Bupivacaine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BUPIVACAINE (BUPIVACAINE)

Composition:

Active substance: bupivacaine hydrochloride;

1 ml of solution contains bupivacaine hydrochloride monohydrate equivalent to 5 mg of bupivacaine hydrochloride;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Local anesthetics. Amides.

ATC code N01BB01.

Pharmacological Properties

Pharmacodynamics

Bupivacaine is a long-acting amide-type local anaesthetic.

Bupivacaine reversibly blocks impulse conduction in nerve fibres by inhibiting sodium ion transport across nerve fibre cell membranes. Similar effects may also occur in excitable membranes of the brain and myocardium.

The most significant property of bupivacaine is its long duration of action. The difference in duration between bupivacaine administered with and without adrenaline is relatively small. Bupivacaine is particularly suitable for prolonged epidural blockade. Lower concentrations have less effect on motor nerve fibres, have a shorter duration of action, and may be suitable for prolonged analgesia, for example, during labour or in the postoperative period.

Pharmacokinetics

The rate of absorption depends on the dose, route of administration, and perfusion at the site of injection. Intercostal blocks result in the highest plasma concentrations (4 mg/L after a 400 mg dose) due to rapid absorption, whereas subcutaneous injections in the abdominal area result in the lowest plasma concentrations. In children, rapid absorption and high plasma concentrations are observed following caudal blockade (approximately 1.0–1.5 mg/L after a dose of 3 mg/kg).

Bupivacaine is completely absorbed from the epidural space, followed by a two-phase elimination model: the initial elimination half-life is 7 minutes, and the subsequent phase is 6 hours. Slow absorption is the rate-limiting factor for bupivacaine elimination and explains why the elimination half-life is longer after epidural administration than after intravenous administration.

The steady-state volume of distribution of bupivacaine is approximately 73 L, the hepatic extraction ratio is about 0.4, total plasma clearance is 0.58 L/min, and the elimination half-life is 2.7 hours.

The elimination half-life in neonates is longer—up to 8 hours—compared to adults. In children aged 3 months and older, the elimination half-life is similar to that in adults.

Pharmacokinetics in children is similar to that in adults.

Plasma protein binding is approximately 96%, primarily to α1-acid glycoprotein. After major surgical intervention, levels of this protein may increase, leading to higher total plasma concentrations of bupivacaine. However, the concentration of unbound (free) bupivacaine remains unchanged. This explains why plasma concentrations exceeding toxic levels may still be well tolerated.

Bupivacaine is almost completely metabolized in the liver, primarily via aromatic hydroxylation to 4-hydroxybupivacaine and via N-dealkylation to pipecolylxylidine (PPX), both mediated by cytochrome P450 3A4. Therefore, clearance depends on hepatic perfusion and the activity of the metabolizing enzyme.

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

Clinical characteristics.

Indications.

Bupivacaine 0.5% solution is used for the production of local anesthesia by percutaneous infiltration, peripheral nerve block(s), and central neural block (caudal or epidural), i.e., it is applied by a specialist in situations where prolonged anesthesia is required. Since sensory nerve block is more pronounced than motor block, bupivacaine is particularly effective in relieving pain, for example, during childbirth.

Contraindications.

Hypersensitivity to the active substance, to amide-type local anesthetics, or to excipients of the medicinal product.

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

Bupivacaine should not be used for epidural anesthesia in patients with marked arterial hypotension, such as in cardiogenic or hypovolemic shock.

Epidural anesthesia, regardless of the local anesthetic used, has its own 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; spinal tuberculosis; purulent skin infection at or near the site of lumbar puncture; coagulation disorders or ongoing anticoagulant therapy.

Interaction with other medicinal products and other forms of interaction.

Caution should be exercised when using bupivacaine concomitantly with medicinal products structurally related to local anesthetics, such as class IB antiarrhythmics, since their toxic effects are additive.

