Ipradual

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IPRAVAL

Composition:

Active substances: ipratropium bromide, fenoterol hydrobromide;

1 ml (20 drops) of inhalation solution contains ipratropium bromide 261 mcg, equivalent to 250 mcg of anhydrous ipratropium bromide; fenoterol hydrobromide 500 mcg;

Excipients: benzalkonium chloride, disodium edetate, sodium chloride, 1 M hydrochloric acid solution, purified water.

Pharmaceutical form. Inhalation solution.

Main physicochemical properties: colorless or almost colorless odorless solution.

Pharmacotherapeutic group.

Drugs for the treatment of obstructive respiratory diseases. Adrenergic agents in combination with anticholinergic agents. ATC code R03AL01.

Pharmacological Properties

Pharmacodynamics

The medicinal product Ipratual contains two active bronchodilator ingredients: ipratropium bromide, which exerts an anticholinergic effect, and fenoterol hydrobromide, which is a beta-adrenomimetic agent.

Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. It inhibits vagal reflexes through antagonistic interaction with acetylcholine, the neurotransmitter responsible for signal transmission via the vagus nerve. Anticholinergic agents prevent the increase in intracellular Ca++ concentration caused by acetylcholine binding to muscarinic receptors on smooth muscle. The release of Ca++ is mediated by another signaling system involving IP3 (inositol triphosphate) and DAG (diacylglycerol).

Bronchodilation following inhaled administration of ipratropium bromide is primarily due to the local, specific action of the drug, which is not systemic.

Fenoterol hydrobromide is a direct sympathomimetic agent that selectively stimulates beta2-adrenergic receptors within the therapeutic dose range. At higher doses, stimulation of beta1-adrenergic receptors may occur. Activation of beta2-adrenergic receptors leads, via the stimulatory Gs-protein, to activation of adenylate cyclase. Increased levels of cyclic adenosine monophosphate (cAMP) result in activation of protein kinase A and phosphorylation of specific proteins in smooth muscle cells. This leads to phosphorylation of myosin light chain kinase, inhibition of phosphoinositide hydrolysis, and opening of large calcium-activated potassium channels.

Fenoterol hydrobromide causes relaxation of bronchial and vascular smooth muscles and protects against bronchoconstrictor stimuli such as histamine, methacholine, cold air, and allergens (immediate-type reactions). After single-dose administration, fenoterol inhibits the release of bronchoconstrictor and pro-inflammatory mediators from mast cells. Following administration of fenoterol at a dose of 0.6 mg, improvement in mucociliary clearance has been observed.

At higher plasma concentrations of fenoterol—more commonly achieved with oral administration or even intravenous infusion—uterine relaxation has been observed. Additionally, at high doses, metabolic effects of the drug may occur: lipolysis, glycogenolysis, hyperglycemia, and hypokalemia, the latter resulting from increased cellular uptake of K+, particularly in skeletal muscle. The beta-adrenergic effects of fenoterol on the heart, including increased heart rate and cardiac contractions, are related to vascular effects of fenoterol, stimulation of cardiac beta2-adrenergic receptors, and, at supratherapeutic doses, stimulation of beta1-adrenergic receptors. As with other beta-adrenergic agents, QTc prolongation has been observed. For fenoterol in the form of metered aerosol, these effects are minimal and occur only at doses exceeding the recommended levels. However, systemic effects of fenoterol (solution for inhalation) following administration via nebulizer may be greater than with recommended doses of metered aerosol. Clinical significance has not been established. The most commonly observed adverse effect associated with beta-mimetics is tremor. In contrast to the effect on bronchial smooth muscles, systemic effects of beta-mimetics on skeletal muscles lead to the development of tolerance.

When two active bronchodilators are used concomitantly, bronchodilation occurs through two distinct pharmacological mechanisms. Thus, the two active substances exert a combined spasmolytic effect on bronchial muscles, allowing broad application in respiratory diseases associated with impaired airway patency. Effective combined action requires only a very small amount of beta-mimetic, enabling individual dose adjustment and reduction in the number of adverse reactions.

Pharmacokinetics

The therapeutic effect of the combination of ipratropium bromide and fenoterol hydrobromide is achieved through local action on the respiratory tract. Therefore, the pharmacokinetics of bronchodilation are not directly related to the pharmacokinetics of the active ingredients.

