Asthmasol-Solopharm inhalation solution 0.25mg/ml+0.5mg/ml, 20ml

Composition

The solution for inhalation is clear, colorless or slightly colored.

Excipients: sodium chloride-8.8 mg, disodium edetate dihydrate-0.5 mg, hydrochloric acid 1 M solution – up to pH 3.0-4.0, water for injection – up to 1 ml

Pharmacological action

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

Ipratropium bromide is a quaternary ammonium derivative with anticholinergic (parasympatholytic) properties. Bronchodilation during inhaled use of ipratropium bromide is mainly due to local, rather than systemic, anticholinergic effects. Ipratropia bromide inhibits reflexes caused by the vagus nerve, counteracting the effects of acetylcholine-a mediator released from the endings of the vagus nerve. Anticholinergic agents prevent an increase in the intracellular concentration of calcium ions, which occurs due to the interaction of acetylcholine with muscarinic receptors located on the smooth muscles of the bronchi. The release of calcium ions is mediated by a system of secondary mediators, including inositol triphosphate and diacylglycerol. Ipratropium bromide does not adversely affect mucus secretion in the respiratory tract, mucociliary clearance and gas exchange.

Fenoterol selectively stimulates beta_-2-adrenergic receptors at a therapeutic dose. Stimulation of β1-adrenergic receptors occurs when fenoterol is used in high doses. 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 use, fenoterol blocks the release of inflammatory mediators and bronchial obstruction from mast cells. In addition, when using fenoterol in higher doses, an increase in mucociliary clearance was noted.

The 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 beta_-2-adrenergic receptors of the heart, and when used in doses exceeding therapeutic ones, stimulation of beta_-1-adrenergic receptors. As with other beta-adrenergic drugs, prolongation of the QT interval_{c was observed} when used in high doses.

The most common adverse effect of beta-adrenergic agonists is tremor. In contrast to the effect on the smooth muscles of the bronchi, tolerance may develop to the systemic effect of beta-adrenergic agonists, but the clinical significance of this manifestation has not been clarified.

When combined with ipratropium bromide and fenoterol, 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 increases 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 beta-adrenergic component is required, which allows you to individually select an effective dose with almost complete absence of side effects.

In patients with bronchospasm associated with COPD (chronic bronchitis and emphysema), a significant improvement in lung function (an increase in FEV₁ and peak expiratory velocity by 15% or more) was noted within 15 minutes, the maximum effect was achieved in 1-2 hours and lasted in most patients up to 6 hours after use.

Indications

Prevention and symptomatic treatment of obstructive airway diseases with reversible airway obstruction, such as bronchial asthma and, especially, COPD, chronic bronchitis with or without pulmonary emphysema.

Recommendations for use

Solution for inhalation

The dose should be selected individually, depending on the severity of the attack. Treatment is usually started with the lowest recommended dose and discontinued after a sufficient reduction in symptoms is achieved.

Treatment should be carried out under medical supervision (for example, in a hospital setting). Treatment at home is possible only after consulting a doctor in cases where a fast-acting beta-adrenergic agonist in a low dose is not effective enough. The solution for inhalation can be recommended for patients when the aerosol for inhalation cannot be used or if it is necessary to use in higher doses.

In adults (including the elderly) and adolescents over 12 years of age with acute attacks of bronchospasm, depending on the severity of the attack, doses can vary from 1 ml (1 ml=20 drops) to 2.5 ml (2.5 ml=50 drops). In particularly severe cases, it is possible to use the drug in doses up to 4 ml (4 ml=80 drops).

In children aged 6-12 years with acute attacks of bronchial asthma, depending on the severity of the attack, doses can vary from 0.5 ml (0.5 ml=10 drops) to 2 ml (2 ml=40 drops).

In children under 6 years of age (body weight due to the fact that information about the use of the drug in this age group is limited, it is recommended to use the following dose (only under medical supervision): 0.1 ml (2 drops) per kg of body weight, but not more than 0.5 ml (10 drops).

Rules for using the drug

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

The recommended dose should be diluted with 0.9% sodium chloride solution to a final volume of 3-4 ml, and applied (completely) using a nebulizer.

The solution for inhalation should not be diluted with distilled water.

Dilution of the solution should be carried out each time before use; the remains of the diluted solution should be destroyed.

