Ipradual

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IPRAVAL

Composition:

Active substances: ipratropium bromide, fenoterol hydrobromide;

One dose contains ipratropium bromide 21 mcg, equivalent to anhydrous ipratropium bromide 20 mcg; fenoterol hydrobromide 50 mcg;

Excipients: citric acid monohydrate; ethanol 96%; propellant HFC-134a.

Pharmaceutical form. Metered-dose aerosol.

Main physicochemical characteristics: colorless or slightly yellowish or slightly brownish transparent solution with the odor of ethanol, under pressure in a single-piece aluminum container equipped with a metering valve and an inhalation actuator with a protective cap; the preparation is released from the container as an aerosol jet.

Pharmacotherapeutic group.

Drugs for treatment of obstructive airway diseases. Adrenergic agents in combination with other anticholinergic agents. Fenoterol and ipratropium bromide.
ATC code R03AL01.

Pharmacological Properties

Pharmacodynamics

Ipratropium bromide and fenoterol hydrobromide, two active bronchodilator ingredients, are contained in Ipratropium/Fenoterol. Ipravent contains ipratropium bromide, which has an anticholinergic effect, and fenoterol hydrobromide, a beta-adrenergic agonist.

Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. It inhibits vagal reflexes through antagonistic interaction with acetylcholine, the neurotransmitter responsible for vagus nerve impulse transmission. 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 a second messenger system composed of IP3 (inositol triphosphate) and DAG (diacylglycerol).

Bronchodilation following inhaled ipratropium bromide administration is primarily due to local, site-specific action rather than systemic effects.

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 (e.g., to suppress uterine contractions). Binding to beta2-adrenergic receptors leads, via activation of the stimulatory Gs protein, to activation of adenylate cyclase. Increased cyclic AMP levels activate protein kinase A, resulting in phosphorylation of specific proteins in smooth muscle cells. This includes phosphorylation of myosin light chain kinase, inhibition of phosphoinositide hydrolysis, and opening of large calcium-activated potassium channels.

Fenoterol hydrobromide induces 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 administration, fenoterol inhibits the release of bronchoconstrictor and pro-inflammatory mediators from mast cells. Following fenoterol administration at a dose of 0.6 mcg, improvement in mucociliary clearance has been observed.

At higher plasma concentrations of fenoterol—more commonly achieved with oral or even intravenous administration—reduced uterine contractility has been noted. Metabolic effects may also occur at high doses: lipolysis, glycogenolysis, hyperglycemia, and hypokalemia; the latter results from increased potassium uptake, particularly into skeletal muscle. Beta-adrenergic effects of fenoterol on the heart, including increased heart rate and cardiac output, are related to vascular effects of fenoterol, stimulation of cardiac beta2-receptors, and, at supratherapeutic doses, stimulation of beta1-receptors. As with other beta-adrenergic agents, QTc prolongation may be observed. With fenoterol in metered aerosol form, these effects are minimal and occur only at doses exceeding recommended levels. However, systemic effects of fenoterol following administration via nebulizer (solution for inhalation) may be greater than with recommended doses of metered aerosol. Clinical significance remains unclear. Tremor is the most commonly observed adverse effect associated with beta-mimetics. Unlike their effect on bronchial smooth muscle, systemic effects of beta-mimetics are subject 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 disorders associated with airway obstruction. Effective combined action requires only a very small amount of beta-mimetic, enabling individual dose titration and reduction in the incidence of adverse effects.

Pharmacokinetics

The therapeutic effect of the combination of ipratropium bromide and fenoterol hydrobromide is exerted locally on the airways. Therefore, the pharmacokinetics of bronchodilation are not directly related to the systemic pharmacokinetics of the active ingredients.

After inhalation, approximately 10–39% of the administered dose deposits in the lungs, depending on 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 to sulfate conjugates. Absolute bioavailability after oral administration is low (approximately 1.5%).

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

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

Approximately 40% of fenoterol binds to plasma proteins. Preclinical animal studies indicate that fenoterol and its metabolites cross the blood-brain barrier. Total fenoterol clearance is 1.8 L/min, with renal clearance at 0.27 L/min.

In an excretion balance study, total renal excretion (over 2 days) of radioactivity (including parent compound and all metabolites) accounted for 65% of the dose after intravenous administration, while fecal excretion accounted for 14.8% of the dose. After oral administration, total urinary excretion of radioactivity was approximately 39% of the dose, and fecal excretion 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 metered-dose inhaler (Ipratropium/Fenoterol). Based on these data, total systemic bioavailability of ipratropium bromide after oral and inhaled administration is estimated to be 2% and 7–28%, respectively. Therefore, the swallowed portion of ipratropium bromide is unlikely to contribute significantly to systemic effects.