After inhalation, approximately 10–39% of the administered dose deposits in the lungs, depending on the formulation, inhalation technique, and delivery device. The remainder remains in the inhaler mouthpiece, mouth, and upper respiratory tract (oropharynx).

There is no evidence that the pharmacokinetics of the combination differ from those of the individual components.

Fenoterol hydrobromide. The portion of the drug that is swallowed is primarily metabolized into sulfate conjugates. Absolute bioavailability after oral administration is low (approximately 1.5%).

After intravenous administration, free fenoterol and conjugated fenoterol account for approximately 15% and 27% of the administered dose in 24-hour urine, respectively. After inhalation via the metered-dose aerosol Ipratual, approximately 1% of the inhaled dose is excreted as free fenoterol in 24-hour urine. Based on this, the total systemic bioavailability of inhaled fenoterol hydrobromide is estimated to be 7%.

Kinetic parameters characterizing the disposition of fenoterol were calculated based on plasma concentrations after intravenous administration. Following intravenous dosing, the AUC (area under the plasma concentration-time curve) can be described by a three-compartment model, with a terminal elimination half-life of approximately 3 hours. According to this three-compartment model, the steady-state volume of distribution (Vdss) of fenoterol is approximately 189 L (≈2.7 L/kg).

Approximately 40% of the drug is protein-bound in plasma. Preclinical animal studies have shown that fenoterol and its metabolites cross the blood-brain barrier. Total clearance of fenoterol is 1.8 L/min, and renal clearance is 0.27 L/min.

In excretion balance studies, total renal clearance (over 2 days) of radioactivity (including parent compound and all metabolites) accounted for 65% of the dose after intravenous administration, while total radioactivity in feces amounted to 14.8% of the dose. After oral administration, total radioactivity in urine was approximately 39% of the dose, and total radioactivity in feces was 40.2% of the dose over 48 hours.

Ipratropium bromide. Cumulative renal excretion (0–24 hours) of ipratropium (parent compound) was approximately 46% of the dose after intravenous administration, less than 1% after oral administration, and approximately 3–13% after inhalation via the metered-dose inhaler Ipratual. Based on these data, total systemic bioavailability of ipratropium bromide after oral and inhaled administration is estimated at 2% and 7–28%, respectively. Therefore, the swallowed portion of ipratropium bromide has negligible impact on systemic exposure.

Kinetic parameters characterizing the disposition of ipratropium were calculated based on plasma concentrations after intravenous administration. A rapid biphasic decline in plasma concentration is observed. The apparent volume of distribution at steady state (Vdss) is approximately 176 L (≈2.4 L/kg). The drug binds minimally (<20%) to plasma proteins. Preclinical animal studies indicate that the quaternary amine ipratropium does not cross the blood-brain barrier.

The elimination half-life of the terminal phase is approximately 1.6 hours. Total clearance of ipratropium is 2.3 L/min, with renal clearance at 0.9 L/min. After intravenous administration, approximately 60% of the dose is metabolized, likely primarily in the liver via oxidation.

In excretion balance studies, total renal clearance (over 6 days) of radioactivity (including parent compound and all metabolites) was 72.1% of the dose after intravenous administration, 9.3% after oral administration, and 3.2% after inhalation. Total radioactivity in feces was 6.3% of the dose after intravenous administration, 88.5% after oral administration, and 69.4% after inhalation. The primary route of elimination of radioactivity after intravenous administration is via the kidneys. The elimination half-life of total radioactivity (parent compound and all metabolites) is 3.6 hours. Binding of the main urinary metabolites to muscarinic receptors is negligible, and metabolites are considered pharmacologically inactive.

Clinical characteristics.

Indications

Prevention and symptomatic treatment of chronic obstructive airway diseases: allergic and non-allergic (endogenous) bronchial asthma; exercise-induced asthma; chronic obstructive bronchitis with or without emphysema.

During long-term therapy, concomitant anti-inflammatory treatment should be prescribed.

Contraindications

Hypersensitivity to fenoterol hydrobromide, atropine-like substances, or any other components of the drug; hypertrophic obstructive cardiomyopathy, tachyarrhythmia.

Interaction with other medicinal products and other forms of interactions

Concomitant long-term use of Ipradol with other anticholinergic agents has not been studied and therefore is not recommended.

Concomitant use of the following medicinal products/classes of medicinal products may affect the efficacy of Ipradol.

