Biblok

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BIBLOCK (BIBLOCK)

Composition:

Active substance: esmolol hydrochloride;

1 ml contains esmolol hydrochloride 10 mg;

Excipients: sodium acetate trihydrate, glacial acetic acid, sodium chloride, sodium hydroxide, concentrated hydrochloric acid, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless or slightly yellow liquid.

Pharmacotherapeutic group. Selective beta-adrenoreceptor blockers.

ATC code C07AB09.

Pharmacological properties.

Pharmacodynamics.

Esmolol hydrochloride is a beta-selective (cardioselective) adrenergic receptor blocker without significant intrinsic sympathomimetic or membrane-stabilizing activity when administered at therapeutic doses.

Esmolol hydrochloride is chemically related to the phenoxypropanolamine class of beta-blockers.

Due to its pharmacological properties, the drug BIBLOK has a rapid onset of action and a very short duration of effect, allowing for rapid dose adjustments.

When an appropriate loading dose is administered, steady-state blood concentrations are achieved within 5 minutes. However, the therapeutic effect is achieved earlier than stable plasma concentrations. The infusion rate can be adjusted to achieve the desired pharmacological effect.

The drug BIBLOK possesses the well-known hemodynamic and electrophysiological properties of beta-blockers:

• reduction in heart rate at rest and during exercise;
• reduction in elevated heart rate induced by isoprenaline;
• prolonged recovery time of the SA node;
• delayed AV conduction;
• prolongation of the AV interval during normal sinus rhythm and atrial stimulation without delay in the His-Purkinje tissue;
• prolongation of the PQ interval, induction of second-degree AV block;
• prolongation of the functional refractory period of the atria and ventricles;
• negative inotropic effect with reduced ejection fraction;
• reduction in arterial blood pressure.

Pharmacokinetics.

Absorption

The kinetic parameters of esmolol in healthy adults are linear, and plasma concentration is proportional to the dose. If a loading dose is not administered, steady-state blood concentration is achieved within 30 minutes at doses ranging from 50 to 300 mcg/kg/min.

Distribution

The distribution half-life of esmolol hydrochloride is very short, approximately 2 minutes.

The volume of distribution is 3.4 L/kg.

BIBLOK is 55% bound to human plasma proteins, whereas its acid metabolite is bound only to 10%.

Biotransformation

The metabolism of esmolol hydrochloride is dose-independent at doses ranging from 50 to 300 mcg/kg/min. Esmolol hydrochloride is metabolized within erythrocytes by esterase-mediated hydrolysis of the ester group, forming an acid metabolite (ASL-8123) and methanol.

Elimination

The elimination half-life after intravenous administration is approximately 9 minutes.

Total clearance is 285 mL/kg/min and is independent of hepatic blood flow or any other organ. Esmolol hydrochloride is excreted by the kidneys, partially unchanged (less than 2% of the administered dose) and partially as the acid metabolite, which has weak beta-blocking activity (less than 0.1% that of esmolol). The acid metabolite is excreted in urine, with an elimination half-life of approximately 3.7 hours.

Clinical characteristics.

Indications.

Supraventricular tachycardia (excluding pre-excitation syndromes) or non-compensatory sinus tachycardia

BIBLOK is indicated for rapid control of heart rate in patients with atrial fibrillation or atrial flutter in the perioperative or postoperative period, or under other circumstances when short-term control of ventricular rate is desired using a short-acting agent.

BIBLOK is also indicated in non-compensatory sinus tachycardia if, in the physician’s opinion, the degree of tachycardia requires specific intervention.

Tachycardia and arterial hypertension in the perioperative period

Treatment of tachycardia and arterial hypertension occurring during induction of anesthesia and tracheal intubation, during surgery, after awakening from anesthesia, and in the postoperative period, if, in the physician’s opinion, the degree of tachycardia requires specific intervention.

BIBLOK is not indicated for use in children under 18 years of age (see section "Special instructions").

BIBLOK is not intended for use in chronic conditions.

Contraindications.

