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

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

Ipratropium bromide is a quaternary ammonium derivative with anticholinergic (parasympatholytic) properties. Bronchodilation during inhalation administration of ipratropium bromide is mainly due to local rather than systemic anticholinergic action. Ipratropium bromide inhibits vagus nerve reflexes by counteracting the effects of acetylcholine, a mediator released from the vagus nerve endings. Anticholinergic agents prevent the increased intracellular concentration of calcium ions that occurs due to the interaction of acetylcholine with muscarinic receptors located on bronchial smooth muscle. Calcium ion release is mediated by a system of secondary mediators, which include inositol triphosphate and diacylglycerol. Ipratropium bromide has no adverse effect on airway mucus secretion, mucociliary clearance, and gas exchange.

Phenoterol selectively stimulates β₂-adrenoreceptors at the therapeutic dose. Stimulation of β₁-adrenoreceptors occurs when fenoterol is used at high doses. Fenoterol relaxes the smooth muscles of the bronchi and vessels and counteracts the development of bronchospastic reactions due to the influence of histamine, methacholine, cold air and allergens (immediate-type hypersensitivity reactions). Immediately after administration, fenoterol blocks the release of mediators of inflammation and bronchoobstruction from mast cells. In addition, an increase in mucociliary clearance has been observed when using fenoterol in higher doses.

The effects of the drug on cardiac activity, such as increased heart rate and force, are due to the vascular action of fenoterol, the stimulation of β<₂ adrenoreceptors of the heart and, when used in doses greater than therapeutic, by stimulation of β₁ adrenoreceptors. As with other beta-adrenergic drugs, prolongation of the QT interval_c has been observed when used in high doses.

The most common adverse effect of β-adrenoreceptor agonists is tremor. In contrast to effects on bronchial smooth muscle tolerance may develop to systemic effects of β-adrenoreceptor agonists, but the clinical significance of this manifestation is not clear.

When using ipratropium bromide and fenoterol together, the bronchodilator effect is achieved by affecting different pharmacological targets. The mentioned substances complement each other, as a result the antispasmodic effect on the bronchial muscles increases and a wider therapeutic effect is achieved in case of bronchopulmonary diseases accompanied by airway obstruction. The complementary effect is such that a lower dose of the beta-adrenergic component is required to achieve the desired effect, which allows an individual selection of the effective dose with virtually no side effects.

In patients with bronchospasm associated with COPD (chronic bronchitis and pulmonary emphysema), a significant improvement in pulmonary function (increase in OEF₁ and peak expiratory rate by 15% or more) was noted within 15 min, the maximum effect was achieved in 1-2 h and lasted in most patients until 6 h after administration.

Indications

Active ingredient

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 1M solution – to pH 3.0-4.0, water d / i – to 1 ml.

Interaction

The concomitant use of other beta-adrenomimetics, anticholinergic drugs and xanthine derivatives (e.g., theophylline) may increase the bronchodilator effect of the drug.

The bronchodilator effect of the drug may be significantly impaired if beta-adrenoblockers are prescribed simultaneously.

The hypokalemia associated with the use of beta-adrenomimetics may be enhanced by concomitant use of xanthine derivatives, corticosteroids and diuretics. This fact should be paid special attention when treating patients with severe forms of obstructive airways disease.

Hypokalemia may increase the risk of arrhythmias in patients receiving digoxin. In addition, hypoxia may increase the negative effect of hypokalemia on heart rhythm. In such cases, monitoring of serum potassium concentration is recommended.

Beta2-adrenomimetics should be used with caution in patients who have received MAOI inhibitors and tricyclic antidepressants, because these drugs can potentiate the effects of beta-adrenergic agents.

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

The co-administration of the drug with cromoglycic acid and/or GCS increases the effectiveness of therapy.

Directions for use

Inhalation solution

The dose should be chosen individually, depending on the severity of the attack. Treatment usually begins with the lowest recommended dose and is discontinued when sufficient reduction in symptoms has been achieved.

Treatment should be done under medical supervision (e.g., in a hospital setting). Home treatment should only be undertaken in consultation with a physician if a low-dose, rapid-acting β-adrenoreceptor agonist is insufficient. An inhaled solution may be recommended for patients when an aerosol for inhalation cannot be used or when higher doses are necessary.

In adults (including the elderly) and adolescents over 12 years of age in acute attacks of bronchospasm, doses may vary from 1 ml (1 ml=20 drops) to 2.5 ml (2.5 ml=50 drops) depending on the severity of the attack. In particularly severe cases, doses as high as 4 ml (4 ml=80 drops) may be used.

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

In children under 6 years of age (body weight <22 kg), due to the fact that information about the use of the drug in this age group is limited, the following dose is recommended (subject to medical supervision only): 0.1 ml (2 drops) per kg of body weight, but no more than 0.5 ml (10 drops).

The rules for use

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

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

The inhalation solution should not be diluted with distilled water.

The dilution must be done each time before use; any leftover diluted solution must be discarded.

The diluted solution should be used immediately after preparation.

