Bupivacaine solution for injection 5 mg/ml ampoule 5 ml No. 10

Instructions Bupivacaine solution for injection 5 mg/ml ampoule 5 ml No. 10

Composition

active ingredient: bupivacaine;

1 ml of solution contains bupivacaine hydrochloride, calculated as 100% substance, 5 mg;

Excipients: sodium chloride, diluted hydrochloric acid or sodium hydroxide, water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: clear colorless liquid.

Pharmacotherapeutic group

Local anesthetics. Amides.

ATX code N01B B01.

Pharmacological properties

Pharmacodynamics

Bupivacaine-ZN contains bupivacaine, a long-acting amide-type local anesthetic. Bupivacaine reversibly blocks the conduction of impulses along nerve fibers by inhibiting the transport of sodium ions across nerve membranes. Similar effects can also be observed on excitatory membranes of the brain and myocardium.

The most significant property of bupivacaine is its long duration of action. The difference between the duration of action of bupivacaine in combination with and without adrenaline is relatively small. Bupivacaine is particularly suitable for long-term epidural block. Lower concentrations have less effect on motor nerve fibers and a shorter duration of action, and may also be suitable for long-term analgesia, for example during labor or in the postoperative period.

Pharmacokinetics

The rate of absorption depends on the dose, route of administration and perfusion at the injection site. Intercostal blocks result in the highest plasma concentrations (4 mg/l after a 400 mg dose) due to rapid absorption, while subcutaneous injections into the abdomen result in the lowest plasma concentrations. In children, rapid absorption and high plasma concentrations are observed with caudal blocks (approximately 1.0-1.5 mg/l after a 3 mg/kg dose).

Bupivacaine exhibits complete and biphasic absorption from the epidural space, with elimination half-lives of approximately 7 min and a subsequent elimination half-life of 6 h. Slow absorption is the rate-limiting factor in the elimination of bupivacaine and explains why the elimination half-life is longer after epidural administration than after intravenous administration.

The volume of distribution of bupivacaine at steady state is approximately 73 L, the hepatic extraction coefficient is approximately 0.40, the total plasma clearance is 0.58 L/min, and the half-life is 2.7 hours.

The half-life in newborns is up to 8 hours longer than in adults. In children from 3 months of age the half-life is the same as in adults.

Plasma protein binding is approximately 96%, with binding predominantly to α1-glycoprotein. After major surgery, the level of this protein may increase and give a higher total plasma concentration of bupivacaine. However, the concentration of unbound bupivacaine remains unchanged. This explains why plasma concentrations that exceed toxic levels may be well tolerated.

Bupivacaine is almost completely metabolized in the liver, primarily by aromatic hydroxylation to 4-hydroxybupivacaine and N-dealkylation to PPX, both of which are mediated by cytochrome P450 3A4. Thus, clearance is dependent on hepatic perfusion and metabolizing enzyme activity.

Bupivacaine crosses the placental barrier. The concentration of free bupivacaine is the same in the mother and fetus. However, the total plasma concentration is lower in the fetus, which has a lower degree of binding to plasma proteins.

Indication

Infiltration anesthesia in cases where it is necessary to achieve a significant duration of effect, for example, to eliminate postoperative pain.

Long-term conduction anesthesia or epidural anesthesia in cases where the addition of adrenaline is contraindicated and the use of potent muscle relaxants is undesirable. Anesthesia in obstetrics.

Contraindication

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

Bupivacaine should not be used for intravenous regional anesthesia (Bier's block).

Bupivacaine should not be used for epidural anesthesia in patients with severe hypotension, for example in the case of cardiogenic or hypovolemic shock.

Epidural anesthesia, regardless of the local anesthetic used, has its contraindications, which include: diseases of the nervous system in the active stage, such as meningitis, poliomyelitis, intracranial hemorrhage, subacute combined degeneration of the spinal cord due to pernicious anemia and tumors of the brain and spinal cord; tuberculosis of the spine; purulent skin infection at or near the site of the lumbar puncture; blood clotting disorders or current treatment with anticoagulants.

Interaction with other medicinal products and other types of interactions

Specific interaction studies between local anesthetics and class III antiarrhythmics (e.g. amiodarone) have not been performed, but caution is advised in this case.

Application features

Before starting treatment, it is necessary to conduct a test for individual sensitivity.

Procedures using regional or local anesthetics, except for the simplest ones, should always be performed with equipment available for resuscitation. Intravenous catheters should be placed before the local anesthetic is administered in the case of large blocks.