Specific interaction studies between local anesthetics and class III antiarrhythmics (e.g., amiodarone) have not been conducted; therefore, caution is recommended when used concomitantly (see also section "Special precautions for use").

Special precautions for use

Cardiac arrest and fatal outcomes have been reported following the use of bupivacaine for epidural anesthesia or peripheral nerve blocks. In some cases, resuscitation was difficult or impossible despite adequate therapy.

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

High systemic concentrations of bupivacaine have been associated with ventricular arrhythmias, ventricular fibrillation, sudden cardiovascular collapse, and death.

Appropriate resuscitation equipment must be available whenever local or general anesthesia is administered. Overdose or accidental intravenous injection may lead to toxic reactions characterized by marked anxiety, twitching, or seizures progressing to coma, apnea, and cardiovascular collapse.

Regional or local anesthesia must always be performed in a properly equipped and staffed facility. Appropriate resuscitation equipment must be immediately available whenever local or general anesthesia is administered. Prior to initiating any nerve block, intravenous access must be established in the patient to allow for administration of medications in case resuscitation is required. The responsible physician must take necessary precautions to avoid intravascular injections (see section "Method of administration and dosage") and must be familiar with the diagnosis and management of adverse effects, systemic toxicity, and other complications (see section "Overdose").

Large peripheral nerve blocks may require large volumes of local anesthetic administered in highly vascularized areas, often near major blood vessels. In such cases, the risk of intravascular injection and/or systemic absorption is increased, potentially leading to high plasma concentrations.

Although regional anesthesia is often the optimal method, certain patients require special attention due to the risk of developing serious adverse effects:

• elderly patients and patients with poor general health;
• patients with partial or complete heart block — because local anesthetics may depress myocardial conduction;
• patients with progressive liver disease or severe renal dysfunction;
• pregnant women in late gestation;
• patients receiving Class III antiarrhythmic agents (e.g., amiodarone) — they should be under close monitoring and ECG surveillance, as cardiac effects may be additive.

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

• epidural anesthesia may cause cardiovascular depression, particularly in the presence of concomitant hypovolemia. Caution should be exercised when administering the drug to patients with cardiovascular impairment;
• in rare cases, retrobulbar injections may reach the cranial subarachnoid space and cause, for example, transient blindness, cardiovascular failure, apnea, and seizures. These symptoms require immediate treatment;
• retro- and peribulbar injections of local anesthetics may carry a risk of persistent ocular muscle dysfunction. The main causes include traumatic nerve injury and/or local toxic effects on muscles and nerves due to the injected anesthetic. The extent of such complications depends on the degree of trauma, the concentration of the local anesthetic, and its exposure time. Therefore, the lowest effective dose should be selected. Vasoconstrictors may enhance tissue reactions and should be used only when indicated;
• accidental intravascular injections in the head and neck region may cause cerebral symptoms even with low doses;
• paracervical block may occasionally cause fetal bradycardia or tachycardia; therefore, fetal heart rate should be carefully monitored.

Post-marketing reports have described cases of chondrolysis in patients receiving prolonged intra-articular infusions of local anesthetics after surgical procedures. In most reported cases, chondrolysis affected the shoulder joint. Due to multiple etiological factors and conflicting data in the scientific literature, a causal relationship has not been established. Prolonged intra-articular infusions are not an approved route of administration for Bupivacaine.

Hypotension and bradycardia may occur as normal physiological responses following central neural blockade. Epidural and subarachnoid blocks may lead to hypotension and bradycardia. The risk of such outcomes may be reduced, for example, by administering vasoconstrictor agents. Hypotension should be promptly treated with intravenous sympathomimetics, repeated as necessary.

The smallest effective dose should be used. With each repeated dose of bupivacaine hydrochloride, blood levels may increase significantly due to slow accumulation of the drug. Tolerance depends on the patient's condition. Reduced doses should be administered to debilitated patients, elderly patients, or those in critical condition, according to their physical status. The maximum recommended dose should not be exceeded. Continuous or repeated administration of the drug may lead to cumulative toxicity and tachyphylaxis.

