BlokkoS, 5 mg/ml 4 ml 10 pcs

Pharmacodynamics:

Bupivacaine is a long-acting local anesthetic of the amide type. It reversibly blocks impulse conduction along the nerve fiber by disrupting the transport of sodium ions through sodium channels. Can have a similar effect in the brain and myocardium.

The most characteristic feature of bupivacaine is the duration of its action, which does not depend much on the addition of epinephrine to it. Bupivacaine is the drug of choice for continuous epidural anesthesia. In low concentrations it has less effect on motor fibers and has a shorter duration of action, which is useful for short-term pain relief, for example, during childbirth or after surgery.

The relative density of the drug solution is 1004 at 20 °С (which is equivalent to 1000 at 37 °С, the force of gravity has little effect on its distribution in the subarachnoid space. For subarachnoid administration, a small dose is administered, resulting in a relatively low concentration and a short duration of blockade. With subarachnoid administration of bupivacaine not containing dextrose, anesthesia is less predictable but more prolonged than with bupivacaine solution containing dextrose.

Pharmacokinetics:

The pKa value of bupivacaine is 8.2; the partition coefficient is 346 (at 25°C in n-octanol/phosphate buffer medium pH 7.4).

The absorption rate depends on the dose, the route of administration and the blood supply at the injection site. In intercostal blockade due to rapid absorption, the maximum plasma concentration is 4 mg/l (when administered 400 mg); plasma concentrations are lower in subcutaneous injections into the abdominal region. In children with caudal blockade, there is rapid absorption and high plasma concentrations of about 1-1.5 mg/l (when administered 3 mg/kg) are achieved.

Bupivacaine is completely absorbed from the epidural space, the half-life is biphasic and is 7 min and 6 h, respectively. Slow absorption limits the elimination rate of bupivacaine, which explains the longer elimination half-life after epidural injection than when administered intravenously.

The equilibrium volume of distribution of bupivacaine is 73 L, the hepatic extraction coefficient is 0.40, total plasma clearance is 0.58 L/min, and the plasma elimination half-life is 2.7 h. The half-life in infants may be longer than in adults, up to 8 hours. In children older than 3 months the half-life is equal to that of adults.

The binding to plasma proteins is 96%, mainly by α1-acid glycoprotein. After major surgery, the concentration of this protein may be elevated, which may result in a higher total plasma concentration of bupivacaine. The free fraction of bupivacaine is unchanged. Therefore, the potentially toxic plasma concentration is well tolerated.

Bupivacaine is almost completely metabolized in the liver, mainly by aromatic hydroxylation to 4-hydroxybupivacaine and N-dealkylation to pipecolyloxylidine, both reactions catalyzed by CYP3A4 isoenzyme. Thus, clearance depends on hepatic blood flow and the activity of metabolizing enzymes.

Bupivacaine penetrates through the placenta, the concentration of unbound bupivacaine in the fetus is equal to that of the mother. Because of the lower binding to plasma proteins, the fetal total plasma concentration is lower.

In intrathecal administration
Bupivacaine is well soluble in lipids with an oil/water distribution ratio of 27.5.

Bupivacaine is completely absorbed from the subarachnoid space in two phases with a half-life of 50-400 minutes. Slow absorption is a limiting factor in the excretion of bupivacaine, which explains its longer half-life than with intravenous administration.

The absorption from the subarachnoid space is relatively slow, which, combined with the low dose required for spinal anesthesia, results in a relatively low maximum plasma concentration (0.4 mg/mL per 100 mg of the drug).

Indications

Anesthesia

• Surgical anesthesia in adults and children over 12 years.
• Acute pain in adults and children over 1 year.
• Infiltration anesthesia when a long anesthetic effect is required, such as in postoperative pain.
• Long lasting anesthesia or epidural anesthesia in cases where the addition of epinephrine is contraindicated and significant muscle relaxation is undesirable. Anesthesia in obstetrics.