• Hypersensitivity to the components of the drug or to other beta-blockers (cross-sensitivity between beta-blockers is possible);
• severe sinus bradycardia (heart rate less than 50 beats per minute);
• sinoatrial node dysfunction syndrome; severe disturbances of AV conduction (without a pacemaker); second- or third-degree AV block;
• cardiogenic shock;
• severe arterial hypotension;
• decompensated heart failure;
• concomitant or recent intravenous administration of verapamil. BIBLOK must not be administered within 48 hours after discontinuation of verapamil (see section "Interaction with other medicinal products and other types of interactions");
• pheochromocytoma, if untreated;
• pulmonary hypertension;
• acute asthma attack;
• metabolic acidosis.

Interaction with other medicinal products and other types of interactions.

BIBLOK should be used with caution in combination with other antihypertensive agents or agents that may cause hypotension or bradycardia: the therapeutic effects of BIBLOK or adverse effects such as hypotension or bradycardia may be potentiated.

Calcium antagonists such as verapamil and, to a lesser extent, diltiazem, may have a negative effect on myocardial contractility and AV conduction. This combination should not be prescribed to patients with conduction disorders. BIBLOK should not be administered within 48 hours after discontinuation of verapamil (see section "Special instructions").

Calcium antagonists such as dihydropyridine derivatives (e.g., nifedipine) may increase the risk of hypotension. In patients with heart failure, treatment with beta-blockers may lead to cardiac arrest. Careful titration of BIBLOK and appropriate hemodynamic monitoring are recommended.

Concomitant use of BIBLOK, class I antiarrhythmic agents (such as disopyramide, quinidine), and amiodarone may potentiate effects on intra-atrial conduction time and induce a negative inotropic effect.

Concomitant use of BIBLOK with insulin or oral antidiabetic agents may enhance the blood glucose-lowering effect (particularly with non-selective beta-blockers). Beta-adrenergic blockade may mask symptoms of hypoglycemia (such as tachycardia), although other manifestations such as dizziness and increased sweating will not be affected.

Anesthetics. If the patient’s volume status is uncertain or antihypertensive agents are used concomitantly, reflex tachycardia may be attenuated and the risk of hypotension increased. Continued beta-blockade reduces the risk of arrhythmias during induction and intubation. If the patient is receiving another beta-blocking agent in addition to BIBLOK, the anesthesiologist should be informed. Dosage of each agent may need to be adjusted as necessary to maintain desired hemodynamics.

Combination of BIBLOK with ganglion blockers may enhance the hypotensive effect.

Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect of beta-blockers.

Particular caution should be exercised when flotafeniin or amisulpride is used concomitantly with beta-blockers.

Concomitant use of tricyclic antidepressants (such as imipramine and amitriptyline), barbiturates or phenothiazines (such as chlorpromazine), and other antipsychotic agents (such as clozapine) may enhance the blood pressure-lowering effect. To avoid unexpected hypotension, the dosage of BIBLOK should be reduced.

Patients receiving beta-blockers who are at risk of developing anaphylactic reactions may be more sensitive to allergen exposure (accidental, diagnostic, or therapeutic). Patients on beta-blockers may not respond to usual doses of adrenaline used in the treatment of anaphylactic reactions.

Beta-blockers, including BIBLOK, have been associated with muscle weakness and may theoretically reduce the effectiveness of anticholinesterase agents in the treatment of muscle weakness.

Sympathomimetic agents may counteract the effects of beta-adrenergic blockers when used concomitantly. The dose of each agent may require adjustment based on patient response, or the appropriateness of alternative agents should be evaluated.

Drugs that deplete catecholamine stores, such as reserpine, may have additive effects when administered with beta-blockers. Patients receiving BIBLOK and catecholamine-depleting agents should be carefully monitored for signs of hypotension or marked bradycardia, which may lead to dizziness, loss of consciousness, or orthostatic hypotension.

Concomitant use of beta-blockers with moxonidine or alpha-2 agonists (e.g., clonidine) increases the risk of rebound hypertension. If clonidine or moxonidine is used in combination with a beta-blocker and discontinuation of both agents is required, the beta-blocker should be discontinued first, followed by clonidine or moxonidine several days later.

Concomitant use of beta-blockers with ergot derivatives may lead to severe peripheral vasoconstriction and arterial hypertension.