The diluted solution should be used immediately after cooking.

The duration of inhalation can be controlled by the consumption of the diluted solution.

The solution for inhalation can be used using various commercial models of nebulizers. The dose reaching the lungs and the systemic dose depend on the type of nebulizer used and may be higher than the corresponding doses when using a metered-dose aerosol (which depends on the type of inhaler). In cases where wall-mounted oxygen is available, the solution is best applied at a flow rate of 6-8 l/min.

Follow the instructions for use, maintenance, and cleaning of the nebulizer.

Metered dose aerosol for inhalation

The dose is set individually.

To stop seizures, adults and children over 6 years of age are prescribed 2 inhaled doses. If there is no relief of breathing within 5 minutes, you can prescribe 2 more inhaled doses.

The patient should be informed to immediately consult a doctor if there is no effect after 4 inhaled doses and additional inhalations are required.

Metered-dose aerosol in children should only be used as prescribed by a doctor and under adult supervision.

For long-term and intermittent therapy,1-2 inhalations are prescribed for 1 reception, up to 8 inhalations/day (on average,1-2 inhalations 3 times/day).

For bronchial asthma, the drug should only be used as needed.

Rules for using the drug

The patient should be instructed about the correct use of metered-dose aerosol.

Before using the metered-dose spray for the first time, double-tap the bottom of the can.

Each time a metered-dose aerosol is used, the following rules must be observed.

1. Remove the protective cap.

2. Take a slow, deep breath out.

3. While holding the balloon, wrap your lips around the mouthpiece. The balloon must be pointed upside down.

4. While inhaling as deeply as possible, quickly press the bottom of the cylinder until 1 inhaled dose is released. Hold your breath for a few seconds, then remove the mouthpiece from your mouth and exhale slowly. Repeat steps to get the 2nd inhaled dose.

5. Put on a protective cap.

6. If the spray bottle has not been used for more than 3 days, press the bottom of the bottle once before use until an aerosol cloud appears.

The balloon is designed for 200 inhalations. The cylinder should then be replaced. Although some contents may remain in the balloon, the amount of drug released during inhalation is reduced.

Since the balloon is opaque, the amount of drug in the balloon can be determined as follows: after removing the plastic mouthpiece from the cylinder, 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.

You should clean the inhaler at least once a week. It is important to keep the mouthpiece of the inhaler clean so that particles of the drug substance do not block the release of the aerosol.

During cleaning, first remove the protective cap and remove the balloon from the inhaler.A stream of warm water is passed through the inhaler; it is necessary to make sure that the drug and/or visible dirt are removed. After cleaning, shake the inhaler and allow it to dry in the air, without using heating devices. Once the mouthpiece is dry, insert the bottle into the inhaler and put on the protective cap.

The contents of the cylinder are under pressure. The cylinder must not be opened and exposed to heat above 50°C.

Contraindications

Hypertrophic obstructive cardiomyopathy; tachyarrhythmia; I and III trimesters of pregnancy; children under 6 years of age (aerosol for inhalation); hypersensitivity to fenoterol and other components of the drug; hypersensitivity to atropine-like drugs.

With caution: angle-closure glaucoma, arterial hypertension, diabetes mellitus, recent myocardial infarction (within the last 3 months), heart and vascular diseases (chronic heart failure, coronary heart disease, arrhythmia, aortic stenosis, severe lesions of the cerebral and peripheral arteries), hyperthyroidism, pheochromocytoma, prostatic hyperplasia, bladder neck obstruction, cystic fibrosis, II trimester of pregnancy, lactation, children and adolescents from 6 to 18 years of age (aerosol for inhalation).

Side effects

the Frequency of adverse reactions was determined in accordance with who recommendations: very often (>1/10); often (>1/100, <1/10); infrequently (>1/1000, <1/100); rare (>1/10 000, <1/1000); very rare (<1/10 000), including individual messages; frequency unknown (frequency cannot be estimated according to the available data).

From the immune system: rarely – hypersensitivity reactions, anaphylactic reactions.

From the side of metabolism and nutrition: rarely-hypokalemia, metabolic acidosis.

Mental disorders: infrequently-nervousness; rarely – feelings of anxiety, mental disorders.

