Esmolol

LIBROCK injection for 10 mg / ml

Instruction manual

For medical use of the drug

Byblok

(biblock)

Structure:

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.

Dosage form.

Injection.

Basic physical and chemical properties: transparent liquid, colorless or light yellow in color.

Pharmacotherapeutic group.

Selective beta-adrenergic blockers.

Code ATX C07A B09.

Pharmacological properties.

Pharmacodynamics

Esmolol hydrochloride is a beta-selective (cardioselective) adrenergic receptor blocker without significant internal sympathomimetic or membrane-stabilizing activity when used in therapeutic doses. Esmolol hydrochloride is chemically bonded to the phenoxypropanolamine class of beta-blockers. The drug BIBLOK has a fast onset of action, its very short duration, so that the dose can be quickly adjusted.

When an appropriate saturating dose is used, equilibrium blood concentrations are reached within 5 minutes. However, the therapeutic effect is achieved earlier than stable plasma concentrations. The rate of infusion can be adjusted to obtain the desired pharmacological effect.

The drug BIBLOK has hemodynamic and electrophysiological properties of beta-blockers:

• a decrease in heart rate during rest and exercise;
• reduction of increased heart rate caused by isoprenaline;
• increased recovery time of the sinoatrial node;
• delayed atrioventricular conduction;
• prolongation of the AV interval with normal sinus rhythm and with atrial stimulation without delay in the His - Purkinje tissue;
• lengthening of time PQ, induction of AV blockade of the II degree;
• prolongation of the functional refractory period of the atria and ventricles;
• negative inotropic effect with a decrease in ejection fraction;
• lowering blood pressure.

Pharmacokinetics

The kinetic parameters of esmolol in healthy adults are linear, the plasma concentration is proportional to the dose. If a saturating dose is not used, then an equilibrium concentration in the blood is reached within 30 minutes at doses from 50 to 300 μg / kg / min. The half-life of esmolol hydrochloride is very short - about 2 minutes. The volume of distribution is 3.4 l / kg.

Esmolol hydrochloride is metabolized in red blood cells by hydrolysis of the ether group under the influence of esterase to an acid metabolite (ASL-8123) and methanol. The metabolism of esmolol hydrochloride is independent when the dose is between 50 and 300 mcg / kg / min. BIBLO binds to human plasma proteins by 55%, and the acid metabolite - only by 10%.

The half-life after intravenous administration is about 9 minutes. The total clearance is 285 ml / kg / min; it is independent of circulation in the liver or any other organ. Esmolol hydrochloride is excreted by the kidneys: partly in unchanged form (less than 2% of the administered amount), partly in the form of an acid metabolite with a weak (less than 0.1% of that of esmolol) beta-blocking activity. The acid metabolite is excreted in the urine, its half-life is about 3.7 hours.

Clinical characteristics.

Indications.

Supraventricular tachyarrhythmia, including atrial fibrillation, atrial flutter, and sinus tachycardia.

Tachycardia and arterial hypertension in the perioperative period.

LIBRARY is indicated for supraventricular tachycardia (with the exception of syndromes of premature ventricular excitation) and for quick control of the ventricular rhythm in patients with atrial fibrillation or flutteratria in the pre- and postoperative period or in other circumstances when short-term ventricular rhythm control with a short-acting drug is desirable. LIBRARY is also indicated for tachycardia and arterial hypertension in the perioperative period and for non-compensatory sinus tachycardia, if, according to the doctor, the degree of tachycardia requires special intervention. LIBRARY is not intended for use in chronic conditions.

Contraindications

• Severe sinus bradycardia (heart rate less than 50 beats per minute); sinus node dysfunction syndrome; violation of atrioventricular and sinoauricular conduction; av blockade of the second or sixth degree; cardiogenic shock; severe hypotension; decompensated heart failure; childrens age (up to 18 years); breast-feeding; hypersensitivity to the components of the drug or other beta-blockers (cross-sensitivity between beta-blockers is possible); simultaneous intravenous administration of calcium channel antagonists, when the cardiac effects of another drug are still ongoing; concurrent or recent intravenous administration of verapamil (the drug cannot be administered within 24 hours after discontinuation of verapamil); pheochromocytoma, in the absence of its treatment; pulmonary hypertension; acute asthma attack; metabolic acidosis.

Interaction with other drugs and other types of interactions.

Caution is required every time the biblock drug is used with other antihypertensive drugs or agents that can cause hypotension or bradycardia: they can enhance the therapeutic effects of the biblock drug or the side effects of hypotension or bradycardia.