Kinetic parameters characterizing ipratropium disposition 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 an excretion balance study, 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 fecal excretion of radioactivity 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 renal. The elimination half-life of total radioactivity (parent compound and all metabolites) is 3.6 hours. Binding of major urinary metabolites to muscarinic receptors is negligible, and metabolites are considered pharmacologically inactive.

Clinical characteristics.

Indications.

Prophylaxis and symptomatic treatment of chronic obstructive disorders of airway patency: allergic and non-allergic (endogenous) bronchial asthma; exercise-induced asthma; chronic obstructive bronchitis with or without emphysema; preparation for "lung opening" and support of aerosol therapy with corticosteroids, mucolytics, saline solution, cromoglycic acid, and antibiotics.

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

Contraindications.

Hypersensitivity to fenoterol hydrobromide or to anticholinergic substances or to any of the excipients of this medicinal product.

Hypertrophic obstructive cardiomyopathy and tachyarrhythmia.

Interaction with other medicinal products and other forms of interactions.

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

Concomitant administration of the following medicinal products/classes of medicinal products may influence the effect of Ipratropium.

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). In particular, they may potentiate the effects on the cardiovascular system.

Reduction of effect:

• concomitant administration of beta-blockers.

Other possible interactions

Hypokalemia associated with the use of beta-mimetics may be intensified by concomitant administration 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 when aerosolized ipratropium or its combination with beta2-agonists enters the eyes.

Also, treatment with Ipratropium may reduce the hypoglycemic effect of antidiabetic medicinal products. However, this is expected only at high doses, typically used for systemic administration (tablets or injections/infusions).

If inhalation anesthetics are planned, it should be taken into account that fenoterol should be discontinued at least 6 hours before the start of anesthesia.

Special precautions for use.

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

Like other inhaled medicinal products, Ipratidual may cause paradoxical bronchospasm, which can be life-threatening. If paradoxical bronchospasm occurs, Ipradual should be discontinued immediately and alternative therapy initiated.

Ipradual should be used only after careful assessment of benefit/risk ratio, especially when doses higher than recommended are used, in the following cases:

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

Use of sympathomimetic medicinal products, including Ipradual, may result in undesirable cardiovascular effects. Post-marketing data and scientific publications provide evidence of 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) receiving Ipradual should be advised to seek medical help if they experience chest pain or other symptoms indicating worsening cardiac function. Particular attention should be paid to evaluating symptoms such as dyspnea and chest pain, as they may have either respiratory or cardiac origin.

Ipradual, like other anticholinergic agents, should be used with caution:

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

There have been reports of isolated ocular complications (such as mydriasis, increased intraocular pressure, narrow-angle glaucoma, eye pain) following accidental exposure of the eyes to nebulized ipratropium or its combination with beta₂-agonists.

Caution! Patients must be thoroughly instructed on the correct use of the metered-dose inhaler Ipradual. Care should be taken to avoid spraying the medication into the eyes.

Symptoms of acute narrow-angle glaucoma include:

• Eye pain or discomfort;
• Blurred vision;
• Appearance of halos;
• Colored 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 eye drops promoting pupil constriction should be initiated immediately, and specialized medical help should be sought without delay.

Patients with cystic fibrosis may be more susceptible to gastrointestinal motility disorders when using anticholinergic agents. Gastrointestinal motility usually returns to normal after discontinuation of treatment.

Long-term use.

Patients with bronchial asthma should use Ipradual only as prescribed by a physician. In patients with mild COPD, use "as needed" (symptomatic treatment) may be more appropriate than regular use.

It should be remembered that anti-inflammatory therapy should be used 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 drugs containing beta₂-agonists, such as Ipradual, to relieve symptoms of bronchial obstruction may indicate worsening disease control.

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

There have been reports of several cases of increased risk of severe complications of the underlying disease, as well as fatal outcomes, associated with long-term treatment of bronchial asthma using excessively high doses of inhaled beta₂-sympathomimetics without sufficient anti-inflammatory therapy. A causal relationship has not been fully established. However, inadequate anti-inflammatory therapy may have serious consequences.

Other sympathomimetic bronchodilators should be used concomitantly with Ipradual only under medical supervision (see section "Interaction with other medicinal products and other forms of interaction").

Excessive therapy with beta₂-agonists may lead to potentially serious hypokalemia. Serum potassium levels should be monitored, especially in patients with low baseline potassium levels. Increased blood glucose levels may also occur. Therefore, blood glucose levels should be monitored in diabetic patients.

In rare cases, immediate hypersensitivity reactions such as urticaria, angioedema, rash, bronchospasm, oropharyngeal edema, and anaphylactic reactions may occur after administration of Ipradual.