With intrathecal administration

Spinal anesthesia in lower extremity surgery, including hip surgery, lasting 3-4 h and not requiring pronounced motor block.

Active ingredient

Bupivacaine

Composition

1 ampoule (4 ml) contains as active ingredient

bupivacaine hydrochloride monohydrate in terms of dry substance 20 mg;

Associates:

Sodium chloride 32.0 mg,

Dietate 0.4 mg,

0.1 M hydrochloric acid solution or 0.1 M sodium hydroxide solution to pH 4.0-6.5,

Injectable water to 4 ml.

How to take, the dosage

Bupivacaine should only be administered by or under the supervision of physicians experienced in local anesthesia. In order to achieve the desired degree of anesthesia, the lowest possible dose should be administered.

Inadvertent intravascular injection should never be allowed under any circumstances. Aspiration testing is recommended prior to and during the administration of the drug. The product should be administered slowly at 25-50 mg/min or in portions while maintaining continuous verbal contact with the patient and monitoring the heart rate. During epidural administration, a dose of 3-5 ml of bupivacaine with epinephrine is administered in advance. In case of accidental intravascular injection there is a short-term increase in heart rate, in case of accidental intrathecal injection there is a spinal block. If toxic signs occur, administration should be stopped immediately.

The following are indicative doses that should be adjusted depending on the depth of anesthesia and the patient’s condition.

Infiltration anesthesia: 5-60 ml of 2.5 mg/ml (12.5-150 mg bupivacaine) or 5-30 ml of 5 mg/ml (25-150 mg bupivacaine).

Diagnostic and therapeutic blockade: 1-40 ml of drug at a concentration of 2.5 mg/ml (2.5-100 mg bupivacaine), e.g., 1-5 ml (2.5-12.5 mg) trigeminal nerve blockade and 10-20 ml (25-50 mg) cervicothoracic sympathetic trunk node blockade.

Intercostal blockade: 2-3 ml of the drug at a concentration of 5 mg/ml (10-15 mg bupivacaine) per nerve, not exceeding the total of 10 nerves.

Large blockades (e.g., epidural block, sacral or brachial plexus block): 15-30 ml of the drug at a concentration of 5 mg/ml, (75-150 mg bupivacaine).

Anesthesia in obstetrics (e.g. epidural and caudal anesthesia in natural childbirth): 6-10 ml of drug at a concentration of 2.5 mg/ml (15-25 mg bupivacaine) or 6-10 ml of drug at a concentration of 5 mg/ml (30-50 mg bupivacaine).

The initial dose may be repeated every 2-3 hours.

Epidural anaesthesia for caesarean section: 15-30 ml 5 mg/ml (75-150 mg bupivacaine).

Epidural analgesia as an intermittent bolus injection: 20 ml at 2.5 mg/ml (50 mg bupivacaine) initially, then every 4-6 hours, depending on the number of damaged segments and patient age, 6-16 ml at 2.5 mg/ml (15-40 mg bupivacaine).

Epidural analgesia as a continuous infusion (e.g., postoperative pain):

¹ If no bolus was administered during the previous hour.

² Do not exceed the maximum recommended daily dose (see below).

Additional administration of the drug is possible during surgical procedures.

The dose of bupivacaine should be reduced if narcotic analgesics are used concomitantly.

The patient’s blood pressure, heart rate and other signs of potential toxicity should be monitored regularly during prolonged administration of the drug. If toxic effects occur, the drug should be stopped immediately.

Maximum recommended doses

The maximum recommended single dose, based on 2 mg/kg body weight, is 150 mg for adults over four hours. This is equivalent to 60 ml of 2.5 mg/ml (150 mg bupivacaine) and 30 ml of 5 mg/ml (150 mg bupivacaine).

The maximum recommended daily dose is 400 mg. However, when calculating the total daily dose, the patient’s age, build, and other relevant conditions should be taken into account.

Children 1-12 years of age

Regional anesthesia should be performed by a physician experienced in children with appropriate technique of administration.

