Atracuria besylate - instructions for use, dose, side effects, contraindications

Atracuria besylate is a highly selective, competitive, nondepolarizing muscle relaxant of peripheral action, reducing the sensitivity of n-cholino receptors of skeletal muscles to acetylcholine, blocking neuromuscular transmission, causing temporary relaxation of skeletal muscles (including respiratory).It has a rapid onset of action (within 2-2.5 minutes), which allows intubation of the trachea in the first 90 seconds from the moment of its administration at a dose of 0.5-0.6 mg / kg. The speed of development of the neuromuscular blockade of the vocal cords of the larynx, necessary for intubation of the trachea, vecuronium bromide and pancuronium bromide.

In a dose of 0.2-0.6 mg / kg, the expected relaxation of skeletal muscles, which is proportional to the amount administered, is 20-35 min. The miorelaksiruyuschee action comes and stops faster than with the introduction of pancuronium bromide. The rate of recovery of the neuromuscular transmission after the administration of atracurium bezylate (single and repeated) is constant, which allows the administration of repeated doses at predetermined time intervals. Restoration of normal neuromuscular transmission without the use of cholinesterase inhibitors occurs after 35 min and does not depend on the total dose and the function of the excretory and metabolism organs. The onset of action is 2-5 times faster than other nondepolarizing muscle relaxants.

In therapeutic doses, it has insignificant m-cholino-and ganglion-blocking activity.Promotes the release of histamine.

Atracuria besylate does not have a direct effect on intraocular pressure.

In this way, atracurium bezylate is applicable in ophthalmic surgical practice.

Pharmacokinetics:

Time to reach the maximum concentration (T_max) in the plasma - 1.7-10 minutes (on average 3-5 minutes).

The connection with plasma proteins is high (about 80%). The half-distribution period is 2-3.4 min. Do not penetrate the placental barrier at clinically significant concentrations. The duration of neuromuscular blockade does not depend on the intensity of hepatic metabolism and the rate of excretion by the kidneys. At physiological values, the pH of the blood and body temperature without the participation of enzymes is metabolized (Hoffman elimination) to laudanosine and quaternary monoacrylate; in a small degree hydrolyzed by plasma esterases, so the duration of action does not depend on the function of the liver and kidneys. Metabolites are pharmacologically inactive. Physiological changes in blood pH have little effect on the duration of the action. Under hypothermia (body temperature 25-26 ° C), the metabolic rate decreases. Plasma studies in patients with low pseudocholinesterase activity have shown that the products of atra- caria bezilate metabolism do not change. Do not cumulate.Half-life (T_1/2) - 20 minutes.

It is excreted by the kidneys and with bile (less than 10% - unchanged).

Hemofiltration and hemodiafiltration have a minimal effect on the concentrations of atracurium besylate and its metabolites (including laudanosine) in the blood plasma. The influence of hemodialysis and hemoperfusion on the concentration of atracurium besylate and its metabolites in blood plasma is unknown.

In patients with impaired renal and / or liver function, higher concentrations of atra- kurium besylate metabolites were observed.

Indications:

Miorelaxation for intubation of the trachea and artificial ventilation (ALV), relaxation of skeletal muscles during surgical operations and for ventilation in intensive care units (ICU).

Contraindications:

Hypersensitivity to atracurium bezilate, cisatracurium bezylate, benzenesulfonic acid and benzyl alcohol.

Children: the period of newborns (up to 1 month).

Hypersensitivity to histamine.

Carefully:

In predisposed patients atracurium bezylate can cause the development of reactions associated with the release of histamine. Caution should be exercised when administering atracuria bezialate to patients with histamine hypersensitivity in the anamnesis.Safety of atracurium has not been established in patients with bronchial asthma.

For patients who have experienced hypersensitivity reactions to other muscle relaxants, caution should also be taken when introducing atracuria bezialate, since a high incidence of cross-sensitivity between muscle relaxants (> 50%) has been identified (see "Contraindications"). As with other non-depolarizing muscle relaxants, hypersensitivity to atracurium bezialate can be observed in patients with severe myasthenia gravis gravis, other neuromuscular diseases and severe electrolyte imbalance.

Pregnancy and lactation:

The use of the drug during pregnancy and during breastfeeding is possible only if the expected benefit for the mother exceeds the potential risk to the fetus and the baby.