Study data on the interaction between BIBLOK and warfarin show that their concomitant use does not alter plasma warfarin levels. However, concentrations of BIBLOK were clearly higher when used concomitantly with warfarin.

When digoxin and BIBLOK were administered intravenously to healthy volunteers, digoxin blood levels occasionally increased by 10–20%. Concomitant use of cardiac glycosides and BIBLOK may prolong AV conduction time. Digoxin did not affect the pharmacokinetics of BIBLOK.

In a study of the interaction between morphine and BIBLOK administered intravenously to healthy volunteers, BIBLOK had no effect on morphine blood levels. However, the steady-state level of BIBLOK increased by 46% in the presence of morphine, although no other pharmacokinetic parameters were altered.

The effect of BIBLOK on the duration of neuromuscular blockade induced by succinylcholine chloride or mivacurium was studied in patients undergoing surgery. BIBLOK did not affect the onset speed of neuromuscular blockade induced by succinylcholine chloride, but prolonged its duration by 5 to 8 minutes. BIBLOK moderately prolonged the clinical duration (18.6%) of mivacurium and the recovery index after its administration (6.7%).

Although the interactions observed in studies with warfarin, digoxin, morphine, succinylcholine chloride, or mivacurium are not of major clinical significance, BIBLOK should be carefully titrated in patients receiving concomitant therapy with these agents.

Special precautions for use.

It is recommended to continuously monitor arterial blood pressure and ECG in all patients receiving BIBLOK.

The use of BIBLOK for rate control in patients with supraventricular arrhythmia should be performed with caution if the patient has hemodynamic instability or is receiving other agents that reduce one or more of the following functions: peripheral resistance, myocardial filling, myocardial contractility, or electrical impulse conduction in the myocardium. Despite the rapid onset and offset of BIBLOK, severe reactions may occur, including loss of consciousness, cardiogenic shock, and cardiac arrest. Several fatal cases have been reported in complex clinical situations where BIBLOK was likely used for ventricular rate control.

The most commonly observed adverse effect is dose-dependent hypotension, although it may occur at any dose. This effect can be severe. If hypotension develops, the infusion rate should be reduced or, if necessary, discontinued. Hypotension is usually reversible (within 30 minutes after discontinuation of BIBLOK infusion). In some cases, additional measures may be required to restore blood pressure. Particular caution is required when selecting dosage and during maintenance infusion in patients with low systolic arterial pressure.

Bradycardia, including severe bradycardia, and cardiac arrest have been reported during BIBLOK administration. BIBLOK should be used with special caution in patients with pre-existing low heart rate and only when the expected potential benefit outweighs the risk.

The drug is contraindicated in patients with pre-existing severe sinus bradycardia (see section "Contraindications"). If pulse rate decreases to less than 50–55 beats per minute at rest and the patient experiences symptoms related to bradycardia, dosage should be reduced or infusion discontinued.

Sympathetic stimulation is necessary to maintain circulation in patients with congestive heart failure. Beta-blockade carries a potential risk of further depression of myocardial contractility and acceleration of severe heart failure development. Prolonged myocardial depression due to beta-blockers may in some cases lead to heart failure.

Caution should be exercised when using BIBLOK in patients with cardiac dysfunction. BIBLOK (esmolol hydrochloride) should be discontinued at the first signs of impending heart failure. Although discontinuation of the drug may be sufficient due to its short elimination half-life, specific treatment may also be considered. BIBLOK is contraindicated in patients with decompensated heart failure (see section "Special precautions for use").

Due to their negative effect on conduction time, beta-blockers should be used with caution in patients with first-degree heart block or other conduction disorders (see section "Special precautions for use").

BIBLOK should be administered with caution and only after prior use of alpha-receptor blockers in patients with pheochromocytoma.

Caution is required when using BIBLOK for treatment of arterial hypertension following induced hypothermia.

Patients with bronchospastic disease should generally not be prescribed beta-blockers. Due to its relative beta₁-selectivity and titratability, BIBLOK may be cautiously used in patients with bronchospastic disease. However, since beta₁-selectivity is not absolute, BIBLOK should be carefully titrated to determine the lowest effective dose. If bronchospasm occurs, infusion should be immediately stopped and a beta₂-agonist administered if necessary.

