Bupivacaine, 5 mg/ml 4 ml 5 pcs

Pharmacodynamics

A long-acting local anesthetic of the amide type, 4 times stronger than lidocaine. It reversibly blocks impulse conduction along the nerve fiber due to its effect on sodium channels. Can have similar effect in the brain and myocardium.

It has a hypotensive effect and slows the heart rate. Postoperative analgesia is maintained for 7-14 hours with intercostal blockade. After a single epidural injection the duration of effect when using the concentration of 5 mg/ml is from 2 to 5 hours, and up to 12 hours for peripheral nerve blockade.

The use of solutions at a concentration of 2.5 mg/ml has less effect on the motor nerves.

Pharmacokinetics

The systemic absorption of bupivacaine depends on the dose, method of administration and vascularization of the area of administration.
The anesthetic effect occurs quickly; in comparison with other local anesthetic agents the anesthetic effect of bupivacaine is much longer.

It has been noted that the analgesic effect persists for some time after return of sensitivity, which makes it possible to reduce the doses of analgesics. Bupivacaine is completely absorbed from the epidural space; absorption is biphasic.

The time of reaching maximum plasma concentration (TCmax) during caudal epidural and conduction anesthesia is 30-45 minutes, with a subsequent decrease to insignificant levels within 3-6 hours. Total plasma clearance of bupivacaine is 580 ml/min, the volume of distribution – 73 l. Terminal elimination half-life (T1/2) is 2.7 h. Hepatic extraction index is 0.4.

The binding to plasma proteins (mainly to alpha 1-acid glycoprotein) is 95%. Increased concentration of alpha 1-acid glycoprotein in the postoperative period may increase the total plasma concentration of bupivacaine, while the concentration of the unbound fraction does not change, and the total plasma concentration exceeding the toxic concentration (2.3-3 mg/l) is well tolerated. During intercostal blocks (due to rapid absorption), the highest concentrations of the drug in plasma are determined (1-4 mg/l after administration of a total dose of 400 mg), while after p/c administration in the anterior abdominal wall area creates the lowest concentration in plasma.

In children, rapid absorption and high plasma concentrations of the drug (1-1.5 mg/L, administered dose 3 mg/kg) are observed with caudal blockade

In newborns, the T1/2 is 8.1 h, and in children over 3 months, the T1/2 is the same as in adults. It penetrates through the placenta by passive diffusion. The binding to plasma proteins in the fetus is lower than in the mother, the concentration of the unbound fraction in the fetus and mother is the same.

Secreted with the mother’s milk. Bupivacaine is metabolized in the liver, mainly by conjugation with glucuronic acid. The main metabolite is 2,6-pipecoloxylidine. Patients with liver disease, especially those with severe hepatic dysfunction, have a higher risk of toxic reactions after the use of amide-type local anesthetics.

Extracted mainly by the kidneys, only 6% of bupivacaine is excreted unchanged in the urine. After epidural administration, about 0.2% of unchanged bupivacaine, 1% of 2,6-pipecoloxylidine and about 0.1% of 4-hydroxybupivacaine are detected in the urine. Pharmacokinetic parameters may be significantly altered by factors affecting urinary pH and renal blood flow, depending on the route of administration and patient age, as well as in patients with liver and kidney disease.

In clinical studies, the maximum analgesic and anesthetic effect occurred faster in elderly patients than in younger patients. In elderly patients a higher maximum plasma concentration of the drug was also observed after administration of the drug. Total plasma clearance was decreased in these patients.

Bupivacaine does not usually cause irritation or tissue damage, or methemoglobinemia, when the recommended doses are followed.

Indications

Surgical anesthesia in adults and children over 12 years of age.
Infiltration anesthesia, when it is necessary to achieve a long-term anesthetic effect, for example, for postoperative pain.
Long-acting conduction anesthesia or epidural anesthesia in cases in which the addition of epinephrine is contraindicated and significant muscle relaxation is not required.
Anesthesia in obstetrics.

Pharmacological effect

Pharmacodynamics

A long-acting local anesthetic of the amide type, 4 times stronger than lidocaine. Reversibly blocks the conduction of impulses along the nerve fiber due to its effect on sodium channels. May have a similar effect in the brain and myocardium.

It has a hypotensive effect and slows down the heart rate. Postoperative analgesia is maintained for 7-14 hours with intercostal blockade. After a single epidural injection, the duration of effect when using a concentration of 5 mg/ml ranges from 2 to 5 hours, and up to 12 hours with peripheral nerve block.

The use of solutions at a concentration of 2.5 mg/ml has less effect on motor nerves.

Pharmacokinetics

Systemic absorption of bupivacaine depends on the dose, method of administration, and vascularization of the area of ​​administration.
The anesthetic effect occurs quickly; Compared to other local anesthetics, the anesthetic effect of bupivacaine is significantly longer.

