Astmasol Neo, aerosol 20 mcg/dose+50 mcg/dose 200 doses

Bronchodilator combined (m-cholinoblocker + ß2-adrenomimetic selective) ATX code: R03AL01 Pharmacological properties

Pharmacodynamics

The drug contains two components with bronchodilator activity: ipratropium bromide – m-cholinoblocker and fenoterol – ß2-adrenomimetic.

The bronchodilation by inhaled administration of ipratropium bromide is mainly due to local rather than systemic anticholinergic action.

Ipratropium bromide is a quaternary ammonium derivative with anticholinergic (parasympatholytic) properties. Ipratropium bromide inhibits vagus nerve reflexes. Anticholinergic agents prevent an increase in intracellular calcium ion concentration, 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 disease (chronic bronchitis and pulmonary emphysema), a significant improvement in lung function (increase in forced expiratory volume in 1 second (OOB1) and peak expiratory flow (PEF) by 15% or more) is observed within 15 minutes, the maximum effect is achieved after 1-2 hours and continues in most patients up to 6 hours after administration.

Ipratropium bromide has no adverse effect on airway mucus secretion, mucociliary clearance and gas exchange.

Phenoterol selectively stimulates ß2-adrenoreceptors at therapeutic dose.

Stimulation of ß2-adrenoceptors occurs at high doses.

Phenoterol relaxes the smooth muscles of the bronchi and blood vessels and counteracts bronchoconstriction reactions caused by histamine, methacholine, cold air and allergens (immediate-type hypersensitivity reactions).

Fenoterol blocks the release of mediators of inflammation and bronchoobstruction from mast cells immediately after administration. In addition, increased mucociliary clearance has been observed with fenoterol doses of 0.6 mg.

The ß-adrenergic (ß-adrenoreceptor stimulating) effects of the drug on cardiac activity, such as increased heart rate and force, are due to the vascular action of fenoterol, stimulation of ß2-adrenoreceptors of the heart, and when using doses greater than therapeutic, stimulation of ß1-adrenoreceptors.

As with other ß-adrenergic drugs, prolongation of the QTC interval is noted with high doses. When fenoterol was used with metered dose aerosol inhalers (MDIs), this effect was inconsistent and was noted when doses higher than recommended were used.

Tremor is the most common undesirable effect when using ß-adrenoreceptor agonists. When these two active agents are used together, the bronchodilator effect is achieved by affecting different pharmacological targets. These substances complement each other, and as a result the antispasmodic effect on the bronchial muscles is increased and a greater breadth of therapeutic action in bronchopulmonary diseases accompanied by airway constriction is provided.

The complementary action is such that a lower dose of the ß-adrenergic component is required to achieve the desired effect, allowing an individualized effective dose with virtually no side effects.

In acute bronchoconstriction, the effect of the drug develops quickly, allowing it to be used in acute attacks of bronchospasm.

Pharmacokinetics

There is no evidence that the pharmacokinetics of the combined product containing ipratropium bromide and phenoterol differ from those of each of the individual components.

Ipratropium bromide absorption

Ipratropium bromide. When administered by inhalation, ipratropium bromide is characterized by extremely low absorption from the respiratory mucosa.

The plasma concentration of ipratropium bromide is at the lower limit of determination, and can only be measured when high doses of the active substance are used. After inhalation the lungs usually receive (depending on the dosage form and inhalation method) 10-30% of the administered dose of ipratropium bromide. Most of the dose is swallowed and enters the gastrointestinal tract.

A portion of the dose of ipratropium bromide that enters the lungs quickly reaches the systemic bloodstream (within minutes). The total systemic bioavailability of ipratropium bromide administered orally and inhaled is 2% and 7-28%, respectively.

Phenoterol.

Depending on the method of inhalation and the inhalation system used, about 10-30% of fenoterol reaches the lower airways, and the rest is deposited in the upper airways and swallowed. As a result, some amount of inhaled fenoterol reaches the gastrointestinal tract.