If a patient is already receiving a beta₂-receptor stimulating agent, dosage adjustment of this agent may be required.

The drug should be used with caution in patients with a history of wheezing or asthma.

BIBLOK should be used with caution in patients with diabetes mellitus or suspected or actual hypoglycemia. Beta-blockers may mask prodromal symptoms of hypoglycemia such as tachycardia. However, dizziness and increased sweating will not be affected. Concomitant use of beta-blockers and antidiabetic agents may potentiate the effect of antidiabetic drugs (lowering of blood glucose).

Infusion site reactions have been reported with the use of the 10 mg/mL formulation. These reactions include irritation and inflammation at the infusion site, as well as more severe reactions such as thrombophlebitis, necrosis, and blistering, particularly in case of extravasation (see section "Adverse reactions"). Infusion into small-diameter veins or using butterfly-type catheters should be avoided. If an infusion site reaction occurs, an alternative infusion site should be used.

Beta-blockers may increase the frequency and duration of angina attacks in patients with Prinzmetal's angina due to alpha-receptor-mediated coronary artery spasm. Nonselective beta-blockers should not be prescribed to such patients, and beta₁-selective blockers should be used only with extreme caution.

In patients with hypovolemia, BIBLOK may blunt reflex tachycardia and increase the risk of vascular insufficiency. Therefore, the drug should be used with caution in such patients.

Beta-blockers should be used with great caution in patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication) due to the risk of exacerbating these conditions.

Use of certain beta-blockers, particularly for intravenous administration, including BIBLOK, has been associated with elevated serum potassium levels and hyperkalemia. This risk is increased in patients with risk factors such as impaired renal function and those undergoing hemodialysis.

Beta-blockers may increase sensitivity to allergens and the severity of anaphylactic reactions. Patients receiving beta-blockers may not respond to usual doses of epinephrine used to treat anaphylactic or anaphylactoid reactions.

Beta-blockers have been associated with the development of psoriasis or psoriasiform rashes and with exacerbation of psoriasis. Beta-blockers should be prescribed to patients with personal or family history of psoriasis only after careful assessment of expected benefit versus risk.

Beta-blockers such as propranolol and metoprolol may mask certain clinical signs of hyperthyroidism (e.g., tachycardia). Abrupt discontinuation of beta-blocker therapy in patients at risk of or suspected of developing thyrotoxicosis may precipitate a thyroid storm; therefore, such patients require close monitoring.

Sodium content

This medicinal product contains approximately 6.1 mmol (or 140 mg) of sodium in one container (50 mL) and 30.5 mmol (or 700 mg) of sodium in one container (250 mL). This should be taken into account for patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of esmolol hydrochloride in pregnant women are limited. Animal studies have shown reproductive toxicity.

Esmolol hydrochloride is not recommended during pregnancy.

Due to its pharmacological action, adverse effects on the fetus and newborn (particularly hypoglycemia, arterial hypotension, and bradycardia) should be considered during the late stages of pregnancy.

If treatment with BIBLOK is considered necessary, uteroplacental blood flow and fetal development should be monitored. The newborn should be closely observed.

Breastfeeding

Esmolol hydrochloride should not be used in women who are breastfeeding.

It is unknown whether esmolol hydrochloride/metabolites are excreted in breast milk. A risk to newborns/infants cannot be excluded.

Fertility

There are no data on the effect of esmolol on human fertility.

Ability to affect reaction speed when driving or operating machinery.

Use in a hospital setting only.

Administration and Dosage

BIBLOK is an isotonic ready-to-use solution with a concentration of 10 mg/mL, recommended for intravenous administration.

Supraventricular tachyarrhythmia(except ventricular pre-excitation syndromes) or non-compensatory sinus tachycardia

Dosage of the drug in supraventricular tachyarrhythmias should be individually adjusted by titration as indicated in the algorithm below.

Algorithm for initiation and maintenance therapy

Administer a loading dose of 500 mcg/kg/min over 1 minute, followed by a maintenance dose of 50 mcg/kg/min for 4 minutes.