Atracuria bezialate can be used for the purpose of miorelaxation in a caesarean section, since when administered at recommended doses atracurium bezylate penetrates the placental barrier in clinically insignificant amounts.

It is not known whether the atracurium bezylate and its metabolites into breast milk.

Dosing and Administration:

Intravenous (bolus or infusion).

The dose is set individually and depends on the required duration and depth neuromuscular blockade. To determine the individual dose, to monitor neuromuscular function during the entire period of application of the drug.

Adults

Bolus injection

By 0,3-0,6 mg / kg (depending on the required duration of the complete block) provides relaxation for 15-35 minutes.

Conduction of endotracheal intubation is possible within 90 s after intravenous injection of 0.5-0.6 mg / kg.

The duration of complete neuromuscular blockade can be increased by introducing an additional dose of atracurium bezilate at a rate of 0.1-0.2 mg / kg, which is not accompanied by a cumulation of its action. Neuromuscular conduction can be quickly restored by standard doses of cholinesterase inhibitors (neostigmine methylsulfate and others) in combination with atropine (without the appearance of signs of recurrence).

Infusion introduction

After initial bolus administration of the drug at a dose of 0.3-0.6 mg / kg, it can be administered by continuous intravenous infusion at a rate of 0.3-0.6 mg / kg / hr to maintain neuromuscular blockade during prolonged surgical operations.The drug can be used by intravenous infusion during coronary artery bypass grafting. Induced hypothermia of the body to a temperature of 25-26 ° C leads to a decrease in the rate of inactivation of atracurium bezilate, therefore, in order to maintain complete neuromuscular blockade, the rate of infusion of the drug should be reduced approximately 2-fold.

Atracuria besylate is compatible with the following infusion solutions:

Infusion solutions	Stability period, h
A solution of sodium chloride (0.9%)	24 hours
A solution of dextrose (5%)	8 ocloc'k
Ringer's solution	8 ocloc'k
A solution of sodium chloride (0.18%) and dextrose (4%)	8 ocloc'k
Hartmann's solution	4 hours

When diluted in the above solutions until atraquarium at least 0.5 mg / ml is obtained, the solution remains stable for a fixed period of time under normal illumination and at temperatures above 30 ° C.

Children

The initial dose of the drug in children aged 1 month to 2 years with halothane anesthesia is 0.3-0.4 mg / kg.

Children aged 2 years or older receive the drug in adult doses in terms of body weight.

Children may need more frequent use of maintenance doses than adults.

Elderly patients

It is used in doses for adults, but the initial dose is recommended to be reduced to a minimum therapeutic dose and injected more slowly.

Patients with impaired hepatic and / or renal function

If the liver and / or kidney function is impaired, including at the terminal stage of hepatic or renal insufficiency, the drug is prescribed in standard doses.

Patients with diseases of the cardiovascular system

For patients with severe cardiovascular failure, an initial dose of 0.3 to 0.4 mg / kg of the drug should be administered for at least 60 seconds.

It is also recommended to use low initial doses in combination with long-term administration of the drug in patients with bronchial asthma, anaphylactic reactions in the anamnesis, as well as in patients with diseases of the neuromuscular system, severe disturbances of the water-electrolyte balance, carcinomatosis.

It is recommended to use an initial dose of 0.3 to 0.4 mg / kg of atracurium bezilate in adult patients in the case of a previous application of suxamethonium chloride (after its termination).

Application in intensive care units

After initial bolus administration of the drug at a dose of 0.3-0.6 mg / kg, it can be administered by continuous infusion at a rate of 11-13 μg / kg / min (0.65-0.78 mg / kg / h). In different patients, the dose is not the same and may change over time. Some patients may require a dose reduction of up to 4.5 μg / kg / min (0.27 mg / kg / h) or an increase of up to 29.5 μg / kg / min (1.77 mg / kg / h).

Spontaneous recovery of neuromuscular conduction (achievement of the ratio T₄/ T₁> 0.75, i.e. 4 cuts of 2 Hz every 0.5 seconds, the ratio of the 4th cut to the 1st should be> 0.75) usually occurs after about 60 minutes (at the period of clinical trials was 32 to 108 minutes) after the infusion of the drug and does not depend on the duration of its use.