Nervous system disorders: infrequently – headache, dizziness, tremor.

From the side of the visual organ: rarely – glaucoma, increased intraocular pressure, accommodation disorders, mydriasis, blurred vision, eye pain, corneal edema, conjunctival hyperemia, the appearance of a halo around objects and colored spots in front of the eyes.

From the cardiovascular system: infrequently-tachycardia, palpitation, increased systolic blood pressure; rarely-arrhythmia, atrial fibrillation, supraventricular tachycardia, myocardial ischemia, increased diastolic blood pressure.

Respiratory system disorders: often-cough; infrequently-pharyngitis, dysphonia; rarely-bronchospasm, pharyngeal irritation, pharyngeal edema, laryngospasm, paradoxical bronchospasm, dry throat.

From the digestive system: infrequently-vomiting, dry mouth, nausea; rarely-stomatitis, glossitis, gastrointestinal motility disorders, constipation, diarrhea, oral edema.

Dermatological reactions: rarely – urticaria, skin rash, pruritus, angioedema, hyperhidrosis.

Musculoskeletal disorders: rarely-muscle weakness, myalgia, muscle spasm.

From the urinary system: rarely-urinary retention.

Interaction

Concomitant use of other beta-adrenomimetics, anticholinergics, and xanthine derivatives (such as theophylline) may increase the bronchodilator effect of the drug.

It is possible to significantly weaken the bronchodilator effect of the drug with the simultaneous appointment of beta-blockers.

Hypokalemia associated with the use of beta-adrenomimetics may be increased by concomitant use of xanthine derivatives, corticosteroids, and diuretics. This fact should be given special attention in the treatment of patients with severe obstructive airway diseases.

Hypokalemia may lead to an increased risk of arrhythmias in patients receiving digoxin. In addition, hypoxia can increase the negative effect of hypokalemia on the heart rate. In such cases, it is recommended to monitor the concentration of potassium in the blood serum.

Caution should be exercised when prescribing beta_-2-adrenomimetics to patients treated with MAO inhibitors and tricyclic antidepressants, since these drugs can enhance the effect of beta-adrenergic agents.

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

The combined use of the drug with Cromoglicic acid and / or GCS increases the effectiveness of therapy.

Functional features

The therapeutic effect of the combination of ipratropium bromide and fenoterol hydrobromide is due to local action in the respiratory tract. There is no evidence that the pharmacokinetics of the combined drug differ from those of each of the individual components.

Ipratropium bromide

With the inhaled route of use, ipratropium bromide is characterized by extremely low absorption from the respiratory mucosa. The concentration of the Active ingredient in plasma is at the lower limit of determination, and it can only be measured when using high doses of the Active ingredient. After inhalation,10-30% of the administered dose usually enters the lungs (depending on the dosage form and method of inhalation). Most of the dose is swallowed and enters the gastrointestinal tract. Part of the dose of the drug that enters the lungs quickly reaches the systemic bloodstream (within a few minutes). The total systemic bioavailability of ipratropium bromide administered by inhalation is 7-28%.

Being a quaternary nitrogen derivative, it is poorly soluble in fats and weakly penetrates biological membranes. It doesn’t accumulate. Ipratropium bromide binds to plasma proteins to a minimal extent (less than 20%).

It is metabolized in the liver. Up to 8 metabolites of ipratropium are known to bind weakly to muscarinic receptors. It is excreted mainly through the intestines, as well as by the kidneys. About 25% is excreted unchanged, the rest in the form of numerous metabolites.

Fenoterol

Depending on the method of inhalation and the inhalation system used, about 10-30% of the Active ingredient reaches the lower respiratory tract, the rest is deposited in the upper respiratory tract and swallowed. As a result, a certain amount of inhaled fenoterol enters the gastrointestinal tract. Absorption is two-phase : 30% of fenoterol is rapidly absorbed at T_1/2 11 min,70% is absorbed slowly at T_1/2 120 min. There is no correlation between the plasma concentrations of fenoterol achieved after inhalation and AUC. The long-term bronchodilator effect of the drug after inhalation, comparable to the corresponding effect achieved after intravenous use, is not supported by high concentrations of the Active ingredient in the systemic circulation. After oral use, about 60% of fenoterol is absorbed. The time to reach_cmax in blood plasma is 2 hours.