Enhancement of effect and/or increased risk of adverse reactions:

• other beta-adrenergic agents (all routes of administration);
• other anticholinergic agents (all routes of administration);
• xanthine derivatives (e.g., theophylline);
• anti-inflammatory agents (corticosteroids);
• monoamine oxidase inhibitors;
• tricyclic antidepressants;
• halogenated hydrocarbon anesthetics (e.g., halothane, trichloroethylene, and enflurane); particularly, they may potentiate effects on the cardiovascular system.

Reduction of effect:

• concomitant administration of beta-blockers.

Other possible interactions

Hypokalemia associated with the use of beta-adrenergic agonists may be intensified by concomitant use of xanthine derivatives, corticosteroids, and diuretics. This should be given special attention when treating patients with severe airway obstruction.

Hypokalemia may increase the risk of arrhythmias in patients receiving digoxin. In addition, hypoxia may potentiate the negative effects of hypokalemia on cardiac rhythm. In such cases, monitoring of serum potassium levels is recommended.

The risk of acute glaucoma attack (see section "Special precautions") is increased both by inadvertent exposure of nebulized ipratropium to the eyes and by its use in combination with beta2-agonists.

Also, the use of Ipradol may reduce the hypoglycemic effect of antidiabetic medicinal products. However, this is expected only at high doses, typically used for systemic administration (in tablet form or by injection/infusion).

If inhalational anesthetics are planned, fenoterol administration should be discontinued at least 6 hours prior to the start of anesthesia.

Special precautions for use.

In case of acute dyspnea (difficulty breathing) that rapidly progresses, immediate medical attention should be sought.

Like other inhaled medicinal products, the medicinal product Ipradol may cause paradoxical bronchospasm, which can be life-threatening. If paradoxical bronchospasm occurs, administration of Ipradol should be discontinued immediately and alternative therapy initiated.

Conditions in which the medicinal product Ipradol should be used only after careful risk/benefit assessment, especially if the dose exceeds the recommended dose:

• Poorly controlled diabetes mellitus;
• Recent myocardial infarction;
• Myocarditis;
• Severe organic heart or vascular disease (particularly in the presence of tachycardia);
• Hyperthyroidism;
• Pheochromocytoma;
• Use of cardiac glycosides;
• Severe and untreated arterial hypertension;
• Aneurysm.

When using sympathomimetic medicinal products, including Ipradol, cardiovascular effects may occur. Post-marketing data and literature publications report isolated cases of myocardial ischemia associated with beta-agonists. Patients with underlying severe cardiac disease (e.g., ischemic heart disease, arrhythmia, or severe heart failure) who are using Ipradol should be advised to seek immediate medical help if they experience chest pain or other symptoms of cardiac dysfunction. Careful evaluation of symptoms such as dyspnea and chest pain is essential, as they may have either respiratory or cardiac origin.

The medicinal product Ipradol, like other anticholinergic agents, should be used with caution in:

• Patients predisposed to narrow-angle glaucoma;
• Patients with existing obstruction of the urinary tract (e.g., benign prostatic hyperplasia or intravesical obstruction);
• Patients with renal impairment;
• Patients with hepatic impairment.

There have been reports of isolated cases of ocular complications (mydriasis, increased intraocular pressure, narrow-angle glaucoma, eye pain) resulting from accidental ocular exposure to ipratropium bromide aerosol or its combination with beta2-agonists.

Warning! Patients must be thoroughly instructed on the proper use of Ipradol inhalation solution. Care should be taken to avoid spraying the product into the eyes.

Symptoms of acute narrow-angle glaucoma include:

• Eye pain or discomfort;
• Blurred vision;
• Perception of halos around lights;
• Perception of colored halos or spots before the eyes;
• Redness of the eye due to conjunctival or corneal hyperemia.

If any of the above symptoms occur in combination, treatment with miotic eye drops should be initiated immediately and specialized medical help sought without delay.

Patients with cystic fibrosis may be more susceptible to gastrointestinal motility disorders when using this product.

Long-term use

• In patients with bronchial asthma, the medicinal product Ipradol should be used only as needed. In patients with mild chronic obstructive pulmonary disease (COPD), "on-demand" treatment (symptomatic therapy) may be more appropriate than regular use.
• It should be remembered that anti-inflammatory therapy should be initiated or intensified to control airway inflammation and prevent worsening of disease control in patients with bronchial asthma or steroid-dependent forms of COPD.