Side effects:

The undesirable phenomena presented below are listed by the system-organ classes and frequency of occurrence. Frequency of occurrence is defined as follows: very often (≥1/10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10,000 and <1/1000), very rarely (<1/10 000, including individual cases), the frequency is unknown (can not be estimated from the available data).Frequency categories "very often", "often" and "infrequently" were formed on the basis of clinical studies. Frequency categories "rarely", "very rarely" were formed on the basis of spontaneous messages.

Clinical Trials Data

From the side of the cardiovascular system

Often: transient increase / decrease in blood pressure, skin hyperemia, vasodilation (tides), tachycardia, bradycardia

On the part of the respiratory system, the organs of the thorax and the mediastinum

Infrequent: shortness of breath, shortness of breath, bronchospasm, laryngospasm, increased separation of bronchial secretions.

The above undesirable phenomena are associated with the release of histamine.

Post-registration data

From the immune system

Very rarely: anaphylactic and anaphylactoid reactions.

Very rarely reported severe anaphylactic or anaphylactoid reactions up to cardiac arrest, incl. with the simultaneous use of atracurium besylate with anesthetics.

From the nervous system

The frequency is unknown: convulsions.

There have been reports of cases of seizures in patients on intensive care (receiving combination therapy, including atracurium bezylate).Typically, these patients had a predisposition to developing seizures, including head trauma, cerebral edema, viral encephalitis, hypoxic encephalopathy, or uremia. The relationship between the onset of seizures and laudanosine (the metabolite of atracurium bezylate) has not been established. According to the results of clinical the correlation between plasma concentrations of laudanosine and the occurrence of seizures is absent.

From the skin and subcutaneous fat

Rarely: urticaria, rash, itching, erythema, redness at the injection site.

From the side of the musculoskeletal system and connective tissue

The frequency is unknown: myopathy, muscle weakness, lack of neuromuscular blockade, prolonged neuromuscular blockade.

Several cases of myopathy and / or muscle weakness have been reported with long-term use of muscle relaxants in critically ill patients in the intensive care unit. Most of them simultaneously received glucocorticosteroids. This adverse reaction is regarded as uncharacteristic for atracurium bezylate, a connection with the use of the drug has not been established.

Overdose:

Symptoms: long paralysis of skeletal muscles and its consequences are the main signs of an overdose. Also, an overdose of the drug may increase the risk of histamine release and cause cardiovascular reactions, such as tachycardia and hypotension.

Treatment: great importance is to ensure the patency of the airways and performing artificial ventilation of the lungs under positive pressure to restore adequate spontaneous breathing. It is necessary to use sedatives, because the consciousness of patients is not violated. Symptomatic therapy aimed at stabilizing the cardiovascular activity. When the spontaneous recovery of neuromuscular conduction begins, it can be accelerated with the help of cholinesterase inhibitors in combination with atropine.

Interaction:

Neuromuscular blockade caused by atracurium bezilate can be intensified by the use of halothane, isoflurane, enflurane, lithium, magnesium, procainamide and quinidine.

It is possible to intensify the intensity and duration of the neuromuscular blockade caused by nondepolarizing muscle relaxants, including atracurium bezylate,with the simultaneous use of certain antibiotics (aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin and clindamycin); antiarrhythmic drugs (propranolol, blockers of "slow" calcium channels, lidocaine, procainamide and quinidine); diuretics (furosemide and, perhaps, mannitol, thiazides, acetazolamide); magnesium sulfate; ketamine; lithium salts; ganglion blockers (trimetaphane camsylate, hexamethonium benzenesulfonate).

With simultaneous use with drugs that can enhance the manifestations of myasthenia gravis (including latent flow) and provoke the development of myasthenic syndrome, it is possible to increase sensitivity to atracurium bezilate. These drugs include antibiotics, β-adrenoblockers (propranolol, oxprenolol), antiarrhythmic agents (procainamide, quinidine), antirheumatic drugs (chloroquine, penicillamine), trimetaphane camsylate, chlorpromazine, steroid hormones, phenytoin and lithium salts.

The introduction of other non-depolarizing muscle relaxants in combination with atrakury besylate can cause a more pronounced neuromuscular blockade compared with the expected one-atrachium ate equivalent at the equivalent total dose.The synergistic effect may vary depending on the combination of drugs.

When using depolarizing muscle relaxants (for example, suxamethonium chloride) with the aim of increasing the duration of the neuromuscular blockade caused by nondepolarizing muscle relaxants, including atracurium bezylate, it is possible to develop a long and deep miorelaxation, which is difficult to eliminate with cholinesterase inhibitors. Atracuria bezylate Do not enter until the action (neuromuscular block) caused by the suxamethonium chloride is terminated.