Positive response

Continue maintenance dose at 50 mcg/kg/min.

Inadequate response within 5 minutes

Repeat administration of a 500 mcg/kg/min dose over 1 minute.
Increase maintenance dose to 100 mcg/kg/min for 4 minutes.

Positive response

Continue maintenance dose at 100 mcg/kg/min.

Inadequate response within 5 minutes

Repeat administration of a 500 mcg/kg/min dose over 1 minute.
Increase maintenance dose to 100 mcg/kg/min for 4 minutes.

Positive response

Continue maintenance dose at 150 mcg/kg/min.

Inadequate response

Repeat administration of a 500 mcg/kg/min dose over 1 minute.
Increase maintenance dose to 200 mcg/kg/min and continue.

Loading Dose

Depending on the hemodynamic response (heart rate, arterial blood pressure), adjustment of the loading dose may be required.

Maintenance Dose

For continuous and gradual dosing, the effective maintenance dose ranges from 50 to 200 mcg/kg/min. A dose of 25 mcg/kg/min may also be used.

Depending on the desired hemodynamic response, adjustment of the maintenance dose may be necessary.

Administration of doses exceeding 200 mcg/kg/min provides minimal additional heart rate reduction, while the incidence of adverse reactions increases.

The loading and maintenance doses of BIBLOK administered to patients of various body weights are provided in Table 1 and Table 2, respectively.

Table 1

Volume of BIBLOK 10 mg/mL required as initial loading dose of 500 mcg/kg/min

Table 2

Volume of BIBLOK 10 mg/ml required for maintenance doses at infusion rates from 12.5 to 300 mcg/kg/min

1 ml of BIBLOK is equivalent to 10 mg of esmolol.

When the desired safe heart rate or end-point safety value (e.g., reduction in blood pressure) is achieved, the loading infusion should be discontinued and the maintenance dose reduced from 50 to 25 mcg/kg/min or lower. If necessary, the titration step interval may be increased from 5 to 10 minutes.

Perioperative tachycardia and arterial hypertension

For perioperative tachycardia and arterial hypertension, the dosing regimen may be as follows:

• Intraoperative treatment – During anesthesia, when immediate control is required, administer an 80 mg bolus over 15–30 seconds, followed by an infusion of 150 mcg/kg/min. If needed, titrate the infusion rate up to 300 mcg/kg/min. The infusion volume required for patients of different body weights is shown in Table 2.
• After emergence from anesthesia – Administer BIBLOK at a dose of 500 mcg/kg/min for 4 minutes, followed by 300 mcg/kg/min. The infusion volume required for patients of different body weights is shown in Table 2.
• In postoperative settings, when sufficient time is available for titration, administer a loading dose of 500 mcg/kg/min for 1 minute before each titration step to achieve a rapid effect. Use titration steps of 50, 100, 150, 200, 250, and 300 mcg/kg/min, each lasting 4 minutes, and stop after achieving the desired therapeutic effect. The infusion volume required for patients of different body weights is shown in Table 2.

Recommended maximum dose

Higher doses (250–300 mcg/kg/min) may be required for adequate blood pressure control. The safety of doses exceeding 300 mcg/kg/min has not been studied.

Potential effects to consider during BIBLOK dosing

In case of adverse reactions, the dose may be reduced or treatment discontinued. Pharmacological adverse effects resolve within 30 minutes.

If a local reaction develops at the infusion site, switch to an alternative site and take care to prevent extravasation.

Administration beyond 24 hours has not been fully studied. Therefore, infusions lasting longer than 24 hours should be administered with caution.

Infusion should preferably be discontinued gradually due to the risk of rebound tachycardia and rebound hypertension. As with other beta-blockers, caution should be exercised when abruptly discontinuing BIBLOK in patients with ischemic heart disease (IHD), due to the potential for withdrawal effects.

Switching to alternative agents

After achieving desired heart rate control and clinical stability, patients may be switched to alternative medications (e.g., antiarrhythmics or calcium antagonists).