Regular use of increased doses of beta2-agonist-containing products, such as Ipradol, to relieve bronchial obstruction symptoms may lead to worsening disease control.

If bronchial obstruction worsens, simply increasing the dose of beta2-agonists, including Ipradol, beyond the recommended level over a prolonged period is not only unjustified but also dangerous. To prevent life-threatening deterioration, the patient's treatment plan should be reassessed, and adequate anti-inflammatory therapy with inhaled corticosteroids should be considered.

Several cases of increased risk of severe complications of the underlying disease, including fatalities, have been reported during long-term treatment of bronchial asthma with excessively high doses of inhaled beta2-sympathomimetics without adequate anti-inflammatory therapy. A causal relationship has not been fully established. However, adequate anti-inflammatory therapy is critically important.

Other sympathomimetic bronchodilators should be co-administered with Ipradol only under medical supervision (see section "Interaction with other medicinal products and other forms of interaction").

Hypokalemia, potentially serious, may occur with high-dose beta2-agonist therapy (see section "Overdose"). Monitoring of serum potassium levels is recommended in patients with low baseline potassium levels. Increased blood glucose levels may also occur. Therefore, blood glucose levels should be monitored in diabetic patients.

Rarely, immediate hypersensitivity reactions such as urticaria, angioedema, rash, bronchospasm, oropharyngeal swelling, and allergic reactions may occur after administration of Ipradol.

The product contains the preservative benzalkonium chloride and the stabilizer disodium edetate dihydrate. These components may cause bronchospasm in patients with hyperreactive airways.

Use of the medicinal product Ipradol may result in positive doping test results.

Use during pregnancy or breastfeeding

Preclinical data have not shown any adverse effects of fenoterol and ipratropium on pregnancy. However, usual precautions should be observed when using medicinal products during pregnancy. The inhibitory effect of fenoterol on uterine contractility should be considered. Use of beta2-sympathomimetics at the end of pregnancy or in high doses may adversely affect the neonate (tremor, tachycardia, blood glucose fluctuations, hypokalemia).

Fenoterol hydrobromide is excreted in breast milk. Data on the excretion of ipratropium into breast milk are lacking. It is unlikely that ipratropium would reach the infant in significant amounts, especially when administered by inhalation. Ipradol should be used with caution in breastfeeding women.

Data on the effects of combined or individual use of ipratropium bromide and fenoterol hydrobromide on fertility are lacking. Preclinical studies with the individual components—ipratropium bromide and fenoterol hydrobromide—showed no adverse effects on fertility.

Effects on ability to drive and use machines.

No studies have been conducted. Patients should be warned about the possible occurrence of adverse reactions such as dizziness, tremor, accommodation disorders, mydriasis, and blurred vision when using Ipradol. Caution should be exercised when driving or operating machinery. If any adverse reactions occur, patients should avoid potentially hazardous activities.

Method of Administration and Dosage

For inhalation only using a nebulizer.

Treatment should be initiated and conducted under medical supervision, for example, in a hospital setting.

Home treatment, after consultation with an experienced physician, may be recommended for patients in whom low-dose, short-acting beta-agonists such as the medicinal product Ipratropium bromide and fenoterol hydrobromide (Ipratropium Bromide and Fenoterol Hydrobromide) metered-dose aerosol have been insufficient to relieve symptoms. Home treatment may also be recommended for patients who require the use of a nebulizer for other reasons (e.g., due to difficulty using aerosols) or who require higher doses and are familiar with nebulizer use. Therapy should always be initiated with the lowest recommended dose.

The dose should be individually adjusted according to the severity of the acute episode.

Administration of the drug should be discontinued once symptom relief is achieved.

The inhalation solution is intended solely for inhalation via an appropriate nebulizer and must not be taken orally.

To prepare for administration, the recommended dose should be diluted with physiological saline (0.9%) to a final volume of 3–4 mL. The diluted, ready-to-use solution should be inhaled until adequate symptom relief is achieved.

The diluted, ready-to-use solution must be freshly prepared each time before use. The prepared solution should be used immediately after preparation; any remaining diluted solution must be discarded. Patients should follow the manufacturer's instructions for the nebulizer.

It is recommended to inhale the nebulized solution through a mouthpiece intended for use with a nebulizer. If a mouthpiece is not available, a face mask that fits tightly to the face should be used. Patients predisposed to developing glaucoma should take special care to protect their eyes.

