Inspirax, 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 vagus nerve endings.

The 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 bronchial smooth muscles. 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 ipratropium bromide and fenoterol are used together, the bronchodilator effect is achieved by affecting different pharmacological targets.

The above substances complement each other, 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 obstruction is provided. 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 up to 6 h after administration.

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.

.

Active ingredient

Ipratropium bromide, Phenoterol

Composition

The solution for inhalation is clear, colorless or nearly colorless, odorless.

Excipients:

sodium chloride – 8.8 mg,

hydrochloric acid solution 1M – 0.88 mg,

sodium edetate – 0.5 mg,

benzalkonium chloride – 0.1 mg,

purified water – up 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 given special attention when treating patients with severe forms of obstructive airway 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 on 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 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). 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.

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-mentioned undesirable sensations it is necessary to refrain from potentially dangerous activities such as driving vehicles or operating machinery.

.

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.

Perior urinary system disorders: rarely – urinary retention.

.