The duration of inhalation can be controlled by how much of the diluted solution is used.

The inhalation solution can be used with a variety of commercial nebulizer models. The dose reaching the lungs and the system 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). Where wall oxygen is available, the solution is best administered at a flow rate of 6-8 L/min.

The instructions for use, maintenance and cleaning of the nebulizer must be followed.

Dose Aerosol for inhalation

The dose is individualized.

To stop attacks, 2 inhalation doses are prescribed for adults and children over 6 years of age. If breathing relief does not occur within 5 minutes, 2 additional inhalation doses may be prescribed.

The patient should be informed to seek immediate medical attention if there is no effect after 4 inhalation doses and additional inhalations are needed.

Dosed aerosol in children should only be used when prescribed by a physician and under adult supervision.

For prolonged and intermittent therapy, 1-2 inhalations per administration, up to 8 inhalations/day (on average, 1-2 inhalations 3 times/day) are prescribed.

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

The rules for use of the drug

The patient should be instructed on the proper use of the metered dose aerosol.

The first time a metered dose aerosol can is used, the can should be squeezed the bottom twice.

The following rules should be followed each time the dispensed aerosol is used.

1. Remove the protective cap.

2. Take a slow, deep breath out.

3. while holding the balloon, cup your lips around the mouthpiece. The balloon must be pointing upward from the bottom.

4. While taking as deep a breath as possible, quickly press down on the bottom of the balloon until 1 inhalation dose is released. Hold your breath for a few seconds, then take the mouthpiece out of your mouth and breathe out slowly. Repeat for the 2nd inhalation dose.

5 Put on the protective cap.

6 If the aerosol can has not been used for more than 3 days, squeeze the bottom of the can once before use until the aerosol cloud appears.

The can is only good for 200 inhalations. The can should then be replaced. Even though there may still be some left in the can, the amount of medicine released will decrease.

Without transparency, the amount of product in the cylinder can be determined by removing the plastic nozzle from the cylinder and submerging it in a container full of water. The amount of the drug is determined depending on the position of the cylinder in the water.

The inhaler should be cleaned at least once a week. It is important to keep the mouthpiece of the inhaler clean so that particles of medication do not block the release of the aerosol.

When cleaning, first remove the protective cap and remove the can from the inhaler. A stream of warm water is run through the inhaler to ensure that the product and/or visible debris is removed. After cleaning, the inhaler should be shaken and allowed to air dry without the use of heating devices. Once the mouthpiece is dry, insert the can into the inhaler and put on the protective cap.

The contents of the bottle are pressurized. The bottle must not be opened or exposed to heat above 50°C.

Special Instructions

The patient should be informed that if there is a sudden rapid increase in dyspnea (difficulty in breathing), seek immediate medical attention.

Paradoxical bronchospasm

The drug may cause paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm develops, use of the drug should be discontinued immediately and alternative therapy should be used.

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, it should be remembered that anti-inflammatory therapy should be given or intensified to control airway inflammation and the course of the disease.

The regular use of increasing doses of drugs containing beta2-adrenomimetics to relieve bronchial obstruction may cause uncontrolled worsening of the disease course. If bronchial obstruction worsens, increasing the dose of beta2-agonists beyond the recommended dose for an extended period is not only unwarranted but also dangerous. A review of the patient’s treatment plan and adequate anti-inflammatory therapy with inhaled corticosteroids should be considered to prevent a life-threatening worsening of the disease course.

Other sympathomimetic bronchodilators should be administered concomitantly with the drug only under medical supervision.

Visual disorders

The drug should be administered with caution in patients predisposed to the development of closed-angle glaucoma. There have been isolated reports of ocular complications (e.g., increased intraocular pressure, mydriasis, closed-angle glaucoma, eye pain) from inhaled ipratropium bromide (or ipratropium bromide combined with β2 adrenoreceptor agonists) entering the eye. Symptoms of acute closed-angle glaucoma may include pain or discomfort in the eyes, blurred vision, haloing of objects and colored spots in front of the eyes, combined with corneal edema and red eyes, due to conjunctival vascular injection. If any combination of these symptoms is noted, application of eye drops that reduce intraocular pressure and immediate consultation with a specialist is indicated. Patients should be instructed on the proper use of the inhalation solution. To prevent eye contact with the solution, it is recommended that the solution used with the nebulizer be inhaled through a mouthpiece. If a mouthpiece is not available, a face mask that fits snugly over the face should be used. Particular care should be taken to protect the eyes of patients who are prone to developing glaucoma.

Systemic effects

. In conditions such as recent myocardial infarction, diabetes mellitus with inadequate glycemic control, severe organic heart and vascular disease, hyperthyroidism, pheochromocytoma, or urinary tract obstruction (such as in prostatic hyperplasia or bladder cervical obstruction), the drug should be prescribed only after careful risk/benefit assessment, especially when used in doses higher than recommended.

