with concomitant serious heart disease (for example, coronary heart disease, arrhythmias, or severe heart failure) receiving Ipraterol Aeronative should be warned to consult a doctor if they experience heart pain or other symptoms indicating worsening of heart disease. It is necessary to pay attention to symptoms such as shortness of breath and chest pain, as they can be of both cardiac and pulmonary etiology.
Hypokalemia
When using β2-agonists, hypokalemia may occur (see section "Overdose").
In athletes, the use of the drug Ipraterol-aeronativ due to the presence of fenoterol in its composition can lead to positive results of doping tests.
Impact on the ability to drive vehicles and machinery
There have been no studies of the effect of a combination drug containing ipratropium bromide and fenoterol on the ability to drive vehicles and operate machinery. Since the use of the drug may cause the development of such undesirable reactions as dizziness, nervousness, tremor, disturbance of eye accommodation, mydriasis and blurred vision, caution should be exercised when driving vehicles and machinery, as well as when engaging in other potentially hazardous activities that require increased concentration. and speed of psychomotor reactions.
High-quality generics for the treatment of broncho-obstructive diseases: there is light at the end of the tunnel!
Acute and chronic respiratory diseases in the Russian Federation account for about 40% of the total morbidity rate of the country's population (including acute respiratory diseases), while for the period 2000–2008. incidence rates did not fall below 290 cases per 1000 people.
Among respiratory diseases, bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD) predominate. According to experts, the number of patients with asthma is at least 5–6 times higher than official statistics (5.9 million people compared to reported data - 1.3 million people). It has been established that patients suffering from asthma are often disabled. Thus, in Moscow, 41% of patients with asthma receive disability benefits [1].
In the Russian Federation, direct healthcare costs associated with the treatment of asthma amount to about 8.5 billion rubles, of which 66.6% is spent on inpatient treatment, 21.5% on the purchase of medicines, 10.9% on outpatient treatment , 0.9% - for ambulance calls.
In the structure of indirect costs for asthma (about 2.8 billion rubles), the cost of paying for certificates of incapacity for work is 61.4%, disability benefits - 27.3%, the lost contribution to the gross domestic product due to exacerbation of the disease with a certificate of incapacity for work - 11 ,4%.
The total (direct and indirect) costs associated with asthma are about 0.75% of the entire healthcare budget of the Russian Federation [1].
Noteworthy is the fact that the costs of medicines are extremely insufficient and in the overall structure of treatment costs they amount to only 11.0%. Per one patient with asthma, this amounts to 1,418.2 rubles per year.
In this regard, the introduction into practice of new medicinal technologies, the use of which will reduce the burden of the disease and budget costs, is of extreme interest.
According to the modern concept of the World Health Organization (WHO), generic drugs have numerous public health benefits, primarily associated with the affordable price of the drug.
However, the use of a generic drug instead of the original one can be justified only if the doctor is convinced that this will not reduce the effectiveness of treatment and, moreover, will not threaten the patient’s life. In Russia, where most generics and/or substances for their production are produced in developing countries of the Asian region, the problem of the quality of such drugs is especially acute. In addition, the complexity of solving this problem is aggravated by the fact that modern inhaled drugs use high-tech devices as delivery vehicles, the reproduction and production of which requires special efforts and large capital investments.
To establish the equivalence of inhaled drugs, at least 5 steps must be taken [2]:
1) confirmation of the equivalence of the qualitative and quantitative composition of the main and auxiliary substances;
2) establishing the similarity of the delivery vehicles used;
3) assessment of the properties of the inhaler in vitro, including assessment of the particle size of the inhaled dose;
4) study of the pulmonary distribution and systemic pharmacokinetics of the drug in vivo;
5) evidence of similarity in therapeutic effectiveness.
Unfortunately, generic inhaled drugs appearing on the Russian pharmaceutical market are not always fully equivalent to the original drugs.
Thus, L. A. Trukhacheva et al. [3] when studying the degree of equivalence of inhaled fractions on a 7-stage cascade impactor of the new generation Next (Copley Scientific Limited England) for metered-dose aerosol inhalers Seretide, 25/250 (salmeterol xinafoate/fluticasone propionate) mcg/dose, manufactured by GlaxoSmithKline Pharmaceuticals, Poland, and Tevacomb, 25/250 (salmeterol xinafoate/fluticasone propionate) mcg/dose, manufactured by Cipla Ltd., India, established statistical differences in determining such significant parameters as the mass median aerodynamic diameter of particles and the geometric standard deviation from the mass median aerodynamic diameter, as well as the values of the fraction of fine particles (FMP) and the value of the released dose. For salmeterol xinafoate, the FMC values were 42.06% (Seretide) and 35.53% (Tevacomb), respectively, for fluticasone propionate - 42.94% (Seretide) and 35.44% (Tevacomb).