This medicinal product contains a small amount of ethanol (alcohol), less than 100 mg per dose.

Note for athletes: Use of Ipradual may result in a positive doping test.

Use during pregnancy or breastfeeding.

Pregnancy. To date, preclinical studies and clinical experience with Ipradual have not shown any negative effects of fenoterol and ipratropium on pregnancy. However, caution should be exercised when using medicinal products during pregnancy.

It should be remembered that fenoterol has an inhibitory effect on uterine contractility. Use of beta₂-sympathomimetics at the end of pregnancy or in high doses may adversely affect the newborn (tremor, tachycardia, fluctuations in blood glucose levels, hypokalemia).

Breastfeeding. Preclinical studies have shown that fenoterol passes into breast milk. There are no data on the passage of ipratropium into breast milk. It is unlikely, especially with aerosol use, that ipratropium would significantly affect the infant. Ipradual should be used with caution during breastfeeding.

Fertility. Clinical data on the effect on fertility are lacking for both the combination of ipratropium bromide and fenoterol hydrobromide and for each component individually. Preclinical studies on the separate use of ipratropium bromide and fenoterol hydrobromide showed no adverse effects on fertility.

Ability to influence reaction speed when driving or operating machinery.

No studies on the effect of the drug on the ability to drive vehicles or operate machinery have been conducted. However, patients should be warned about the possible occurrence of adverse effects such as dizziness, tremor, accommodation disorders, mydriasis, and blurred vision during treatment with Ipradual. Therefore, caution should be exercised when driving vehicles or operating machinery. If any of the above effects occur, patients should avoid potentially hazardous activities, such as driving or operating technical equipment.

Dosage and Administration

The dose should be individually adjusted depending on the etiology and severity of the disease. The following dosage regimens are recommended for adults and children aged 6 years and older.

To relieve an acute attack of bronchial asthma or an episode of dyspnea, the recommended dose is 100 mcg of fenoterol hydrobromide and 40 mcg of ipratropium bromide (2 inhalations). Generally, one inhalation is sufficient to rapidly alleviate breathing difficulties during an acute attack. If breathing does not significantly improve within 5 minutes after administration of 1–2 inhalations, an additional 1–2 inhalations may be administered. If no effect is observed after a total of 4 inhalations, additional medical interventions may be necessary. In such cases, the patient must immediately consult a physician.

If long-term treatment with Ipratual is considered necessary, the recommended dose is 1–2 inhalations 3–4 times daily. The metered aerosol Ipratual should be used for asthma treatment only as prescribed by a physician. In general, the timing and dose of each inhalation should be determined based on symptoms. The interval between inhalations should be at least 3 hours. The total daily dose should not exceed 12 inhalations, as higher doses do not provide additional therapeutic benefits but may increase the risk of potentially serious adverse effects.

To prevent asthma attacks triggered by physical exertion or anticipated allergen exposure, 2 inhalations should be administered, if possible, 10–15 minutes before the triggering event.

Patients should be instructed in the correct use of the metered aerosol to ensure effective treatment (see Instructions for Use).

Instructions for Use

Proper use of the metered aerosol is essential for successful treatment. Patients must be instructed in the correct use of the metered aerosol. During inhalation, the arrow on the canister should point straight upward and the mouthpiece downward, regardless of the inhalation position. Use while sitting or standing, if possible.

Before the first use of the metered aerosol, remove the protective cap and press the valve twice.

Before each use of the metered aerosol:

1. Remove the protective cap (Fig. 1).

If the metered aerosol canister has not been used for more than 3 days, press the valve once before use until the aerosol appears.

Fig. 1 Fig. 2

1. Breathe out slowly.
2. Holding the inhaler as shown in Fig. 2, place the mouthpiece in the mouth and close lips around it.
3. Breathe in as deeply as possible while simultaneously pressing down on the canister to release one metered dose. Hold breath for several seconds, then remove the mouthpiece from the mouth and breathe out slowly.
4. After use, replace the protective cap.

Patients should be instructed in the correct use of the metered aerosol. Avoid getting the medication in the eyes. The metered aerosol Ipratual should be used in children only as directed by a physician and under adult supervision.

Clean the inhaler at least once a week. It is important to keep the inhaler mouthpiece clean to ensure that the medication does not become thickened and that nothing obstructs the aerosol flow. To clean the inhaler, first remove the dust cap and detach the canister from the inhaler. Rinse the inhaler with water until all thickened medication and/or dirt are completely washed away (Fig. 3).

Fig. 3 Fig. 4

After cleaning, shake the inhaler and allow it to air-dry (Fig. 3). Once the mouthpiece is dry, reattach the canister and dust cap as shown in Fig. 4.