Calcium antagonists such as verapamil and, to a lesser extent, diltiazem, can have a negative effect on contractility and AV conductivity. The combination should not be prescribed to patients with impaired conductivity, and the drug BIBLOK should not be prescribed within 48 hours after discontinuation of verapamil.

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

The simultaneous use of the drug BIBLOK, class I antiarrhythmic drugs (such as disopyramide, quinidine) and amiodarone can enhance the atrial conductivity and induce a negative inotropic effect.

The simultaneous use of the drug BIBLOK and insulin or oral antidiabetic drugs can enhance the effect of lowering blood sugar levels (especially non-selective beta-blockers). Beta-adrenergic blockade can prevent a symptom of hypoglycemia such as tachycardia, but other manifestations, such as dizziness and sweating, will not be affected.

Anesthetics. If the patient’s volume status is not defined or antihypertensive drugs are used at the same time, reflex tachycardia may weaken and the risk of hypotension may increase. Continued beta blockade reduces the risk of arrhythmias during induction and intubation. If a patient receives a beta-blocking drug in addition to BIBLOC, an anesthetist should be informed. The dosage of each drug, if necessary, can be changed to maintain the desired hemodynamics.

The combination of the drug BIBLOK with ganglion blockers can increase the hypotensive effect.

Nonsteroidal anti-inflammatory drugs can reduce the hypotensive effect of beta-blockers.

Particular caution should be exercised when using flactafenin or amisulpride simultaneously with beta-blockers.

The simultaneous use of tricyclic antidepressants (such as imipramine and amitriptyline), barbiturates or phenothiazines (such as chlorpromazine), as well as other antipsychotics (such as clozapine) can enhance the effect of lowering blood pressure. To avoid unexpected hypotension, the dosage of BIBLOK should be adjusted downward.

When using beta-blockers, patients at risk of developing anaphylactic reactions may be more reactive with respect to the influence of the allergen (accidental, diagnostic or therapeutic). Patients receiving beta blockers may not respond to the usual doses of adrenaline used to treat anaphylactic reactions.

Beta blockers, including BIBLOK, caused muscle weakness, so they are theoretically able to reduce the effectiveness of anticholinesterase drugs in the treatment of muscle weakness.

Sympathomimetic drugs can neutralize the effects of beta-adrenergic blockers while using it. The dose of each agent may require adjustment based on the patients response. The use of alternative drugs may be appropriate.

Drugs that stimulate the release of catecholamines, such as reserpine, when administered together with beta-blockers can give an additive effect. Patients who receive BIBLOC and catecholamine-stimulating drugs at the same time should be carefully examined for evidence of hypotension or clear bradycardia, which can lead to dizziness, loss of consciousness, or orthostatic hypotension.

The use of beta-blockers with moxonidine or alpha-2 agonists (e.g. clonidine) increases the risk of ricochet hypertension. If clonidine or moxonidine is used in combination with a beta-blocker and it is necessary to discontinue therapy with both drugs, the first use should be to stop the use of beta-blocker, and then clonidine or moxonidine after a few days.

The use of beta-blockers with derivative horns can lead to severe narrowing of peripheral vessels and arterial hypertension.

Studies of the interaction of the drug BIBLOK and warfarin prove that their simultaneous use does not lead to a change in the plasma levels of warfarin. However, the concentration of the drug BIBLOK with simultaneous use with warfarin was higher.

With the simultaneous intravenous administration of digoxin and BIBLOK, healthy volunteers sometimes experienced an increase in the level of digoxin in the blood by 10–20%. The simultaneous use of cardiac glycosides and the drug BIBLOK can lengthen the time of AV conduction. Digoxin does not affect the pharmacokinetics of the drug BIBLOK.

In studies of the interaction of morphine and the BIBLOK drug with the intravenous administration to healthy volunteers, the effect of the BIBLOK drug on the level of morphine in the blood was not observed. The equilibrium level of the drug BIBLOK in the blood increased in the presence of morphine by 46%, but no other pharmacokinetic parameters did not change.

The effect of the drug BIBLOK on the duration of neuromuscular blockade caused by suxamethonium chloride or myvacuria was studied in patients during surgical operations. LIBRARY did not affect the rate of development of neuromuscular blockade caused by suxamethonium chloride, but its duration was prolonged from 5 to 8 minutes. LIBRARY moderately increased the clinical duration (by 18.6%) of the action of myvacuria and the recovery index after its administration (by 6.7%).