Dose reduction

When switching from BIBLOK to an alternative agent, the physician should carefully review the prescribing information for the selected alternative medication and reduce the BIBLOK dose as follows:

• During the first hour after administration of the first dose of the alternative agent, reduce the BIBLOK infusion rate by half (50%);
• After administration of the second dose of the alternative agent, assess the patient’s response; if satisfactory control is achieved within the first hour, discontinue the BIBLOK infusion.

Additional dosing information

Once the desired therapeutic effect or end-point safety value (e.g., reduced blood pressure) is achieved, immediately discontinue the loading dose and reduce the basal dose to 12.5–25 mcg/kg/min. The titration step intervals may also be increased from 5 to 10 minutes.

If heart rate or blood pressure rapidly reaches or exceeds the safe limit, the drug should be discontinued, and after heart rate or blood pressure returns to an acceptable level, treatment should be restarted at a lower dose without administering a loading dose.

Special patient groups

Elderly patients

Treatment of elderly patients should be initiated cautiously with a lower dose.

No specific studies have been conducted in elderly patients. However, analysis of data from 252 patients aged 65 years and older showed no differences in pharmacodynamic effects compared to patients under 65 years of age.

Patients with renal impairment

Caution is required when administering BIBLOK by infusion to patients with renal impairment, as the acidic metabolite of BIBLOK is excreted unchanged by the kidneys. Elimination of the acidic metabolite is significantly reduced in patients with end-stage renal disease, with the elimination half-life increasing approximately tenfold compared to normal, and plasma concentrations markedly elevated.

Patients with hepatic impairment

No specific precautions are required in hepatic impairment, as erythrocyte esterases play the primary role in the metabolism of BIBLOK.

Instructions for container use

BIBLOK is an infusion solution supplied in a container with two PVC ports: one for withdrawal of the initial loading dose and one for drug infusion.

The port for withdrawal of the initial loading dose should be used exclusively for obtaining the initial loading dose and is not intended for sequential loading or maintenance infusions. Strict aseptic technique must be observed when withdrawing the initial loading dose.

Do not add other medicinal products to the container.

The container contents are intended for single use only. After removing the protective cap and starting the infusion, the solution must be used within 24 hours. Unused portions should be discarded. Partially used containers must not be reconnected to the infusion system.

Warning. Do not use containers for sequential connection, as this may result in air embolism due to residual air from one container entering before completion of drug administration from the second container. Do not open the vacuum-sealed laminated foil pouch until ready for use. Do not use the drug if the vacuum-sealed pouch is damaged. The pouch protects against moisture ingress during storage. Sterility of the solution is ensured by container integrity.

Opening the packaging

Open the vacuum-sealed laminated foil pouch and remove the container with solution. Condensation between the container and the pouch, as well as darkened areas on the pouch or container, may occur. This is not abnormal and does not affect the quality or safety of the drug.

Squeeze the container to check for integrity. If mechanical damage is detected, discard the container due to possible loss of sterility.

The solution should not be used if additional particulates are observed or if there is a change in color.

Preparation for infusion: Under aseptic conditions, hang the container on an infusion stand, remove the protective cap from the port, and connect the infusion set.

Children

The safety and efficacy of BIBLOK in children (under 18 years of age) have not been established; therefore, BIBLOK is not indicated for use in children (see section "Special precautions"). Dosing recommendations cannot be provided for this population.

Overdose

Cases of accidental significant overdose with concentrated BIBLOK solutions have been reported. Some of these cases were fatal, while others resulted in permanent disability. Loading doses ranging from 625 mg to 2.5 g (12.5–50 mg/kg) were fatal.

Symptoms

Symptoms of overdose may include severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, respiratory failure, loss of consciousness progressing to coma, seizures, nausea, vomiting, hypoglycemia, and hyperkalemia.

Treatment

Given the short elimination half-life of approximately 9 minutes, the first step in managing toxicity is to discontinue the BIBLOK infusion. The time required for symptoms of overdose to resolve depends on the amount of BIBLOK administered (over 30 minutes when used at therapeutic doses). Mechanical ventilation may be necessary. Subsequently, depending on the observed clinical effects, the following general measures may be taken.

Bradycardia: Intravenous administration of atropine or another anticholinergic agent. If therapeutic measures are insufficient to correct bradycardia, a cardiac pacemaker may be required.