WARNING: The plastic mouthpiece is specifically designed for the Ipratual metered aerosol and ensures accurate dosing of the medication. The mouthpiece should not be used with any other metered aerosol products. The canister is pressurized. Do not open the canister by force.

The canister is opaque, so it is not possible to see when it is empty. The aerosol canister is designed to deliver 200 doses. After all doses have been used, a small amount of liquid may remain in the canister. However, the canister must be replaced at this point, as accurate dosing can no longer be guaranteed.

The amount of medication remaining in the aerosol canister can be checked as follows:

• Shake the canister to check for the presence of liquid;
• Detach the plastic mouthpiece from the canister and place the canister in a container of water. The level of medication in the canister can be estimated by its position in the water (see Fig. 5).

Fig. 5.

Children

For use in children aged 6 years and older, only as prescribed by a physician and under adult supervision.

Overdose

Symptoms

Depending on the duration of overdose, adverse reactions typical of beta2-adrenergic agents may occur: flushing, mild dizziness, headache, tachycardia, palpitations, arrhythmia, hypotension or even shock, arterial hypertension, restlessness, chest pain, excitement, possible extrasystoles, and pronounced tremor in the fingers and throughout the body. Hyperglycemia may develop.

Gastrointestinal disturbances, including nausea and vomiting, may occur, particularly after oral overdose.

When fenoterol has been administered in doses higher than recommended for Ipratual indications, metabolic acidosis and hypokalemia have been observed.

Symptoms of ipratropium bromide overdose (dry mouth, visual accommodation disturbances) are generally mild due to the very low systemic bioavailability of inhaled ipratropium.

Treatment

Treatment with Ipratual should be discontinued. Acid-base balance and electrolyte monitoring should be considered.

Administration of sedatives and tranquilizers; in severe cases, intensive therapy including hospitalization is required. Beta-adrenoreceptor blockers (preferably beta1-selective) may be used as specific antidotes for fenoterol; however, the potential for increased bronchial obstruction caused by beta-blockers must be taken into account, and dosage should be carefully selected in patients with bronchial asthma or COPD due to the risk of developing acute bronchospasm, which may be fatal.

Cardiac monitoring, particularly ECG, is recommended.

Side effects

Like all medicinal products, Ipradual may have side effects.

Most of the adverse effects listed below can be explained by the anticholinergic and beta-adrenergic properties of Ipradual.

Side effects associated with the drug have been identified based on data obtained during clinical trials and post-marketing surveillance.

Frequency according to MedDRA:

very common ≥ 1/10;

common ≥ 1/100, < 1/10;

uncommon ≥ 1/1000, < 1/100;

rare ≥ 1/10000, < 1/1000;

very rare < 1/10000;

not known – cannot be estimated from available data.

Immune system disorders:

rare – anaphylactic reactions*, hypersensitivity*;

not known – purpura.

Metabolism and nutrition disorders:

rare – hypokalaemia*;

very rare – increased blood glucose levels.

Psychiatric disorders:

uncommon – nervousness;

rare – excitement, psychiatric disorders.

Psychiatric disorders may manifest as increased excitability, hyperactive behaviour, sleep disturbances, and hallucinations. These have been observed primarily in children under 12 years of age.

Nervous system disorders:

uncommon – headache, tremor, dizziness;

not known – hyperactivity.

Eye disorders:

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

Cardiac disorders:

uncommon – tachycardia, palpitations;

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

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)*, dryness of throat*;

not known – local irritation.

Gastrointestinal disorders:

uncommon – nausea, vomiting, dry mouth;

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

Skin and subcutaneous tissue disorders:

rare – urticaria, rash, pruritus, angioneurotic oedema*, petechiae, hyperhidrosis*.

Musculoskeletal and connective tissue disorders:

rare – muscle weakness, muscle spasms, myalgia.

Renal and urinary disorders:

rare – urinary retention.

Investigations:

uncommon – increased systolic blood pressure;

rare – decreased diastolic blood pressure, thrombocytopenia.

* Adverse effects not observed in any clinical trial. 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 medicinal products (contained in Ipradual).

As with other inhaled therapies, Ipradual may cause local irritation. The most commonly reported side effects observed 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 continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: http://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store at temperatures not exceeding 25 °C. Do not freeze. Protect from direct sunlight. Keep out of reach of children.

Packaging.

200 doses in aluminium cans, hermetically sealed with a metering valve and fitted with an inhaler nozzle and protective cap. One can per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "Multispray".

Manufacturer's address and location of business activity.

24A-2, Valeriy Petrosov St., Kharkiv, Kharkiv region, 61052, Ukraine.