As absorption is biphasic – 30% of fenoterol is rapidly absorbed with a half-life (T½) of 11 minutes, and 70% is slowly absorbed with a T½ of 120 minutes. There is no correlation between the plasma concentrations of fenoterol achieved after inhalation and the pharmacodynamic “time-effect” curve. Long-term (3-5 hours) bronchodilator effect after inhalation, comparable with the corresponding effect achieved after intravenous administration, is not supported by high concentrations of fenoterol in the systemic bloodstream. After oral administration, about 60% of fenoterol is absorbed. Time of reaching maximum plasma concentration is 2 hours.

Distribution

Ipratropium bromide, which is a quaternary amine, 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%). There are no data on the possibility of penetration of ipratropium bromide through the placental barrier and into the breast milk.

Phenoterol is intensively distributed to organs and tissues. Binding with blood plasma proteins is 40-55%. Fenoterol passes through the placental barrier unchanged and is excreted with breast milk.

Metabolism

Ipratropium bromide is metabolized by oxidation mainly in the liver. Up to 8 metabolites of ipratropium bromide are known, which bind weakly to muscarinic receptors and are considered inactive.

Phenoterol 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 fraction of fenoterol undergoes biotransformation due to the “primary passage” effect through the liver, causing the bioavailability of the drug to fall to approximately 1.5% after oral administration. This explains the fact that the swallowed amount of the drug has almost no effect on the plasma concentration of the active substance achieved after inhalation. Biotransformation of fenoterol in humans occurs primarily by conjugation with sulfates in the intestinal wall.

Ipratropium bromide is excreted mainly through the intestine and also through the kidneys. About 25% is excreted unchanged, the rest is excreted as metabolites.

Phenoterol is excreted by the kidneys and with bile as inactive sulfate conjugates.

In parenteral administration, phenoterol 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

Pharmacokinetics of the combined product containing ipratropium bromide and fenoterol have not been studied in diabetic patients, elderly patients, children, and patients with liver or renal dysfunction.

Indications

Prevention and symptomatic treatment of obstructive airway diseases with reversible airway obstruction: chronic obstructive pulmonary disease (COPD), bronchial asthma, chronic bronchitis complicated or uncomplicated by emphysema.

Active ingredient

Ipratropium bromide, Phenoterol

Composition

Per 1 dose

Active ingredients:

ipratropium bromide monohydrate 0.021 mg, in terms of ipratropium bromide 0.020 mg

Fenoterol hydrobromide 0.050 mg

Excipients:

Anhydrous ethanol (absolute ethyl alcohol) 13.313 mg

Water for injection 0.799 mg

How to take, the dosage

The dose should be adjusted individually. In the absence of other doctor’s instructions, the following doses are recommended:
Adults and children over 6 years

Treatment of attacks

In most cases, 2 inhalation doses of aerosol are sufficient to relieve symptoms. If there is no relief of breathing within 5 minutes, an additional 2 inhalation doses may be used.

If there is no effect after 4 inhalation doses and additional inhalation doses are needed, seek medical attention immediately.

Intermittent and prolonged therapy

Ingest 1-2 inhalations at a time, up to 8 inhalations per day (average of 1-2 inhalations 3 times a day). In bronchial asthma, the drug should be used only as needed.

The drug should only be used in children by prescription and under adult supervision.

Interaction

Long-term concomitant use of the drug with other angicholinergic drugs is not recommended due to the lack of data.
Concomitant use of other ß-adrenomimetic and anticholinergic drugs, including systemic action, and xanthine derivatives (eg, theophylline) may enhance the bronchodilator effect of the drug and lead to increased adverse reactions.

Possible decrease of bronchodilator action of the medicine during simultaneous prescription of ß-adrenoblockers.

Hypokalemia associated with the use of ß-adrenomimetics may be increased by simultaneous prescription of xanthine derivatives, glucocorticosteroids and diuretics. This fact should be paid special attention when treating patients with severe forms of obstructive airways diseases. Hypokalemia may lead to an increased risk of arrhythmias in patients receiving digoxin. In addition, hypoxia may increase the negative effect of hypokalemia on cardiac rhythm. In such cases, monitoring of plasma potassium concentration is recommended.

Caution should be exercised when prescribing ß2-adrenergic drugs in patients receiving monoamine oxidase inhibitors and tricyclic antidepressants, since these drugs can enhance the effect of ß-adrenergic drugs.
Inhalation of agents for general anesthesia such as halogenated hydrocarbon anesthetics (halothane, trichloroethylene, enflurane) may increase the adverse effect of ß-adrenergic agents on the cardiovascular system.