Although the interactions observed during studies using warfarin, digoxin, morphine, suxamethonium chloride or myvacuria are not of clinical significance, the dose of BIBLOC should be carefully titrated for patients receiving concurrent treatment with these drugs.

With simultaneous use with sulfinpyrazone, the antihypertensive effects of beta-blockers may be weakened.

Features of the application.

It is recommended to constantly monitor blood pressure and heart function with the help of ECG in all patients receiving the drug block.

The use of the drug BIBLOK for monitoring the ventricular response in patients with supraventricular arrhythmias should be carried out with caution if the patient has hemodynamic disturbances or takes other drugs that reduce the following functions: peripheral resistance, myocardial filling, myocardial contractility or transmission of an electrical impulse in the myocardium. Despite the rapid onset and termination of the action of the drug BIBLOK, severe reactions can occur, including loss of consciousness, cardiogenic shock, cardiac arrest. Several fatal outcomes have been reported in complex clinical cases where the BIBLOK preparation was probably used to control ventricular rhythm.

Most often, such a side effect as dose-dependent hypotension is observed, but can occur with the use of any dose. Hypotension can be severe. If hypotension develops, the rate of infusion should be reduced or, if necessary, discontinued. Hypotension is usually the opposite (within 30 minutes after discontinuation of the drug BIBLOK). In some cases, additional pressure relief measures may be necessary. Special care must be taken when selecting a dosage and during maintenance infusion to patients with low systolic blood pressure.

When using the drug BIBLOK, cases of bradycardia, including severe bradycardia, and cardiac arrest were noted. BIBLOC should be used with extreme caution in patients with a low level of heart rate before treatment and only when the expected potential benefit outweighs the risk.

The drug BIBLOK is contraindicated in patients with existing severe sinus bradycardia. If the pulse rate decreases to less than 50–55 beats per minute at rest and the patient feels symptoms associated with bradycardia, the dose should be reduced or administration should be stopped.

Sympathetic stimulation is necessary to support blood circulation in congestive heart failure. Beta blockade carries the potential risk of further suppressing myocardial contractility and accelerating the development of severe failure. Prolonged depression of the myocardium as a result of the use of beta-blockers for a certain period of time can in some cases lead to heart failure.

Caution should be exercised when using the drug BIBLOK for patients with impaired heart function. At the first symptoms of the threat of heart failure, BIBLOK (esmolol hydrochloride) should be discontinued. Although, based on the short half-life, drug withdrawal may be sufficient, specific treatment can also be considered. BIBLOK is contraindicated in patients with decompensated heart failure.

Due to the negative effect on the excitation time, beta-blockers can be used in patients with first-degree heart block or other cardiac conduction disorders only with caution.

The drug BIBLOK should be prescribed with caution and only after the preliminary use of alpha-receptor blockers in patients with pheochromocytoma.

Caution is required when using the drug BIBLOK for the treatment of arterial hypertension after induced hypothermia.

Patients with bronchospastic disease should not be given beta-blockers at all. Based on the relative beta1 selectivity and titration, BIBLOC can be used with caution in patients with bronchospastic disease. However, since beta1 selectivity is not absolute, BIBLO should be carefully titrated to determine the lowest effective dose. In case of bronchospasm, the infusion should be stopped immediately and, if necessary, enter a beta2-agonist.

If the patient is already receiving a beta2 receptor stimulating agent, it may be necessary to review the dose of this drug.

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

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

Reactions at the site of infusion are noted when using the drug BIBLOK both at a concentration of 10 mg / ml and 20 mg / ml. These reactions include irritation and inflammation at the site of infusion, as well as more severe reactions, such as thrombophlebitis, necrosis and the formation of blisters, in particular during extravasation. Infusion into small diameter veins or with a butterfly catheter should be avoided. If a reaction develops at the infusion site, an alternative infusion site should be used.

Beta-blockers can increase the frequency and duration of angina attacks in patients with Prinzmetal angina due to unhindered alpha receptor-mediated coronary artery spasm. Non-selective beta-blockers should not be given to such patients, and beta-selective blockers can only be prescribed with extreme caution.

In hypovolemic patients, BIBLOK can weaken reflex tachycardia and increase the risk of vascular insufficiency. Therefore, BIBLOK should be used with caution in such patients.

In patients with peripheral circulatory disorders (Raynaud’s disease or Raynaud’s syndrome, intermittent claudication) beta-blockers should be used with great caution because of the risk of exacerbation of these diseases.

The use of certain beta-blockers, especially for intravenous administration, including the drug BIBLOK, was associated with an increase in serum potassium levels and hyperkalemia. This risk is increased in patients with risk factors, such as impaired renal function and hemodialysis.