Bronchospasm: Inhaled administration of beta2-sympathomimetics. If this is insufficient, consider intravenous administration of beta2-sympathomimetics or aminophylline.

Symptomatic hypotension: Intravenous administration of fluids and/or pressors.

Cardiovascular depression or cardiogenic shock: Diuretics or sympathomimetics may be administered. The dose of sympathomimetics (depending on symptoms: dobutamine, dopamine, norepinephrine, isoprenaline) should be adjusted according to therapeutic response.

If further treatment is required, the following intravenous agents may be considered, based on clinical situation and physician assessment:

• atropine;
• inotropic agents;
• calcium ions.

Adverse Reactions

If adverse reactions occur, the dose of the drug may be reduced or treatment discontinued.

Most of the adverse reactions observed were mild and transient. The most significant adverse reaction was arterial hypotension. The adverse reactions listed below are presented according to MedDRA system organ classes (SOC) and their frequency.

Frequency of adverse reactions is classified as follows:

very common (≥ 1/10);

common (≥ 1/100, < 1/10);

uncommon (≥ 1/1000, < 1/100);

very rare (< 1/10,000);

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

Metabolism and nutritional disorders

Common: anorexia.

Frequency not known: hyperkalemia, metabolic acidosis.

Psychiatric disorders

Common: depression, anxiety.

Uncommon: abnormal thinking.

Nervous system disorders

Common: dizziness¹, somnolence, headache, paresthesia, attention disturbance, confusion, excitement.

Uncommon: syncope, convulsions, speech disorders.

Eye disorders

Uncommon: visual disturbance.

Cardiac disorders

Uncommon: bradycardia, atrioventricular block, increased pulmonary artery pressure, heart failure, ventricular extrasystoles, nodal rhythm, angina pectoris.

Very rare: sinus pause, asystole.

Frequency not known: accelerated idioventricular rhythm, coronary artery spasm, cardiac arrest.

Vascular disorders

Very common: hypotension.

Uncommon: peripheral ischemia, pallor, flushing.

Very rare: thrombophlebitis²

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnea, pulmonary edema, bronchospasm, wheezing, nasal congestion, stridor, loud gurgling sounds*.

Gastrointestinal disorders

Common: nausea, vomiting.

Uncommon: dysgeusia, dyspepsia, constipation, dry mouth, abdominal pain.

Skin and subcutaneous tissue disorders

Very common: increased sweating¹.

Uncommon: skin discoloration and erythema².

Very rare: skin necrosis (due to extravasation)².

Frequency not known: psoriasis³, angioneurotic edema, urticaria.

Musculoskeletal and connective tissue disorders

Uncommon: bone and muscle pain⁴

Renal and urinary disorders

Uncommon: urinary retention.

General disorders and administration site conditions

Common: asthenia, fatigue, injection and infusion site reactions, inflammation and induration at infusion site.

Uncommon: chills, hyperthermia, swelling and pain¹, burning and ecchymosis at site of administration.

Frequency not known: phlebitis and vesicles at infusion site, blisters¹.

* "Large airway sounds" – continuous gurgling or bubbling sounds typically heard during both inspiration and expiration, caused by movement of fluid and secretions in large airways.

¹ Dizziness and increased sweating in combination with symptomatic hypotension.

² In combination with injection and infusion site reactions.

³ Beta-blockers as a class of medicinal products may in some cases induce psoriasis or exacerbate its course.

⁴ Including interscapular pain and costochondritis.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

1.5 years.

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

Storage conditions

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Do not freeze.

Do not use if precipitate is present in the solution.

Dispose of any unused solution.

Incompatibilities

In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products or sodium bicarbonate solutions.

Packaging

50 ml, 250 ml in polymer containers;

one polymer container in a vacuum-sealed laminated foil pouch;

one pouch together with the instructions for medical use placed in a cardboard carton.

Prescription status

Prescription only.

Manufacturer

TOV "Yuria-Pharm"

Manufacturer's address and location of business activity

108, Kobzarska Street, Cherkasy, Cherkasy region, 18030, Ukraine. Tel.: (044) 281-01-01.