It was noted that after the return of sensitivity, the analgesic effect persists for some time, which makes it possible to reduce the dose of analgesics. Bupivacaine is completely absorbed from the epidural space; absorption is biphasic.

The time to reach the maximum concentration in the blood plasma (TCmax) during caudal epidural and conduction anesthesia is 30-45 minutes, followed by a decrease to an insignificant level within 3-6 hours. The total plasma clearance of bupivacaine is 580 ml/min, the volume of distribution is 73 l. The final half-life (T1/2) is 2.7 hours. The hepatic extraction rate is 0.4.

The binding to plasma proteins (mainly alpha 1-acid glycoprotein) is 95%. An increase in the concentration of alpha 1-acid glycoprotein in the postoperative period can lead to an increase in the total concentration of bupivacaine in plasma, while the concentration of the unbound fraction does not change, and the total plasma concentration exceeding the toxic one (2.3-3 mg/l) is well tolerated. When performing intercostal blockades (due to rapid absorption), the highest concentrations of the drug in plasma are determined (1-4 mg/l after administration of a total dose of 400 mg), while after subcutaneous injection into the area of ​​the anterior abdominal wall it creates the lowest concentration in plasma.

In children, rapid absorption and high plasma concentrations of the drug (1-1.5 mg/l, administered dose 3 mg/kg) are observed with caudal blockade

In newborns, T1/2 is 8.1 hours, and in children older than 3 months, T1/2 is the same as in adults. Penetrates the placenta by passive diffusion. The connection with plasma proteins in the fetus is lower than in the mother, the concentration of the unbound fraction in the fetus and mother is the same.

Secreted into mother’s milk. Bupivacaine is metabolized in the liver, mainly by conjugation with glucuronic acid. The main metabolite is 2,6-pipecoloxylidine. Patients with liver disease, especially those with severe hepatic impairment, are at higher risk of toxic reactions following the use of amide-type local anesthetics.

Excreted primarily by the kidneys, only 6% of bupivacaine is excreted unchanged in the urine. Following epidural administration, approximately 0.2% unchanged bupivacaine, 1% 2,6-pipecoloxylidine, and approximately 0.1% 4-hydroxybupivacaine are found in urine. Pharmacokinetic parameters may be significantly modified by factors affecting urinary pH and renal blood flow, depending on the route of administration and the age of the patient, as well as in patients with liver and kidney disease.

In clinical studies, the maximum analgesic and anesthetic effect occurred faster in elderly patients than in younger patients. In elderly patients, higher maximum plasma concentrations of the drug were also observed after drug administration. The total plasma clearance in these patients was reduced.

When taken at recommended doses, bupivacaine does not usually cause irritation or tissue damage or methemoglobinemia.

Special instructions

When performing regional and local anesthesia, with the exception of the most simple blocks, equipment for resuscitation should be available for immediate use. When performing extensive blockades, an intravenous catheter must be installed before administering a local anesthetic.
Cases of cardiac arrest or death have been reported during the use of bupivacaine for epidural anesthesia or peripheral blockade. In some cases, resuscitation was difficult or impossible despite proper implementation.
Peripheral nerve blockade involves the injection of a large volume of local anesthetic into highly vascularized areas, often close to large vessels. In such cases, the risk of accidental intravascular injection of local anesthetic and/or systemic absorption of the drug increases, which in turn may lead to increased plasma concentrations. Like all other local anesthetics, at high concentrations in the blood, bupivacaine can have toxic effects on the central nervous system and cardiovascular system. This applies in particular to inadvertent intravascular administration or administration into highly vascularized areas.
Certain types of blocks may be associated with serious adverse reactions, such as:

Epidural anesthesia may be accompanied by depression of the cardiovascular system, especially against the background of hypovolemia. Therefore, caution should be exercised in patients with impaired cardiovascular function.
In rare cases, with retrobulbar administration, the drug may penetrate into the cranial subarachnoid space, resulting in temporary blindness, cardiovascular collapse, apnea and convulsions. These symptoms require immediate treatment.
With retrobulbar and peribulbar administration of local anesthetics, there is a small risk of permanent dysfunction of the eye muscles.
The main causes are trauma and/or local toxic effects of the administered drug on muscles and/or nerves.
Accidental intravascular administration of local anesthetics to the head and neck region, even at low doses, can cause symptoms of CNS toxicity.
Paracervical block sometimes results in fetal bradycardia/tachycardia, so fetal heart rate should be closely monitored.

The severity of such tissue reactions depends on the degree of injury, the concentration of the local anesthetic, and the duration of exposure of the tissue to the local anesthetic. Therefore, the lowest effective dose of the drug should be used.