Cardiac arrest and death have been reported with bupivacaine for epidural anesthesia or peripheral nerve block. Sometimes resuscitation was difficult or impossible despite adequate therapy.

Patients taking class III antiarrhythmics (e.g. amiodarone) should be closely monitored by staff; ECG monitoring of cardiac function is required due to possible cardiac complications.

Extensive peripheral nerve blocks may require the use of large volumes of local anesthetic in highly vascularized areas, often in the vicinity of large vessels. In such cases, there is an increased risk of intravascular injection and/or systemic absorption, which may result in high plasma concentrations.

As with all local anesthetics, bupivacaine in high doses may cause acute toxic effects on the central nervous and cardiovascular systems. This is particularly true in the event of accidental intravascular administration or injection into highly vascularized areas.

Some regional anesthesia techniques may be associated with severe adverse reactions:

• Epidural anesthesia may cause depression of cardiovascular function, especially in cases of concomitant hypovolemia. Caution should be exercised when using the drug in patients with impaired cardiovascular function;
• In rare cases, retrobulbar injections may reach the cranial subarachnoid space and cause, for example, temporary blindness, cardiovascular failure, apnea, and seizures. These symptoms should be treated immediately;
• Retro- and peribulbar injections of local anesthetics carry a certain risk of developing persistent ocular muscle dysfunction;
• In the post-marketing period, cases of chondrolysis have been reported in patients receiving long-term intra-articular infusions of local anesthetics following surgical procedures. Most cases of chondrolysis have involved the shoulder joint. Given the multiple etiological factors and the conflicting information in the scientific literature regarding the mechanism of action, a causal relationship has not been established. Long-term intra-articular infusions are not an approved indication for use.

The main causes are traumatic nerve damage and/or local toxic effects on muscles and nerves due to the administration of local anesthetic. The extent of such complications depends on the extent of the injury, the concentration of local anesthetic and its exposure. For this reason, the lowest effective dose should be chosen.

Accidental intravascular injection in the neck and head area may cause cerebral symptoms even at low doses.

Caution should be exercised in patients with second- and third-degree AV block, as local anesthetics may reduce myocardial conduction. Elderly patients, patients with severe liver disease and severe renal impairment, and patients with poor general condition also require special attention.

Epidural anesthesia may cause hypotension and bradycardia. This risk can be reduced by intravenous crystalloid or colloid solution. Hypotension should be corrected immediately, for example by intravenous administration of ephedrine 5-10 mg, repeated as necessary. In children, ephedrine is administered in a dose appropriate for age and body weight.

Epidural anesthesia may cause intercostal muscle paralysis and respiratory distress in patients with pleural effusion. Patients with septicemia are at increased risk of developing intraspinal abscesses, especially in the postoperative period.

Use during pregnancy or breastfeeding

There is no evidence of adverse effects on human pregnancy, but bupivacaine should not be used in early pregnancy unless the benefits are considered to outweigh the risks.

Bupivacaine passes into breast milk, but in such small amounts that there is no risk of exposure to the child when using the drug in therapeutic doses.

Ability to influence reaction speed when driving vehicles or other mechanisms

Depending on the dose and method of administration, bupivacaine may have temporary effects on movement and coordination.

Method of administration and doses

It is important to take special care to avoid accidental intravascular injections. It is recommended to perform an aspiration test before and during the administration of the total dose. For high doses, a test dose of 3–5 ml of bupivacaine with adrenaline should be administered epidurally, since accidental intravascular injection may cause, for example, a transient increase in heart rate, and accidental intrathecal injection may cause spinal block. Verbal contact with the patient should be maintained for 5 minutes after the test dose and the heart rate should be checked periodically. In addition, aspiration should be performed before the total dose, which should be administered slowly, at a rate of 25–50 mg/min, in stages, while maintaining constant verbal contact with the patient. If symptoms of intoxication occur, the drug should be discontinued immediately.

The recommended doses are given below. The dosage should be adjusted depending on the degree of blockade and the general condition of the patient.

For infiltration anesthesia, bupivacaine hydrochloride 25–150 mg should be administered.

For intercostal block, 10–15 mg should be administered per nerve for a total of 10 nerves.

For large nerve blocks (e.g. epidural, sacral and brachial plexus anesthesia), 75–150 mg should be administered.

For obstetric anesthesia (e.g. epidural anesthesia and caudal anesthesia for vaginal delivery or vacuum extraction), 30–50 mg of bupivacaine hydrochloride should be administered. The doses given are initial doses and may be repeated every two to three hours if necessary.

For epidural block (when performing a cesarean section), 75–150 mg of bupivacaine should be administered.