Combined use of the drug with cromoglycic acid and/or glucocorticosteroids increases the effectiveness of therapy

Special Instructions

Dyspnea

In case of sudden rapid onset of dyspnea (difficulty in breathing), consult a physician immediately.

In children

In children, Astmasol® neo should only be used as prescribed by a physician and under adult supervision.
Use in children under 6 years of age is contraindicated due to lack of experience of use.

Hypersensitivity

After using Astmasol® neo it is possible to have immediate hypersensitivity reactions, the signs of which in rare cases can be: urticaria, angioedema, rash, bronchospasm, oropharyngeal edema, anaphylactic shock.

Paradoxical bronchospasm

Astmasol® neo, like other inhaled medicines, may cause paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm develops, use of Astmasol® neo should be discontinued immediately and alternative therapy should be switched to.

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.

Patients with bronchial asthma should be mindful of the need for anti-inflammatory therapy to control airway inflammation and the course of the disease.

The regular use of increasing doses of drugs containing ß2-adrenomimetics, such as Astmasol® neo, to relieve bronchial obstruction may cause uncontrolled worsening of the disease course. In case of worsening of bronchial obstruction, increasing the dose of ß2-adrenomimetics, including Astmasol® neo, beyond the recommended dose for a long time is not only unreasonable, but also dangerous. A review of the patient’s treatment plan and adequate anti-inflammatory therapy with inhaled glucocorticosteroids should be considered to prevent a life-threatening worsening of the disease course.

Other sympathomimetic bronchodilators should be administered concomitantly with Astmasol® Neo under medical supervision only.

Gastrointestinal disorders

In patients with a history of cystic fibrosis, gastrointestinal motility disorders are possible.

Visual disorders

Astmasol® neo must be used with caution in patients with a predisposition to closed-angle glaucoma. There have been anecdotal reports of ocular complications (e.g., increased intraocular pressure, mydriasis, closed-angle glaucoma, eye pain) from inhaled ipratropium bromide (or ipratropium bromide combined with ß2-adrenomimetics) in the eye.

The symptoms of acute closed-angle glaucoma may include pain or discomfort in the eyes, blurred vision, haloing around objects and colored spots in front of the eyes, combined with corneal edema and redness of the eyes due to conjunctival hyperemia. If any combination of these symptoms develops, eye drops to decrease intraocular pressure and immediate consultation with a specialist are indicated.

Patients should be instructed on the proper use of Astmasol® neo inhalation medication. Patients with a predisposition to glaucoma should be especially careful to protect their eyes.

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 neck obstruction) Astmasol® neo should be used only after careful risk/benefit assessment, especially when using doses higher than recommended.

Impacts on the cardiovascular system

Rare cases of myocardial ischemia have been reported when taking ß2-adrenomimetics. Patients with concomitant serious heart disease (e.g., coronary heart disease, arrhythmias, or severe heart failure) receiving Astmasol® neo 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 when using ß2-adrenomimetics (see section on Overdose).
In athletes, the use of Astmasol® Neo may lead to positive results in doping tests due to its presence in phenoterol. It should be taken into consideration that the drug contains a small amount of ethanol (13,313 mg in one dose).

Impact on driving and operating machinery

There have been no studies of the effect of the drug on driving and operating machinery.
Caution should be exercised when performing these activities since dizziness, tremor, eye accommodation disorders, mydriasis and blurred vision may occur. In case of the above-mentioned undesirable effects, one should refrain from potentially dangerous activities, such as driving vehicles and operating machinery.

Contraindications

Hypertrophic obstructive cardiomyopathy, tachyarrhythmia, hypersensitivity to phenoterol hydrobromide, atropine-like substances or any other components of the drug. 1st trimester of pregnancy, children under 6 years of age.

With caution

. The drug should be used with caution in patients with such diseases as closed-angle glaucoma, coronary insufficiency, arterial hypertension, insufficiently controlled diabetes, recently suffered myocardial infarction, severe organic heart and vascular diseases, hyperthyroidism, pheochromocytoma, prostatic hypertrophy, bladder cervical obstruction, cystic fibrosis, childhood.