Beta blockers, including BIBLOC, have been reported to contribute to the development of hyperkalemic renal tubular acidosis. In addition, acidosis can usually be accompanied by decreased myocardial contractility. LIBRARY should be used with caution in patients with metabolic acidosis.

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

Beta-blockers have been associated with the development of psoriasis or psoriasis-like rashes and exacerbation of psoriasis. In patients with a personal or family history of psoriasis, beta-blockers should be prescribed only after a thorough analysis of the expected benefits and risks.

Beta blockers, including BIBLOK, caused muscle weakness. LIBRARY should be used with caution in patients with myasthenia gravis.

Beta blockers such as propranolol and metoprolol may mask some of the clinical signs of hyperthyroidism (such as tachycardia). The abrupt cessation of treatment with beta-blockers in patients at risk of developing or suspected of developing thyrotoxicosis can cause a thyrotoxic crisis, and such patients need careful monitoring.

Elderly patients

Elderly patients should be treated with caution. In general, dose selection for elderly patients should be carried out with caution, starting with the lowest of the recommended dose range, given the high frequency of decreased renal or cardiac function, concomitant diseases and treatment with other drugs.

Patients with impaired liver function

There are no special warnings for patients with impaired liver function, because LIBRARY is metabolized by red blood cell esterases.

This medicine contains about 1.22 mmol (or 28 mg) of sodium in one bottle. This should be considered for patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Data on the use of esmolol hydrochloride in pregnant women is limited. Esmolol hydrochloride is not recommended during pregnancy.

When considering the possibility of using the drug during the late period of pregnancy, side effects on the fetus and newborn (especially hypoglycemia, hypotension and bradycardia) should be taken into account.

If treatment with BIBLOK is considered necessary, uteroplacental circulation and fetal growth should be monitored.

It was reported that the use of the drug in the II and III trimesters of pregnancy or during childbirth caused bradycardia of the fetus, which continued after the cessation of drug infusion. If pregnant women receive treatment immediately before birth, the effect of beta-blockers can persist in newborns for several days after birth and can lead to clinically significant bradycardia, respiratory failure, hypoglycemia and arterial hypotension. A newborn baby needs close monitoring.

It is not known whether LIBRARY is excreted in breast milk. The risk to newborns / infants cannot be ruled out.

The use of BIBLOC is contraindicated for women with breastfeeding.

The ability to influence the reaction rate when driving vehicles or other mechanisms.

It is applied in the conditions of a hospital.

Dosage and administration.

A drug is a ready-to-use solution with a concentration of 10 mg / ml, recommended for intravenous administration. it can be used to administer loading or bolus doses with a hand syringe.

Supraventricular tachyarrhythmia

An effective dose of BIBLOK for the treatment of supraventricular tachyarrhythmia is from 50 to 200 μg / kg / min, although doses of up to 300 μg / kg / min have been used. For some patients, a dose of 25 mcg / kg / min was sufficient. With supraventricular tachyarrhythmia, the dose of BIBLOK can be selected individually by titration, in which each next step consists of a loading dose and the subsequent administration of a maintenance dose.

Scheme of treatment initiation and maintenance therapy.

The introduction of a loading dose of 500 μg / kg / min for 1 minute, then the introduction of a maintenance dose of 50 μg / kg / min for 4 minutes. *

Positive answer

Administration of a maintenance dose of 50 mcg / kg / min.

Inadequate response within 5 minutes

Repeat the dose of 500 mcg / kg / min for 1 minute. Raise the maintenance dose to 100 mcg / kg / min for 4 minutes.

Positive answer

Administration of a maintenance dose of 100 mcg / kg / min.

Inadequate response within 5 minutes

Repeat the dose of 500 mcg / kg / min for 1 minute.

Raise the maintenance dose to 150 mcg / kg / min for 4 minutes.

Positive answer

Administration of a maintenance dose of 150 mcg / kg / min.

Inadequate response within 5 minutes

Repeat the dose of 500 mcg / kg / min for 1 minute. Raise the maintenance dose to 200 mcg / kg / min for 4 minutes.

* After reaching the desired safe value of heart rate (for example, when lowering blood pressure), load infusion is stopped and the basic interval of doses of maintenance infusion is reduced from 50 μg / kg / min to 25 μg / kg / min or lower. If necessary, you can increase the interval between titration steps from 5 to 10 minutes.

Note: with the introduction of maintenance doses above 200 mcg / kg / min, significant benefits were not observed, and the safety of doses above 300 mcg / kg / min has not been studied.