Impact on the cardiovascular system

In post-marketing studies, there have been rare cases of myocardial ischemia when taking β-adrenoreceptor agonists. Patients with concomitant serious heart disease (e.g., CHD, arrhythmias, or severe heart failure) receiving the drug should be warned to seek medical attention if heart pain or other symptoms suggestive of worsening heart disease occur. Symptoms such as shortness of breath and chest pain should be noted, as they may be of cardiac or pulmonary etiology.

Hypokalemia

Hypokalemia may occur with the use of β2 adrenoreceptor agonists.

In athletes, the use of the drug, due to its presence in phenoterol, may lead to positive results in doping tests.

Additional excipients

The product, in aerosol inhaled form, contains a preservative, benzalkonium chloride, and a stabilizer, disodium edetate dihydrate. During inhalation, these components may cause bronchospasm in sensitive patients with airway hyperresponsiveness.

The effect of the drug on the ability to drive vehicles and use 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 such adverse events as dizziness, tremor, accommodation disorder, mydriasis, blurred vision may occur. Therefore, caution should be recommended when driving motor transport or using machinery. If patients experience the above undesirable sensations it is necessary to refrain from potentially dangerous activities such as driving vehicles or operating machinery.

Features

The therapeutic effect of the combination of ipratropium bromide and fenoterol hydrobromide is a consequence of 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

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

As a quaternary nitrogen derivative, it is poorly soluble in fat and poorly penetrates through biological membranes. It does not cumulate. 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, which weakly bind to muscarinic receptors. It is excreted mainly through the intestine and also by the kidneys. About 25% is excreted unchanged, the rest as numerous metabolites.

Phenoterol

Depending on the inhalation method and inhalation system used, about 10-30% of the active substance reaches the lower airways, the rest is deposited in the upper airways and is swallowed. As a result, some amount of inhaled fenoterol enters the gastrointestinal tract. Absorption is biphasic – 30% of fenoterol is rapidly absorbed with T1/2 11 min, 70% is slowly absorbed with T1/2 120 min. There is no correlation between plasma concentrations of fenoterol achieved after inhalation and AUC. Long-term bronchodilator effect of the drug after inhalation, comparable with the corresponding effect achieved after IV administration, is not supported by high concentrations of the active substance in the systemic bloodstream. After oral administration, about 60% of phenoterol is absorbed. Time to reach Cmax in plasma is 2 hours.

The binding to plasma proteins is 40-55%. Fenoterol unchanged passes through the placental barrier and is excreted with breast milk.

Metabolized in the liver. After 24 hours, 60% of the administered intravenous dose and 35% of the ingested dose is excreted in the urine. This portion of the active substance undergoes biotransformation due to the “first pass” effect through the liver, as a result, the bioavailability of the drug after oral administration drops to approximately 1.5%. This explains the fact that the swallowed amount of the drug has almost no effect on the level of the active substance in blood plasma after inhalation. Biotransformation of fenoterol in humans occurs primarily by conjugation with sulfates in the intestinal wall.

Extracted by the kidneys and with the bile as inactive sulfate conjugates. When parenterally administered, phenoterol is excreted accordingly in a three-phase model with T1/2 of 0.42 min, 14.3 min and 3.2 h.

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: Closed-angle glaucoma, arterial hypertension, diabetes mellitus, recent myocardial infarction (within the last 3 months), heart and vascular disease (chronic heart failure, CHD, arrhythmia, aortic stenosis, pronounced lesions of cerebral and peripheral arteries), hyperthyroidism, pheochromocytoma, prostatic hyperplasia, bladder cervical obstruction, cystic fibrosis, II trimester pregnancy, lactation, children and teenagers from 6 to 18 years (aerosol for inhalation).

Side effects

The frequency of adverse reactions was determined according to WHO recommendations: Very common (>1/10); common (>1/100, <1/10); infrequent (>1/1000, <1/100); rare (>1/10 000, <1/1000); very rare (<1/10 000), including individual reports; frequency unknown (frequency cannot be calculated from available data).

Immune system disorders: rare – hypersensitivity reactions, anaphylactic reactions.

Metabolism and nutrition: rarely – hypokalemia, metabolic acidosis.

Mental disorders: infrequent – nervousness; rare – anxiety, mental disorders.

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

An organ of vision: rarely – glaucoma, increased intraocular pressure, accommodation disorders, mydriasis, blurred vision, eye pain, corneal edema, conjunctival hyperemia, appearance of a halo around objects and colored spots before eyes.

Cardiovascular system disorders: infrequent – tachycardia, palpitations, increased systolic blood pressure; rare – arrhythmia, atrial fibrillation, supraventricular tachycardia, myocardial ischemia, increased diastolic BP.

The respiratory system: frequently – cough; infrequently – pharyngitis, dysphonia; rarely – bronchospasm, pharyngeal irritation, pharyngeal edema, laryngospasm, paradoxical bronchospasm, dry throat.

The digestive system: infrequent – vomiting, dry mouth, nausea; rarely – stomatitis, glossitis, GI motility disorders, constipation, diarrhea, edema of the mouth.

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

Muscular system disorders: rare – muscle weakness, myalgia, muscle spasm.

The urinary system: rarely – urinary retention.

Similarities