Side effects

Many of the listed undesirable effects may be a consequence of anticholinergic and ß-adrenergic properties of the drug. Use of Astmasol® neo, like any inhalation therapy, may cause local irritation.

The most common adverse effects reported in clinical trials were cough, dry mouth, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, palpitation, vomiting, increased systolic blood pressure and nervousness.
The frequency of adverse reactions that may occur during therapy was determined in accordance with the recommendations of the World Health Organization: Very common (>1/10), common (>1/100, < 1/10), infrequent (>1/1000, < 1/100), rare (>1/10000, < 1/1000), very rare (< 1/10000), unspecified frequency (frequency cannot be estimated from available data).

Immune system disorders. Rare: anaphylactic reaction, hypersensitivity.
Metabolic and nutritional disorders. Rare: hypokalemia.

Psychiatric disorders. Infrequent: nervousness. Rare: agitation, mental disorders.

Nervous system disorders. Infrequent: headache, tremor, dizziness.

VIight organ disorders. Rare: glaucoma, increased intraocular pressure, accommodation disorders, mydriasis, blurred vision, eye pain, corneal edema, conjunctival hyperemia, appearance of a halo around objects.

Cardiovascular system disorders. Infrequent: increased heart rate, tachycardia, palpitations. Rare: arrhythmia, atrial fibrillation, supraventricular tachycardia, myocardial ischemia.

Respiratory, thoracic and mediastinal disorders. Often: cough. Infrequent: pharyngitis and dysphonia. Rare: bronchospasm, pharyngeal irritation, pharyngeal edema, laryngospasm, paradoxical bronchospasm, dry pharynx.

Gastrointestinal tract disorders. Infrequent: vomiting, nausea, dry mouth. Rare: stomatitis, glossitis, gastrointestinal motility disorders, diarrhea, constipation, edema of the oral cavity.

Skin and subcutaneous tissue disorders. Rare: urticaria, itching, rash, angioedema, hyperhidrosis.

Muscular and connective tissue disorders. Rarely: muscle weakness, muscle spasm, myalgia.

Rare disorders of the kidneys and urinary tract. Rare: urinary retention.

Laboratory and instrumental data. Infrequent: increase in systolic blood pressure. Rarely: increase in diastolic blood pressure.

Overdose

Symptoms

Symptoms of overdose are usually associated with the effects of fenoterol. Symptoms due to overstimulation of (3-adrenoreceptors may occur. The most probable are tachycardia, palpitations, tremors, arterial hypertension or arterial hypotension, increased difference between systolic and diastolic blood pressure, increased pulse pressure, increased angina pains, arrhythmia and feeling of blood “rush” to the face, metabolic acidosis, hypokalemia, feeling of heaviness behind the chest, increased bronchoobstruction.

Possible symptoms of ipratropium bromide overdose (such as dry mouth, eyes accommodation disorders), taking into account the wide therapeutic action of the drug and local method of administration, are usually poorly expressed and temporary.

Treatment

The drug administration must be stopped. The blood acid-base balance monitoring data should be taken into account. The use of sedative drugs, anxiolytic drugs (tranquilizers), in severe cases – intensive therapy is recommended.
As a specific antidote the use of (ß-adrenoblockers, preferably selective ß1-adrenoblockers is possible.

However, one should remember about the possible increase in bronchial obstruction under the influence of ß-adrenoblockers and carefully select the dose for patients with bronchial asthma or chronic obstructive pulmonary disease due to the risk of severe bronchospasm, which can lead to death.

Pregnancy use

Pregnancy

Existing clinical experience has shown that fenoterol and ipratropium have no adverse effects on pregnancy. Nevertheless, the usual precautions should be taken when using these drugs during pregnancy, especially in the first trimester. The inhibitory effect of fenoterol on uterine contractility should be taken into account.

Breastfeeding

Preclinical studies have shown that fenoterol hydrobromide can penetrate into breast milk. No such data have been obtained for ipratropium. Significant exposure of the infant to ipratropium, especially when used as an aerosol, is unlikely. Nevertheless, taking into account the ability of many drugs to penetrate into the breast milk, caution should be exercised when prescribing Astmasol® Neo to women who are breast feeding.

Similarities

Berodual, Berodual N