The doses in children listed in the table are approximate. Variability is possible. In children of high body weight, it is usually necessary to reduce the dose based on ideal body weight. Generally accepted anesthesia guidelines should be used in determining methods of anesthesia and taking into account individual patient characteristics.

The minimum dose necessary to achieve adequate anesthesia should be administered.

(b) In thoracic epidural anesthesia, the drug shall be administered in increasing doses until the desired level of pain relief is achieved.

The dose in children is calculated on the basis of 2 mg/kg body weight.

In order to prevent the drug from entering the vascular system, an aspiration test should be performed before and during the administration of the main dose. The drug should be administered slowly, dividing the total dose into several injections, especially in lumbar and thoracic epidural anesthesia, continuously monitoring vital signs.

Peritonsillar infiltration anesthesia in children from 2 years of age: at a dose of 7.5 mg and 12.5 mg per tonsillectomy at a bupivacaine concentration of 2.5 mg/ml.

Iliopsoas/iliac/subiliac nerve blockade in children from 1 year of age: 0.1-0.5 ml/kg at a bupivacaine concentration of 2.5 mg/ml, equivalent to 0.25-1.25 mg/kg. In children 5 years of age and older, the drug may be administered at a concentration of 5 mg/ml at a dose of 1.25-2 mg/kg.

Penile blockade: 0.2-0.5 ml/kg at a concentration of 5 mg/ml, corresponding to 1.25-2 mg/kg.

The data on epidural anesthesia in children (bolus or continuous administration) are limited.

Preparation method

If a solution with a concentration of 2.5 mg/ml is required, the drug with a concentration of 5 mg/ml is diluted with water for injection in a ratio of 1:1.

In intrathecal administration

Bupivacaine should only be administered by or under the supervision of physicians experienced in local anesthesia. The lowest possible dose should be administered to achieve the desired degree of anesthesia.

The doses given below are adult doses. The dose should be adjusted on an individual basis.

Elderly patients and patients in late pregnancy should have the dose reduced.

The recommended injection site is at the L3 level.

There is no clinical experience with a dose greater than 20 mg. Intravenous access should be provided prior to administration.

Injection is done only after confirmation of entry into the subarachnoid space (clear cerebrospinal fluid flowing from the needle or aspiration). If this fails, only one more attempt at a different level and smaller volume should be made. One reason for lack of response could be poor distribution of drug in the subarachnoid space, which can be corrected by repositioning the patient.

In children weighing less than 40 kg

Bupivacaine, solution for injection, 5 mg/ml, approved for use in children.

The main difference between adults and children is that newborns and infants have larger cerebrospinal fluid volumes, requiring a relatively higher dose per kg body weight compared to adults to achieve the same degree of blockage.

Regional anesthesia should be performed by a physician experienced in pediatric patients with appropriate insertion techniques.

The doses in children listed in the table are indicative. Variations are possible. Generally accepted guidelines for anesthesia should be used in determining anesthesia techniques and taking into account the individual characteristics of patients. The minimum dose necessary to achieve adequate anesthesia should be administered.

Interaction

Caution should be exercised when using bupivacaine concomitantly with other local anesthetics or class Ib antiarrhythmic agents, as they may potentiate each other’s toxic effects.

The interaction of local anesthetics and class III antiarrhythmic agents (e.g., amiodarone) has not been studied separately, however, caution is recommended with their simultaneous use (see also section “Special Considerations”).

The alkalinization may lead to precipitation, because the solubility of bupivacaine is reduced at pH > 6.5.

In preparation for administration, avoid prolonged contact of the medication with metal objects, as metal ions may cause reactions at the injection site, manifesting as soreness and swelling.

When epinephrine is added to the local anesthetic solution, concomitant use with monoamine oxidase inhibitors and tricyclic antidepressants should be avoided if possible, since a persistent increase in arterial pressure may develop. If such concomitant therapy is necessary, the patient should be closely monitored. Concomitant use with vasopressors and uterotonic agents (ergot derivatives) may lead to persistent high blood pressure and cerebrovascular complications. Phenothiazine and butyrophenone derivatives may decrease or reverse the pressor effect of epinephrine.

