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.
• Infiltration anesthesia when a long lasting anesthetic effect is required, such as in postoperative pain.
• Long-term anesthesia or epidural anesthesia in cases where the addition of epinephrine is contraindicated and significant muscle relaxation is not required.
• Anesthesia in obstetrics.

Active ingredient

Bupivacaine

Composition

1 ml of the solution contains:

How to take, the dosage

Bupivacaine should only be used by or under the supervision of physicians experienced in local anesthesia. The minimum dose to achieve adequate anaesthesia should be used.
Care should be taken to avoid accidental intravascular administration of bupivacaine.

A suction test is recommended before and during the administration of the drug. The drug should be administered slowly, at a rate of 25-50 mg bupivacaine per minute, or in fractional doses, while maintaining continuous verbal contact with the patient and monitoring the heart rate. A test dose of 3-5 mL of Bupivacaine is recommended for epidural administration. Thus, in case of accidental intravascular injection, there is a short-term increase in heart rate, and in case of accidental intrathecal injection, symptoms of spinal block may develop. If symptoms of toxicity occur, the drug should be stopped immediately.

The following doses are for guidance; the choice of dose is based on the depth of anesthesia and general condition of the patient.

Infiltration anesthesia. 5-30 ml of preparation (25-150 mg bupivacaine).

Intercostal blockade: 2-3 ml of preparation (10-15 mg bupivacaine) for one nerve, not more than 10 nerves in total.

Extensive blocks (for example, epidural block, sacral block, brachial plexus block): 15-30 ml of drug (75-150 mg bupivacaine).

Epidural anesthesia for cesarean section: 15-30 ml of drug (75-150 mg bupivacaine).

Maximum recommended doses

Maximum recommended dose of bupivacaine, determined on the basis of 2 mg/kg body weight, for adults is 150 mg for 4 hours (equivalent to 30 ml of Bupivacaine 5 mg/ml). The maximum recommended daily dose is 400 mg. The total dose of the drug should be adjusted according to the age and condition of the patient and other relevant circumstances.

Efficacy and safety of Bupivacaine 5 mg/ml in children under 12 years of age has not been established, the available data are limited.

Efficacy and safety of Bupivacaine for epidural bolus or continuous infusion has not been established, the available data are limited.

Interaction

Bupivacaine should be used with caution in patients receiving other local anesthetics or class lb antiarrhythmic drugs because of the possibility of additive toxic effects.

The combined use of bupivacaine with local anesthetics and class III antiarrhythmic drugs (such as amiodarone) has not been studied in drug interaction studies, but caution is recommended when these drugs are prescribed simultaneously (see section “Specific Notes”).

Special Instructions

When performing regional and local anesthesia, with the exception of the simplest blockages, resuscitation equipment must be available for immediate use. When extensive blockades are performed, an intravenous catheter should be inserted before the local anesthetic is administered.
Cases of cardiac arrest or death have been noted during the use of bupivacaine for epidural anesthesia or peripheral blockade. In some cases resuscitation was difficult or impossible despite proper resuscitation.
Peripheral nerve block is associated with the administration of a large volume of local anesthetic in an area of high vascularity, often close to major vessels. In such cases, there is an increased risk of accidental intravascular injection of the local anesthetic and/or systemic absorption of the drug, which in turn may lead to increased plasma concentrations. Like all other local anesthetics, bupivacaine may have toxic effects on the CNS and cardiovascular system at high blood concentrations. This applies especially to accidental intravascular administration or administration in an area of high vascularization.
Certain types of blockades may be associated with serious adverse reactions, such as:

• Epidural anesthesia may be accompanied by cardiovascular depression, especially with hypovolemia. Therefore, caution should be exercised in patients with cardiovascular dysfunction.
• In rare cases of retrobulbar injection, penetration into the cranial subarachnoid space is possible with temporary blindness, cardiovascular collapse, apnea, and seizures. These symptoms require immediate treatment.
• In retrobulbar and peribulbar injections of local anesthetics, there is a small risk of persistent ocular muscle dysfunction.
  The main causes are trauma and/or local toxic effects of the injected drug on muscles and/or nerves.
• Inadvertent intravascular injection of local anesthetics in the head and neck region, even at low doses, can cause CNS side toxicity symptoms.
• Paracervical blockade sometimes results in fetal bradycardia/tachycardia, so the fetal heart rate should be monitored carefully.

The severity of such tissue reactions depends on the degree of injury, the concentration of the local anesthetic, and the duration of tissue exposure 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 decrease myocardial conduction. Caution should be exercised in patients with severe hepatic or renal dysfunction, elderly or frail patients.

Patients receiving class III antiarrhythmic drugs (e.g., amiodarone) should be closely monitored with ECG monitoring given the risk of cardiovascular complications due to possible additive effects. Arterial hypotension and bradycardia may occur with epidural anesthesia.

The possibility of these complications can be reduced by prior administration of crystalloid or colloidal solutions. In cases of arterial hypotension, therapy should be given immediately, such as intravenous ephedrine at a dose of 5-10 mg; if necessary, the administration can be repeated. Cases of chondrolysis during postoperative prolonged intra-articular infusion of local anesthetics have been noted.