Caution should be exercised in patients with stage II or III atrioventricular block, since local anesthetics may reduce myocardial conduction. Caution should be exercised in patients with severe hepatic or renal impairment, elderly or debilitated patients.

Patients receiving class III antiarrhythmic drugs (eg, amiodarone) should be closely monitored with ECG monitoring, taking into account the risk of developing cardiovascular complications due to the possible additive effect. Hypotension and bradycardia may occur during epidural anesthesia.

The likelihood of these complications can be reduced by prior administration of crystalloid or colloid solutions. In case of arterial hypotension, therapy should be carried out immediately, for example, ephedrine should be administered intravenously at a dose of 5-10 mg; the administration can be repeated if necessary. Cases of chondrolysis have been reported with postoperative prolonged intra-articular infusion of local anesthetics.

In most of the reported cases, infusion was performed into the shoulder joint. A cause-and-effect relationship with the use of anesthetics has not been established due to the presence of several predisposing factors. Bupivacaine is not approved for extended intra-articular infusion.

Impact on the ability to drive vehicles and machinery

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

Active ingredient

Bupivacaine

Composition

1 ml of solution contains:

Active ingredient:
Bupivacaine hydrochloride monohydrate
5.28 mg
(in terms of bupivacaine hydrochloride)
5.0 mg
Excipients:
Sodium chloride
8.0 mg
Hydrochloric acid solution 1M
to pH from 4.5 to 6.5
Sodium hydroxide solution 1M
to pH from 4.5 to 6.5
Water for injections
up to 1.0 ml

Pregnancy

Adequate and well-controlled studies have not been conducted to determine the effects of bupivacaine on the fetus in pregnant women. The drug should be used during pregnancy only if the expected benefit to the mother outweighs the possible risk to the fetus.

The addition of epinephrine to bupivacaine may reduce uterine blood flow and contractility, especially if the anesthetic solution is inadvertently introduced into the maternal vessels.

Paracervical blockade is contraindicated.

Bupivacaine passes into breast milk. The drug can cause serious side effects in the child, so if bupivacaine must be administered, breastfeeding should be stopped.

Contraindications

Hypersensitivity to any of the components of the drug or to other amide-type local anesthetics.
Conditions in which epidural anesthesia is contraindicated:
– current diseases of the central nervous system (CNS), such as meningitis, poliomyelitis, intracranial hemorrhage, as well as CNS neoplasms;
– tuberculosis of the spine;
– pernicious anemia with subacute combined degeneration of the spinal cord;
– pustular skin lesion at the site of the intended puncture or bordering the puncture site;
– cardiogenic or hypovolemic shock;
– bleeding disorders or concomitant anticoagulant therapy.

Bupivacaine 5 mg/ml is not approved for use in children under 12 years of age.
The drug is not used for intravenous regional anesthesia (Bir block).

With caution:
old age;
weakened patients;
atrioventricular block II and III degrees;
severe liver and kidney dysfunction;
women in late pregnancy;
combined use with class III antiarrhythmic drugs (for example, amiodarone);
combined use with other local anesthetics or drugs that are structurally similar to amide-type local anesthetics, such as class lb antiarrhythmic drugs (for example, lidocaine, mexiletine);
paracervical blockade.

Side Effects

Adverse reactions caused by Bupivacaine 5 mg/mL are difficult to distinguish from physiological manifestations of nerve block (eg, hypotension, bradycardia), reactions caused directly (eg, nerve injury) or indirectly (eg, epidural abscess) by needle insertion.
Nerve tissue damage is a rare but known complication of regional anesthesia, particularly epidural and spinal anesthesia.

Information on symptoms and treatment of acute systemic toxicity is provided in the Overdose section.

Very common (≥1/10)
Cardiovascular system: arterial hypotension
From the gastrointestinal tract (GIT): nausea
Frequent (≥1/100, <1/10) From the nervous system: paresthesia, dizziness
From the cardiovascular system: bradycardia, arterial hypertension
From the gastrointestinal tract: vomiting
From the genitourinary system: urinary retention
Uncommon (≥1/1000, <1/100) From the nervous system: symptoms of toxicity from the central nervous system (convulsions, perioral paresthesia, numbness of the tongue, hyperacusis, visual disturbances, loss of consciousness, tremor, dizziness, noise and ringing in the ears, dysarthria) Rare (≥1/10000, <1/1000) From the cardiovascular system: cardiac arrest, arrhythmia
From the nervous system: neuropathy, peripheral nerve damage, arachnoiditis, paresis, paraplegia
From the respiratory system: respiratory depression
On the part of the visual organs: diplopia
From the immune system: allergic reactions, anaphylactic shock.

Children

Pediatric patients experience the same adverse reactions as adult patients, but early detection of local anesthetic toxicity in children may be difficult if the block is performed under sedation or general anesthesia.