Previously, we established that the reproduced drug mentioned above differs from the original one in the amount of impurities it contains. Despite the fact that both drugs met the stated requirements of regulatory documentation, the amount of impurities of fluticasone propionate in the generic was at the upper limit of the permissible norm (no more than 0.4%) and amounted to 0.385%. In addition, trace amounts of bromine (0.7 ppm) were found in Tevacombe, the presence of which is not generally assumed by the current regulatory documentation [4].
In connection with the above, great hopes are placed on new domestic developments in the field of asthma treatment, which, in particular, is being dealt with. Currently, the company has developed a whole line of generic inhaled drugs using modern delivery vehicles, the properties of which have been thoroughly studied in laboratory and clinical studies.
One of the studies was devoted to the study of the aerodynamic characteristics of the drug Beclomethasone-aeronativ, a dosed aerosol for inhalation produced by Nativa LLC (Russia) in comparison with the drugs Beclazon Eco, 250 mcg/dose, produced by Norton Waterford (Ireland) and Clenil, 250 mcg /dose, produced by Chiesi Pharmaceuticals S.p.A. (Italy), in which indicators such as dosing uniformity and the size of the respirable fraction were assessed using the Andersen cascade impactor.
The results of the studies are given in table. 1.
Thus, as follows from the above data, the drug Beclomethasone-aeronativ produced by Nativa LLC (Russia) in comparison with the drugs Beclazon Eco 250 mcg/dose, produced by Norton Waterford (Ireland) and Clenil 250 mcg/dose (Chiesi Pharmaceuticals S.p.A., Italy) demonstrate comparable results in terms of dosage uniformity and respirable fraction.
The next study was devoted to assessing the aerodynamic characteristics of the drug Ipraterol-native, solution for inhalation 0.25 mg/ml + 0.5 mg/ml (ipratropium bromide + fenoterol). The proportion of small particles can vary significantly when using devices from different manufacturers and different models. In addition, the respirable fraction may depend on the viscosity of the drug medium and on its prior dilution, for example, with saline or when mixed with another drug.
A comparison of the compositions of the generic and the original drug showed that the qualitative composition of the drugs differs only in one of the preservatives: benzalkonium chloride in Ipraterol-native was replaced by sodium benzoate (Table 2).
The respirable fraction as a percentage was determined as the ratio of the sum of the masses of particles deposited on cascades 2 to 7 to the sum of the masses of all cascades and the L-shaped tube.
The results of the studies are presented in Fig. 1–4.
Thus, the drugs Ipraterol-Nativ (Nativa LLC) and Berodual (Boehringer Ingelheim) in the form of nebulization solutions during comparative aerodynamic tests showed complete identity in the size of the respirable fraction and particle size distribution profiles.
Two more similar studies were devoted to the study of the aerodynamic properties of the drug Saltikazon-native (Nativa LLC, Russia) in comparison with the drug Seretide Multidisc (Glaxo Operations UK Ltd., UK) and the drug Formisonide-native (Nativa LLC, Russia ) in comparison with the drug Symbicort Turbuhaler (AstraZeneca, UK)2. The design of the mentioned studies was similar to previous ones.
It is gratifying to note that according to the results of the studies mentioned above, both generic drugs demonstrated comparable results in terms of dosage uniformity and respirable fraction in relation to the original ones.
So, the currently available evidence of the comparability of the quality characteristics of generics in relation to well-known original drugs allows us to hope that a worthy replacement for expensive imported drugs has appeared on the Russian pharmaceutical market, providing equivalent effectiveness and safety profile in patients with broncho-obstructive diseases.
Literature
- Socio-economic losses from bronchial asthma and chronic obstructive pulmonary disease in the Russian Federation. Consolidated report. M.: RBOF “Quality of Life”. 125 pp.
- Daley-Yates PT, Parkins DA Establishing bioequivalence for inhaled drugs; weighing the evidence // Expert Opin. Drug Deliv. 2011; 1:112.
- Trukhacheva L. A., Gorpinchenko N. V., Dementyev S. P. Comparative in vitro study of the equivalence of metered-dose aerosol inhalers Seretide and Tevacomb using a new generation Next impactor // Clinical pharmacology and therapy. 2012. No. 21 (4). pp. 73–77.
- Zyryanov S.K., Aisanov Z.R. Reproduced inhalation drugs: how to evaluate their properties? // Pulmonology. 2012. No. 3. pp. 115–118.
S. K. Zyryanov, Doctor of Medical Sciences, Professor Zh. A. Galeeva1, Candidate of Medical Sciences Yu. B. Belousov, Doctor of Medical Sciences, Professor
GBOU VPO RNIMU im. N. I. Pirogova Ministry of Health of the Russian Federation, Moscow
1 Contact information
2 The drugs Saltikazon-native and Formisonide-native are not registered in the Russian Federation. There are permissions to conduct clinical trials of these drugs. Currently, the research status is “Completed”.