When used in combination with opioid drugs, the dose of bupivacaine should be reduced.

During the infusion, blood pressure and heart rate should be monitored regularly and the patient should be observed for possible symptoms of intoxication. If signs of toxicity occur, the infusion should be stopped immediately.

Maximum recommended doses

The maximum recommended dose to be used during the same occasion is calculated at a rate of 2 mg/kg body weight; for adults the maximum dose is 150 mg over 4 hours.

The maximum recommended daily dose is 400 mg. The total dose should be adjusted depending on the patient's age, body weight and other relevant circumstances.

Children.

It is not used in children for the indicated indications.

Overdose

Symptoms: systemic toxic reactions mainly occur in the central nervous system and in the cardiovascular system. Such reactions can be caused by high blood concentrations of local anesthetic in the event of accidental intravascular administration, overdose or particularly rapid absorption with strong blood circulation.

CNS symptoms are similar for all amide local anesthetics, while cardiovascular symptoms depend more on the properties of the drug administered.

Accidental intravascular injections of local anesthetics can cause immediate (seconds to minutes) systemic toxic reactions. In case of overdose, systemic toxicity occurs later (15–60 min after injection) due to the slower increase in blood concentrations of the local anesthetic.

Cardiovascular effects are usually more serious. These effects are usually preceded by signs of CNS toxicity, which, however, may be masked by general anesthesia or deep sedation, such as with benzodiazepines or barbiturates. High systemic concentrations of local anesthetics may result in hypotension, bradycardia, arrhythmias, and even cardiac arrest. Cardiovascular toxic effects are often associated with depression of the cardiac and myocardial conduction systems, resulting in decreased cardiac output, hypotension, AV block, bradycardia, and occasionally ventricular arrhythmias, including ventricular tachycardia, ventricular fibrillation, and cardiac arrest. These conditions are often preceded by signs of severe CNS toxicity, such as convulsions, but in rare cases cardiac arrest has occurred without preceding CNS effects. After very rapid intravenous injection, such high blood concentrations of bupivacaine can be achieved in the coronary vessels that the effects on the circulatory system occur independently or before the onset of CNS effects. Given this mechanism, myocardial depression may develop even as the first symptom of intoxication.

Treatment.

In case of total spinal block, adequate ventilation of the lungs should be ensured (patency of the patient's airway, oxygenation, intubation and artificial lung ventilation (MVL), if necessary). In case of arterial hypotension/bradycardia, a vasopressor with an inotropic effect should be administered.

If signs of acute systemic toxicity occur, local anesthetics should be discontinued immediately. Treatment should be directed at maintaining adequate ventilation, oxygenation, and circulation. If necessary, artificial ventilation should be provided. If convulsions do not spontaneously resolve within 15 to 20 seconds, administer 1 to 3 mg/kg sodium thiopental intravenously to facilitate ventilation, or administer 0.1 mg/kg diazepam intravenously (this agent acts much more slowly). Prolonged convulsions compromise the patient's breathing and oxygenation. Injection of muscle relaxants (e.g., suxamethonium 1 mg/kg) provides favorable conditions for ventilation and oxygenation, but requires experience in tracheal intubation and mechanical ventilation. In case of bradycardia, administer atropine.

In case of circulatory depression, intravenous infusions are performed, dobutamine and, if necessary, norepinephrine are administered (initially 5 μg/kg/min, increasing by 0.05 mg/kg/min every 10 min if necessary) with hemodynamic monitoring in more complex cases. A trial of ephedrine is also possible.

In case of circulatory arrest, pneumocardiac resuscitation measures should be initiated immediately.

It is important to maintain adequate oxygenation, respiration, and circulation while correcting acidosis.

In case of cardiac arrest, prolonged resuscitation measures may be necessary.

Adverse reactions

Adverse effects caused by the drug itself may be difficult to distinguish from the physiological effects of nerve blockade (e.g., decreased blood pressure, bradycardia), and from phenomena caused directly by the needle puncture (e.g., nerve damage).

Neurological damage is a rare but well-known consequence of regional, especially epidural and spinal anesthesia.

Expiration date

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Incompatibility

Alkalization may cause precipitation, as bupivacaine is poorly soluble at pH above 6.5.

Packaging

5 ml in an ampoule; 10 ampoules in a cardboard box;

5 ml in an ampoule; 5 ampoules in a blister; 2 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "People's Health".

Location of the manufacturer and address of its place of business

Ukraine, 61002, Kharkiv region, Kharkiv city, Kulykivska street, building 41.