Special Instructions

The administration of local anesthetics must be carried out in the immediate vicinity of the resuscitation equipment. Venous access should be provided before large blockades are started.

There have been reports of cardiac arrest or death during the use of bupivacaine for epidural anesthesia or peripheral block. In some cases resuscitation was difficult or impossible despite adequate treatment.

Blockade of major peripheral nerves may require the administration of large volumes of local anesthetics into well-circulated areas of the body, often near major blood vessels. In such situations, there is an increased risk of intravascular bupivacaine administration or systemic absorption, which can lead to high blood concentrations of the local anesthetic.

Like other local anesthetics, bupivacaine may cause acute central nervous and cardiovascular toxic reactions if high blood concentrations occur during the local anesthetic procedure. This is most often seen in the case of unintentional intravascular injection or when the blood supply to the injection site is good.

Without regard to the local anesthetic agent used, certain types of local anesthesia may produce serious adverse reactions, such as

– Epidural anesthesia, particularly against a background of hypovolemia, may lead to cardiovascular depression. Caution should be exercised in patients with cardiovascular disease.

In retrobulbar administration, the drug may occasionally penetrate into the cranial subarachnoid space, causing temporary blindness, apnea, seizures, collapse and other adverse reactions. These reactions should be managed immediately.

– With retrobulbar and peribulbar administration of local anesthetics, there is some risk of persistent ocular muscle dysfunction. The primary causes are trauma and/or local toxic effects on muscles and/or nerves.

– When inadvertently injected intravascularly into the head and neck area, even at low doses, can cause generalized cerebral symptoms.

The severity of the adverse reactions described above depends on the size of the injury, the concentration of the local anesthetic, and the duration of its exposure to the tissue. Therefore, as with other local anesthetics, the lowest effective dose of bupivacaine should be administered.

Caution should be exercised in patients with grade II or III AV blockade because local anesthetics may interfere with intracardiac conduction. Caution should be exercised when administering the drug in the elderly and patients with severe liver disease, severe renal impairment, or general poor condition.

Patients receiving class III antiarrhythmic agents (e.g., amiodarone) should be closely monitored and have their cardiovascular toxic effects combined with those of bupivacaine.

Lower blood pressure and bradycardia may occur during epidural anesthesia. It is possible to reduce the likelihood of such complications by prior administration of crystalloid and colloidal solutions. If blood pressure decreases, immediate intravenous administration of sympathomimetics (e.g., 5-10 mg of ephedrine) is indicated; if necessary, they should be repeated.

According to post-operative follow-up, chondrolysis has occurred in some patients who received prolonged local anesthetic injections into the joint cavity after surgery. In most cases chondrolysis of the shoulder joint. The cause-and-effect relationship with the administration of bupivacaine has not been conclusively confirmed; several factors may be responsible for chondrolysis. Conflicting data on the mechanism of this condition have been described in the literature. Prolonged intra-articular injection is not an approved indication for bupivacaine.

The solution contains no preservatives, so it should be administered immediately after opening the vial. Residues of the solution must be disposed of.

In children

The safety and effectiveness of bupivacaine in children younger than 1 year have not been studied; only limited data are available.

There are no data on intra-articular block with bupivacaine in children 1-12 years of age.

There are no data on bupivacaine block of large nerves in children 1-12 years of age.

In epidural anesthesia, the drug should be administered slowly, guided by age and body weight, because especially in epidural anesthesia at the chest level, severe hypotension and respiratory distress may occur.

In intrathecal administration

Spinal anesthesia can cause severe blockages and paralysis of the intercostal muscles and diaphragm, particularly in pregnant women.

In elderly patients and patients in late pregnancy, there is an increased risk of high or complete spinal block leading to circulatory and respiratory depression. The dose should be reduced in these patients.