In most of the cases described, the infusion was performed in the shoulder joint. A causal relationship with the use of anesthetics has not been established because of several predisposing factors. Bupivacaine is not approved for prolonged intra-articular infusion.

Effects on driving and operating ability

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

Contraindications

• Hypersensitivity to any of the components of the drug or to other local anesthetics of the amide type.
• Conditions in which epidural anesthesia is contraindicated:
  – current diseases of the central nervous system (CNS) such as meningitis, polio, intracranial hemorrhage, and CNS neoplasms;
  – spinal tuberculosis;
  – pernicious anemia with subacute combined spinal cord degeneration;
  – pustular skin lesions in or adjacent to the proposed puncture site;
  – cardiogenic or hypovolemic shock;
  – clotting 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 (Bier blockade).

With caution:

• older age;
• weakened patients;
• antrioventricular block of degree II and III;
• severe hepatic and renal function impairment;
• women in late pregnancy;
• combined use with class III antiarrhythmic drugs (e.g., amiodarone);
• combined use with other local anesthetics or drugs with structural similarity to amide-type local anesthetics, such as class lb antiarrhythmic drugs (e.g., lidocaine, mexiletine);
• paracervical blockade.

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Side effects

Adverse reactions caused by Bupivacaine 5 mg/ml are difficult to distinguish from the physiological manifestations of nerve block (e.g. arterial hypotension, bradycardia), reactions caused directly (e.g. nerve damage) or indirectly (e.g. 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.

Children

In children the adverse reactions are the same as in adult patients, but the identification of early manifestations of toxicity of local anesthetics in children may be difficult if the blockade is performed against a background of sedation or general anesthesia.

Overdose

Acute systemic toxicity

Symptoms

Symptoms of acute systemic toxicity may be noted in the central nervous system and cardiovascular system. They are due to the high concentration of the 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 vascularization (see section “Special Indications”).

The symptoms of CNS toxicity are similar for all amide type local anesthetic agents, while manifestations of the cardiovascular system vary to a greater extent with the use of different drugs.

Accidental intravascular administration of a local anesthetic may immediately (from a few 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. The initial manifestations of toxicity are usually dizziness, perioral paresthesias, tongue numbness, hyperacusis, tinnitus and ringing in the ears, and visual disturbances. Dysarthria, muscle twitching or tremor are more serious symptoms and precede the development of generalized seizures.

These phenomena should not be mistaken for neurotic behavior. They may be followed by loss of consciousness and the development of large convulsive seizures lasting from several seconds to several minutes. Hypoxia and hypercapnia appear shortly after the onset of convulsions due to increased muscle activity and disruption of the normal respiratory process.

In severe cases apnea may develop. Acidosis increases the toxic effect of local anesthetics. These phenomena are resolved by the metabolism of the local anesthetic and its redistribution from the CNS. Toxic phenomena can be overcome quickly if the anesthetic is not administered in very large quantities. The onset of cardiovascular toxicity symptoms is usually indicative of the severity of the clinical situation.

They are usually preceded by symptoms of CNS toxicity, which may be difficult to recognize in the case of general anesthesia or deep sedation with drugs such as benzodiazepines and barbiturates. Arterial hypotension, bradycardia, arrhythmia and, in some cases, cardiac arrest have been noted against the background of high systemic concentration of local anesthetics.

Toxic reactions from the cardiovascular system are often associated with disturbances of intracardiac conduction and myocardial function, resulting in decreased 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 manifestations of severe CNS toxicity, such as seizures, but in rare cases cardiac arrest has occurred without preceding CNS symptoms. Very rapid intravenous bolus administration may achieve high concentrations of bupivacaine in the coronary arteries, and cardiovascular toxicity may occur without or precede prior 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 in them extensive blockages are often performed against a background of general anesthesia.

Treatment

In case of complete spinal block adequate ventilation should be provided (ensure airway patency, oxygen supply, if necessary – intubation and artificial lung ventilation). In case of arterial hypotension/bradycardia vasopressors are administered, preferably with positive inotropic effect.

If symptoms of acute systemic toxicity occur, the local anesthetic should be stopped immediately. Treatment should be aimed at maintaining adequate ventilation (with oxygen supply) and hemodynamics. Oxygen therapy is necessary in all cases of systemic toxicity. If necessary, intubation and artificial lung ventilation should be resorted to (possibly with hyperventilation).
Diazepam administration is indicated for convulsions, atropine for bradycardia.

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

Ephedrine may also be used. In case of circulatory arrest, prolonged (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 doses of drugs.

Pregnancy use

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

The addition of epinephrine to bupivacaine may decrease uterine blood flow and contractility, especially if the anesthetic solution is accidentally injected into the maternal vessels.

Performing a paracervical block is contraindicated.

Bupivacaine penetrates into breast milk. The drug may cause serious side effects in the baby, so if it is necessary to administer bupivacaine, breastfeeding should be stopped.