Therapy with cholinesterase inhibitors used to treat Alzheimer's disease (eg, donepezil), can shorten the duration of neuromuscular blockade and weaken the muscle relaxant effect of atracurium bezilate.

Special instructions:

Like other muscle relaxants, atracurium bezylate causes paralysis of skeletal muscles, including respiratory, but does not affect consciousness and pain threshold. Atracuria bezylate should be used only during general anesthesia under the supervision of a qualified anesthesiologist in departments where there is equipment for intubation of the trachea and artificial ventilation,Anticholinesterase medications should also be available.

Atracuria besylate can not be administered intramuscularly.

The solution of atracurium besylate for intravenous administration has an acidic pH, therefore it should not be mixed with alkaline solutions (for example, solutions of barbiturates) in one syringe or administered simultaneously with intravenous infusion through the same needle. AT depending on the resulting pH of such mixtures, atracurium bezylate can be inactivated to form free acids.

The solution of atracurium besylate for intravenous administration contains benzyl alcohol. In newborns, benzyl alcohol was associated with an increase in the incidence of neurologic and other complications, sometimes fatal. For use in this category of patients should use the dosage form of the drug, which does not contain benzyl alcohol.

Since there is a risk of cross-allergic reactions to drugs of this pharmacological group, it is necessary to request information from patients about the presence of anaphylactic reactions to other muscle relaxants in the past.

As with the use of other muscle relaxants, in predisposed patients atracurium bezylate can cause the development of reactions associated with the release of histamine, so it should be administered with caution in hypersensitivity to histamine in history.

When administered at the recommended dose range atracurium bezylate does not block the vagus nerve and nerve ganglia, has no clinically significant effect on the heart rate and does not prevent bradycardia caused by anesthetics or vagal nerve stimulation during surgery.

As with other non-depolarizing muscle relaxants, hypersensitivity to atracuria may be observed in patients with myasthenia gravis, other neuromuscular diseases and with severe electrolyte imbalance. The development of neuromuscular blockade caused by nondepolarizing muscle relaxants slows down, and its duration decreases in patients receiving long-term anticonvulsant therapy.

Neuromuscular blockade is quickly and completely eliminated by neostigmine methyl sulfate and the preceding administration of atropine (after 5-10 min). Patients prone to lowering blood pressure, such as hypovolemia, atracurium bezylate it is recommended to enter for at least 60 seconds.

Atracurium bezylate is inactivated in an alkaline medium and should not be mixed in one syringe with sodium thiopental or alkaline solutions.

If a peripheral vein of small caliber is used to inject a solution of atrakury bezilate, then after injection, it should be washed with 0.9% sodium chloride solution.

A solution of atracurium bezylate is hypotonic and should not be used simultaneously through a single system with blood transfusions.

Atracuria bezylate does not cause malignant hyperthermia.

Safety of atracurium besylate has not been established in patients with bronchial asthma.

In patients with burns, resistance to nondepolarizing muscle relaxants, which requires an increase in the doses of these drugs, the magnitude of which depends on the time that has passed after the burn, and on the area of its surface.

Effect on the ability to drive transp. cf. and fur:

Patients who receive the drug should refrain from potentially dangerous species activities related to the need for concentration and increased the speed of psychomotor reactions.

Form release / dosage:Solution for intravenous administration 10 mg / ml.

Packaging:

For 2.5 ml of the drug in a dark glass ampoule (type I USP).

10 ampoules in a cassette of PVC or without are placed together with instructions for use in a cardboard pack.

Storage conditions:

In the dark place at a temperature of 2 to 8 ° C. Do not freeze. The solution of atracurium besylate, which is not used after opening the ampoule, must be destroyed.

Keep out of the reach of children.

Shelf life:

2 years.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002610

Date of registration:04.09.2014 / 20.01.2016

Expiration Date:04.09.2019

The owner of the registration certificate:ARS, LLC ARS, LLC Russia

Manufacturer: & nbsp

CIRON DRUGS & PHARMACEUTICALS, Pvt. Ltd India

Information update date: & nbsp04.10.2017

Illustrated instructions

Instructions

Atracuria bezylate (Atracurium besylate)