The loading dose and maintenance dose of BIBLOK, which are administered to patients with different body weights, are given in table 1 and table 2, respectively.

Table 1

The volume of the drug BIBLOK 10 mg / ml, required as an initial loading dose of 500 μg / kg / min

Volume (ml)	Patient body weight (kg)
	40	50	60	70	80	90	100	110	120
	2	2,5	3	3,5	4	4,5	5	5,5	6

table 2

The volume of the drug BIBLOK 10 mg / ml, necessary for maintenance doses at an infusion rate of 12.5 to 300 μg / kg / min

Patient body weight (kg)	Infusion rate
	12,5 mcg / kg / min	25 mcg / kg / min	50 mcg / kg / min	100 mcg / kg / min	150 mcg / kg / min	200 mcg / kg / min	300 mcg / kg / min
	Amount administered in 1 hour to achieve dose
40	3 ml / hour	6 ml / hour	12 ml / hour	24 ml / hour	36 ml / hour	48 ml / hour	72 ml / hour
50	3.75 ml / hour	7.5 ml / hour	15 ml / hour	30 ml / hour	45 ml / hour	60 ml / hour	90 ml / hour
60	4,5 ml / hour	9 ml / hour	18 ml / hour	36 ml / hour	54 ml / hour	72 ml / hour	108 ml / hour
70	5.25 ml / hour	10.5 ml / hour	21 ml / hour	42 ml / hour	63 ml / hour	84 ml / hour	126 ml / hour
80	6 ml / hour	12 ml / hour	24 ml / hour	48 ml / hour	72 ml / hour	96 ml / hour	144 ml / hour
90	6.75 ml / hour	13.5 ml / hour	27 ml / hour	54 ml / hour	81 ml / hour	108 ml / hour	162 ml / hour
100	7.5 ml / hour	15 ml / hour	30 ml / hour	60 ml / hour	90 ml / hour	120 ml / hour	180 ml / hour
110	8.25 ml / hour	16.5 ml / hour	33 ml / hour	66 ml / hour	99 ml / hour	132 ml / hour	198 ml / hour
120	9 ml / hour	18 ml / hour	36 ml / hour	72 ml / hour	108 ml / hour	144 ml / hour	216 ml / hour

Dosage regimens in case of perioperative use for tachycardia and arterial hypertension

• With intraoperative treatment - during anesthesia, when immediate monitoring is necessary, a dose of 80 mg is bolus administered for 15-30 seconds, and then a dose of 150 μg / kg / min is administered. Titrate the infusion rate, as described above, to 300 mcg / kg / min. The volume of infusion required for patients with different body weights is shown in table 2.
• After the patient is awakened from anesthesia, BIBLOK is administered at a dose of 500 μg / kg / min for 4 minutes and then at a dose of 300 μg / kg / min. The volume of infusion required for patients with different body weights is shown in table 2.
• In postoperative situations, when there is enough time for titration, a loading dose of 500 μg / kg / min is administered for 1 minute before each titration step to obtain a fast action. Titration steps of 50, 100, 150, 200, 250, and 300 μg / kg / min are used for 4 minutes and are stopped after achieving the desired therapeutic effect. The volume of infusion required for patients with different body weights is shown in table 2.

Potential effects that should be considered when dosing BIBLOK.

In case of adverse reactions, the dose of BIBLOC can be reduced or treatment canceled. Pharmacological adverse reactions occur within 30 minutes.

If a local reaction develops at the injection site, the site should be changed to an alternative one and care should be taken to prevent hemorrhage. The use of BIBLOK for over 24 hours has not been fully studied. Therefore, infusions lasting more than 24 hours can only be carried out with caution. It is advisable to stop the infusion gradually due to the risk of ricochet tachycardia and ricochet hypertension. As with other beta-blockers, given the impossibility of eliminating the development of withdrawal effects, caution should be exercised when the administration of the BIBLOK drug is suddenly stopped for patients with coronary heart disease (CHD).

Replacement of the BIBLOK preparation with alternative means

Upon reaching the desired control of heart rate and the stability of the clinical condition of patients, it is possible to switch to alternative antiarrhythmic drugs or calcium antagonists.

Dose reduction

When the BIBLOK drug is replaced by alternative means, the doctor should carefully study the instructions for medical use of the chosen alternative drug and reduce the dose of the BIBLOK drug:

• during the first hour after the first dose of the drug, the rate of BIBLOK infusion is reduced by half (by 50%).
• after the second dose of an alternative drug pro