Binding to plasma proteins is 40-55%. Fenoterol in unchanged form penetrates the placental barrier and is excreted in breast milk.

It is metabolized in the liver. After 24 hours,60% of the intravenous dose and 35% of the oral dose are excreted in the urine. This proportion of the Active ingredient undergoes biotransformation due to the “first pass” effect through the liver, as a result of which the bioavailability of the drug after oral use decreases to approximately 1.5%. This explains the fact that the ingested amount of the drug practically does not affect the level of the Active ingredient in the blood plasma reached after inhalation. Biotransformation of fenoterol in humans occurs mainly by conjugation with sulfates in the intestinal wall.

It is excreted by the kidneys and bile in the form of inactive sulfate conjugates. When parenterally administered, fenoterol is excreted in a three – phase model with T_1/2-0.42 min,14.3 min and 3.2 h, respectively.

Special instructions

The patient should be informed that if there is an unexpected rapid increase in shortness of breath (difficulty breathing), they should immediately consult a doctor.

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 an alternative therapy should be switched.

Long-term use

In patients with bronchial asthma, the drug should only be used as needed. In patients with mild COPD, symptomatic treatment may be preferable to regular use.

In patients with bronchial asthma, one should be aware of the need to conduct or strengthen 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 beta_-2-adrenomimetics to stop bronchial obstruction may cause uncontrolled deterioration of the disease. In the case of increased bronchial obstruction, increasing the dose of beta_-2agonists beyond the recommended dose for a long time is not only not justified, but also dangerous. To prevent a 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 administered simultaneously with the drug only under medical supervision.

Visual disturbances

The drug should be administered with caution in patients predisposed to the development of angle-closure glaucoma.There are isolated reports of complications from the visual organ (for example, increased intraocular pressure, mydriasis, angle-closure glaucoma, eye pain) that developed when inhaled ipratropium bromide (or ipratropium bromide in combination with beta_-2-adrenergic agonists) got into the eyes. Symptoms of acute angle-closure glaucoma may include pain or discomfort in the eyes, blurred vision, the appearance of halos in objects and colored spots in front of the eyes in combination with corneal edema and redness of the eyes, due to conjunctival injection of blood vessels. If there is any combination of these symptoms, the use of eye drops that reduce intraocular pressure is indicated, and immediate consultation with a specialist. Patients should be instructed about the correct use of the inhaled solution. To prevent the solution from getting into the eyes, it is recommended that the solution used with the nebulizer be inhaled through the mouthpiece. In the absence of a mouthpiece, use a mask that fits snugly to the face. Special care should be taken to protect the eyes of patients predisposed to the development of glaucoma.

System 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, with 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 exceeding the recommended ones.

Impact on the cardiovascular system

In post-marketing studies, rare cases of myocardial ischemia have been reported when taking beta-adrenergic agonists. Patients with concomitant serious heart conditions (such as CHD, arrhythmias, or severe heart failure) receiving the drug should be warned to consult a doctor if they experience heart pain or other symptoms that indicate a worsening of heart disease. It is necessary to pay attention to symptoms such as shortness of breath and chest pain, as they can be both cardiac and pulmonary etiology.

Hypokalemia

_{Hypokalemia may occur when beta-2}-adrenergic agonists are used.

In athletes, the use of the drug, due to the presence of fenoterol in its composition, can lead to positive results of doping tests.

Auxiliary substances

The preparation in the form of an aerosol for inhalation contains a preservative, benzalkonium chloride, and a stabilizer-disodium edetate dihydrate. During inhalation, these components can cause bronchospasm in sensitive patients with hyperreactivity of the respiratory tract.

Influence on the ability to drive vehicles and mechanisms

The effect of the drug on the ability to drive vehicles and use mechanisms has not been specifically studied. However, patients should be informed that during treatment with the drug, adverse events such as dizziness, tremor, accommodation disorders, mydriasis, blurred vision may develop. Therefore, caution should be recommended when driving vehicles or using machinery. If patients experience the above-mentioned undesirable sensations, they should refrain from such potentially dangerous activities as driving vehicles or operating mechanisms.

Active ingredient

Ipratropium bromide, Fenoterol

Conditions of release from pharmacies

By prescription

Dosage form

powder for inhalation