The Ipratropium Bromide and Fenoterol Hydrobromide inhalation solution can be used with various nebulizer models. The total dose and the dose reaching the lungs depend on the nebulizer used and may be higher than with the Ipratropium Bromide and Fenoterol Hydrobromide metered-dose aerosol, depending on the device's efficiency.

Recommended Dosage Regimens

Adults and children aged 12 years and older

Emergency treatment of sudden bronchospasm attacks.

Depending on the severity of the acute attack, 1.0–2.5 mL of Ipratropium Bromide and Fenoterol Hydrobrom游戏副本

Adverse reactions.

Most of the adverse reactions listed below can be explained by the anticholinergic and beta-adrenergic properties of the medicinal product Ipratual.

Adverse reactions to the drug were identified based on data obtained during clinical trials and post-marketing pharmacovigilance.

Frequency according to the MedDRA Convention:

very common (≥ 1/10);

common (≥ 1/100, < 1/10);

uncommon (≥ 1/1,000, < 1/100);

rare (≥ 1/10,000, < 1/1,000);

very rare (<1/10,000);

frequency not known (cannot be estimated from the available data).

Immune system disorders:

rare – anaphylactic reactions*, hypersensitivity*;

frequency not known – purpura.

Metabolism and nutrition disorders:

rare – hypokalaemia;

very rare – increased blood glucose levels.

Psychiatric disorders:

uncommon – nervousness;

rare – agitation, psychiatric disorders.

Psychiatric disorders manifest as increased excitability, hyperactive behaviour, sleep disturbances and hallucinations. These were observed mainly in children under 12 years of age.

Nervous system disorders:

uncommon – headache, tremor, dizziness;

frequency not known – hyperactivity.

Eye disorders:

rare – glaucoma*, increased intraocular pressure*, accommodation disorder*, mydriasis*, blurred vision*, eye pain*, corneal oedema*, conjunctival hyperaemia*, visual halos*.

Cardiac disorders:

uncommon – tachycardia, palpitations;

rare – arrhythmia, atrial fibrillation, supraventricular tachycardia*, myocardial ischaemia*;

frequency not known – angina pectoris, ventricular extrasystoles.

Respiratory, thoracic and mediastinal disorders:

common – cough;

uncommon – pharyngitis, dysphonia;

rare – bronchospasm, throat irritation, pharyngeal oedema, laryngospasm*, paradoxical bronchospasm (induced by inhalation)*, dry throat*;

frequency not known – local irritation.

Gastrointestinal disorders:

uncommon – nausea, vomiting, dry mouth;

rare – stomatitis, glossitis, gastrointestinal motility disorder**, diarrhoea, constipation*, oedema of the oral mucosa*, heartburn.

Skin and subcutaneous tissue disorders:

rare – urticaria, rash, pruritus, angioedema*, petechiae, hyperhidrosis*.

Musculoskeletal and connective tissue disorders:

rare – muscle weakness, muscle spasm, myalgia.

Renal and urinary disorders:

rare – urinary retention.

Investigations:

uncommon – increased systolic blood pressure;

rare – decreased diastolic blood pressure, thrombocytopenia.

* Adverse reactions not observed in any clinical trial of the medicinal product Ipratual. Frequency is based on the upper limit of the 95% confidence interval calculated from the total number of patients treated according to the EU Guideline on the Summary of Product Characteristics (3/4968 = 0.00060, meaning "rare" events).

** Patients with cystic fibrosis may be particularly susceptible to gastrointestinal motility disorders when using inhaled anticholinergic components (contained in the medicinal product Ipratual).

Like other inhaled medicinal products, Ipratual may cause symptoms of local irritation. The most commonly reported adverse reactions during clinical trials were cough, dry mouth, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, palpitations, vomiting, increased systolic blood pressure, and nervousness.

Reporting suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua/

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

20 ml in a bottle with dropper; 1 bottle per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "Multispray".

Manufacturer's address and location of operations.

24 Valeriya Petrosova St., lit. "A-2", Kharkiv, 61052, Ukraine.

Marketing Authorisation Holder.

LLC "VALARTIN PHARMA".

Address of the Marketing Authorisation Holder.

60 Hrushevskoho St., Chayky, Kyiv-Sviatoshynskyi District, Kyiv Oblast, 08135, Ukraine.