Spinal anesthesia may result in decreased blood pressure and bradycardia. This risk may be reduced by administration of crystalloid solutions. If blood pressure decreases, it should be managed immediately, e.g., by intravenous injection of 5-15 mg of ephedrine.

In patients with hypovolemia, regardless of its cause, a sudden severe decrease of blood pressure may develop during intrathecal anesthesia.

Spinal anesthesia may result in intercostal paralysis, and therefore, patients with pleural effusion may experience respiratory failure. Septicemia may increase the risk of intraspinal abscesses in the postoperative period.

Neurological complications are a rare consequence of spinal anesthesia and may result in paresthesia, anesthesia, muscle weakness and paralysis. In some cases, these complications are permanent.

Before treatment, the benefits and risks to the patient must be weighed.

Effects on driving and operating machinery

Depending on the dose and route of administration, local anesthetics may have transient effects on motor function and coordination of movement.

Contraindications

Hypersensitivity to any of the components of the drug or to other local anesthetics of the amide type.

Severe arterial hypotension (cardiogenic or hypovolemic shock).

Children under 1 year of age for all indications except intrathecal anesthesia in which the drug may be administered from birth.

Intravenous regional anesthesia (Bier blockade) (accidental penetration of bupivacaine into the bloodstream may cause acute systemic toxic reactions).

Paracervical block in obstetrics.

Conditions that are contraindications to epidural or intrathecal anesthesia:

• Diseases of the central nervous system (e.g., meningitis, tumors, polio, cranial bleeding).
• Purulent skin infections at or near the lumbar puncture site.
• Spinal stenosis, active disease (e.g., spondylitis, tumors, tuberculosis) or trauma (e.g., fracture) to the spine.
• Sepsis, subacute spinal cord degeneration associated with megaloblastic anemia.
• Cardiogenic or hypovolemic shock.
• Blood clotting disorders or active anticoagulant therapy.

With caution

Cardiovascular failure (possible progression), heart block, inflammatory disease or infection of the injection site (in infiltration anesthesia), cholinesterase deficiency, renal failure, advanced age (over 65 years), late pregnancy (III trimester, see the sections “Use of Pregnancy and Pregnancy”, see the section “Administration of Pregnancy”. Sections “Administration in pregnancy and lactation” and “Special indications”), general severe condition, decreased hepatic blood flow (e.g., in chronic heart failure, liver disease), concomitant administration of antiarrhythmic drugs (including β-adrenoblockers), children (1-12 years).

Bupivacaine should be used with caution in patients receiving other local anesthetics or drugs structurally similar to amide-type local anesthetics, such as antiarrhythmic drugs (e.g., lidocaine, mexiletine).

Side effects

Adverse drug reactions caused by the drug may be difficult to distinguish from the physiological manifestations of nerve block (e.g., decreased blood pressure, bradycardia), reactions directly (e.g., nerve damage) or indirectly caused by the administration (e.g., epidural abscess).

Neurological abnormalities are rare but well known adverse drug reactions due to local anesthesia, especially with epidural and intrathecal drug administration.

The symptoms and management tactics for acute systemic toxicity are described in the Overdose section.

Adverse reactions in children are similar to those in adults, but early signs of toxicity of local anesthetics in children may be more difficult to recognize if the blockade is performed under sedation or anesthesia.

In intrathecal administration

Adverse reactions in children are similar to those in adults, but early signs of toxicity of local anesthetics in children may be more difficult to recognize if blockade is performed under sedation or anesthesia.

Overdose

Acute systemic toxicity

Symptoms

Toxic reactions mainly occur in the central nervous and cardiovascular systems. These are due to the high blood concentration of the local anesthetic, which may be due to accidental intravascular administration, overdose, or exceptionally rapid absorption from highly vascularized tissues (see section “Special Precautions”).

The signs of CNS damage are similar for all amide-type local anesthetics, whereas the symptoms of cardiovascular damage vary, both qualitatively and quantitatively.