Interaction

Bupivacaine should be used with caution in patients receiving other local anesthetics or class lb antiarrhythmic drugs due to the potential for additive toxic effects.

The combined use of bupivacaine with local anesthetics and class III antiarrhythmic drugs (for example, amiodarone) has not been studied in drug interaction studies, however, caution is recommended when prescribing these drugs simultaneously (see section “Special Instructions”).

Overdose

Acute systemic toxicity

Symptoms

Symptoms of acute systemic toxicity may occur in the central nervous system and cardiovascular system. They are caused by high concentrations of local anesthetic in the blood as a result of accidental intravascular administration of the drug, overdose, or unusually rapid absorption from an area of ​​high vascularity (see section “Special Instructions”).

Symptoms of CNS toxicity are similar for all amide-type local anesthetics, while cardiovascular manifestations vary more widely between drugs.

Accidental intravascular administration of a local anesthetic may immediately (several seconds to several minutes) cause a systemic toxic reaction. In case of overdose, symptoms of systemic toxicity develop later (15-60 minutes after injection) due to a slower increase in the concentration of local anesthetic in the blood.

Manifestations of CNS toxicity develop gradually in the form of signs and symptoms of CNS dysfunction, the severity of which increases. Initial manifestations of toxicity usually include dizziness, perioral paresthesia, numbness of the tongue, hyperacusis, tinnitus and visual disturbances. Dysarthria, muscle twitching, or tremors are more serious symptoms and precede the development of generalized seizures.

These phenomena should not be mistakenly regarded as neurotic behavior. They may be followed by loss of consciousness and the development of large convulsive seizures lasting from several seconds to several minutes. Due to increased muscle activity and disruption of the normal breathing process, hypoxia and hypercapnia appear soon after the onset of convulsions.

In severe cases, apnea may develop. Acidosis enhances the toxic effect of local anesthetics. These phenomena are resolved due to the metabolism of the local anesthetic and its redistribution from the central nervous system. Relief of toxic effects can occur quickly if the anesthetic was not administered in very large quantities. The appearance of symptoms of toxicity from the cardiovascular system, as a rule, indicates the severity of the clinical situation.

They are usually preceded by symptoms of central nervous system toxicity, which may be difficult to recognize during general anesthesia or deep sedation with drugs such as benzodiazepines and barbiturates. Against the background of high systemic concentrations of local anesthetics, arterial hypotension, bradycardia, arrhythmia and, in some cases, cardiac arrest were noted.

Toxic reactions from the cardiovascular system are often associated with impaired intracardiac conduction and myocardial function, which leads to a decrease in cardiac output, arterial hypotension, atrioventricular block, bradycardia and, in some cases, ventricular arrhythmias, including ventricular tachycardia, ventricular fibrillation and cardiac arrest.

These symptoms are usually preceded by severe CNS toxicity such as seizures, but in rare cases cardiac arrest has occurred without preceding CNS symptoms. With very rapid intravenous bolus administration, high concentrations of bupivacaine can be achieved in the coronary arteries, and cardiovascular toxic effects may occur without or precede CNS symptoms.

In such cases, myocardial depression may be the first symptom of toxicity. Particular attention should be paid to identifying early signs of systemic toxicity in children, since extensive blocks are often performed under general anesthesia.

Treatment

In the case of a complete spinal block, adequate ventilation should be ensured (maintenance of the airway, oxygen supply, and, if necessary, intubation and artificial ventilation of the lungs). For arterial hypotension/bradycardia, vasopressors are administered, preferably with a positive inotropic effect.

If symptoms of acute systemic toxicity occur, local anesthetic administration should be discontinued immediately. Treatment should be aimed at maintaining adequate ventilation (with oxygen) and hemodynamics. In all cases of systemic toxicity, oxygen therapy is necessary. If necessary, intubation and mechanical ventilation (possibly with hyperventilation) should be used.
For convulsions, administration of diazepam is indicated, for bradycardia – atropine.

With the development of vascular shock (arterial hypotension, bradycardia), therapy includes intravenous administration of infusion solutions, vasopressors, inotropic drugs and/or fat emulsions. Intravenous infusion solutions, dobutamine, and, if necessary, norepinephrine should be administered (initially at a dose of 0.05 mcg/kg/min, and, if necessary, increase the dose by 0.05 mcg/kg/min every 10 minutes), guided by monitoring of hemodynamic parameters in more severe cases.

Ephedrine can also be used. If blood circulation stops, long-term (several hours) resuscitation measures may be required. In all cases, acidosis must be corrected. When treating acute toxicity in children, their age and body weight should be taken into account when choosing drug doses.

Storage conditions

In a place protected from light at a temperature not exceeding 25 °C.
Keep out of the reach of children.

Shelf life

2 years.
Do not use after the expiration date stated on the package.

Manufacturer

Ozon, Russia