Inadvertent intravascular administration of a local anesthetic may result in immediate systemic toxic reactions (within seconds to minutes). Signs of systemic toxicity in overdose appear later (15-60 minutes after administration) because the concentration of the local anesthetic in the blood increases slowly.

The CNS intoxication is manifested gradually, with the severity of symptoms increasing gradually. The initial signs are usually dizziness, paresthesias around the mouth, tongue numbness, hyperacusis, tinnitus and visual disturbances. More serious manifestations are dysarthria and myofasciculations, which may precede the onset of generalized seizures. These phenomena should not be mistaken for a neurotic disorder. They may be followed by loss of consciousness and the development of a grand mal seizure lasting from several seconds to several minutes. Hypoxia and hypercapnia increase rapidly during convulsions due to increased muscle activity and insufficient ventilation. In severe cases respiratory arrest may occur. Concomitant acidosis exacerbates the toxic effects of local anesthetics.

The resolution of symptoms is due to the metabolism of the local anesthetic and redistribution from the CNS. The described phenomena are quickly resolved if the overdose was not excessive.

The lesion of the cardiovascular system is usually indicative of a more severe intoxication. It is usually preceded by signs of CNS damage, which may be obliterated if the patient is under anesthesia or deep sedation due to medications such as: benzodiazepines or barbiturates. Due to the high concentration of local anesthetics in the blood, decreased blood pressure, bradycardia, arrhythmias, and cardiac arrest may occur. Toxic cardiovascular manifestations are often due to myocardial depression and conduction disturbances resulting in decreased cardiac output, decreased blood pressure, AV blockade, bradycardia, ventricular arrhythmias including ventricular tachycardia and ventricular fibrillation, and cardiac arrest. These phenomena are often preceded by severe signs of CNS damage, including seizures, but rarely does cardiac arrest occur without concomitant CNS symptoms. After a very rapid intravenous injection, the concentration of bupivacaine in the blood may be quite high. In this case, it quickly reaches the coronary arteries, and the symptoms of circulatory failure occur before the signs of CNS damage. This mechanism causes myocardial depression and may be the first manifestation of intoxication.

In children under general anesthesia, early signs of intoxication are difficult to detect and require close monitoring.

Treatment

If spinal block occurs, ensure adequate ventilation (airway patency, oxygen supply, intubation and artificial ventilation if necessary). In case of decreased blood pressure and/or bradycardia a vasopressor with inotropic effect should be administered.

In case of symptoms of acute systemic intoxication, the drug administration should be stopped immediately. Adequate ventilation, oxygenation and circulatory support should be provided.

In all cases it is necessary to establish oxygen supply, if necessary intubation and controlled ventilation (in some cases with hyperventilation). In convulsions diazepam is administered, in bradycardia – atropine. In circulatory insufficiency – intravenous dobutamine, norepinephrine may be given (starting at 0.05 µg/kg/min, if necessary, increasing the dose by 0.05 µg/kg/min every 10 min), in more severe cases the dose is titrated by hemodynamic monitoring results. Ephedrine may be administered. If the cardiovascular system is severely affected, resuscitation measures may continue for several hours. Any acidosis should be managed.

When controlling systemic intoxication in children, drug doses should be adjusted according to their age and body weight.

Pregnancy use

In paracervical block in obstetrics, bupivacaine may cause severe cardiovascular abnormalities in the fetus. The use of bupivacaine as a paracervical block is contraindicated (see Contraindications).

The use of the drug for the stated indication is possible if the expected benefit to the mother outweighs the possible risk to the fetus.

Bupivacaine penetrates into the breast milk, but when used in therapeutic doses, the effect on the baby is small.

In intrathecal administration

There are no data on adverse effects on pregnancy. When used in pregnant animals at high doses, decreased offspring survival in rats and embryological effects in rabbits have been found. Therefore, bupivacaine should not be used in early pregnancy unless the benefits exceed the risks.

The dose should be reduced in late pregnancy (see section “Special Precautions”). Bupivacaine penetrates into breast milk, but when used in therapeutic doses, the effect on the baby is negligible.