Bupivacaine hydrochloride should be used with caution in patients with epilepsy, impaired cardiac conduction, or hepatic or renal impairment.

Bupivacaine solution should be used with caution in individuals with known hypersensitivity to the drug. Patients with allergic reactions to ester-type local anesthetics (e.g., procaine, tetracaine, benzocaine, etc.) do not typically exhibit cross-sensitivity to amide-type agents such as bupivacaine.

Since bupivacaine is metabolized in the liver, it should be used with caution in patients with hepatic disease or reduced hepatic blood flow (e.g., in severe shock).

Liver function abnormalities with reversible increases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and bilirubin have been reported rarely following repeated injections or prolonged infusions of bupivacaine. Rapid clinical improvement may occur after immediate discontinuation of bupivacaine. If signs of liver dysfunction occur during bupivacaine administration, the drug should be discontinued (see section "Adverse reactions").

When this medicinal product is used for obstetric epidural anesthesia, it is recommended to position the pregnant woman on her side or tilted laterally to avoid caval compression, which may lead to maternal hypotension and fetal acidosis.

Central neural blockade may cause decreased cardiovascular function, especially in the presence of hypovolemia. Epidural and subarachnoid anesthesia should be used with caution in patients with impaired cardiovascular function.

When administering bupivacaine via intra-articular injection, caution is advised in cases of suspected recent extensive intra-articular trauma or the presence of large open joint surfaces created during surgical procedures, as this may accelerate absorption and lead to increased plasma concentrations of the drug.

This medicinal product contains 4.1 mmol/dose of sodium. Caution is advised when administering to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding

Pregnancy. There is no evidence of adverse effects on human pregnancy. Animal studies have shown reduced offspring survival in rats and embryotoxic effects in rabbits following administration of high doses of bupivacaine during pregnancy.

Therefore, bupivacaine should not be used in early pregnancy except when the potential benefit outweighs the risks.

Adverse effects on the fetus due to local anesthetics, such as fetal bradycardia, are most likely to occur following paracervical block. These effects may be due to high concentrations of anesthetic reaching the fetus (see section "Special precautions for use").

Breastfeeding. Bupivacaine passes into breast milk, but in such small amounts that there is no risk of affecting the infant when the drug is used at therapeutic doses.

Effect on ability to drive or operate machinery

In addition to the direct anesthetic effect, local anesthetics may have a minimal effect on mental function and motor coordination, even in the absence of overt central nervous system (CNS) toxicity, and may cause temporary impairment of motor activity and attention.

Method of Administration and Dosage

Bupivacaine must be administered only by physicians experienced in performing regional anesthesia, or under their supervision. The lowest effective dose providing adequate anesthesia should always be used.

Extreme caution must be exercised to avoid accidental intravascular injection. Aspiration should be performed before and during administration of the total dose to detect intravascular placement. The total dose should be administered slowly, at a rate of 25–50 mg/min, or in divided doses, with continuous verbal contact maintained with the patient and monitoring of cardiac rhythm.

For epidural anesthesia, a test dose of 3–5 mL of bupivacaine with adrenaline should be administered first, as accidental intravascular injection may cause transient tachycardia, while accidental intrathecal injection may result in spinal block. If signs of intoxication occur, administration of the drug must be immediately discontinued.

The recommended dosages are listed below. Dosage should be adjusted according to the extent of block and the patient's general condition.

For infiltration anesthesia, administer 5–30 mL of Bupivacaine 5 mg/mL (25–150 mg bupivacaine hydrochloride).

For intercostal block, administer 2–3 mL of Bupivacaine 5 mg/mL (10–15 mg bupivacaine hydrochloride) per nerve, up to a total of 10 nerves.

For major nerve blocks (e.g., epidural, sacral anesthesia, brachial plexus anesthesia), administer 15–30 mL of Bupivacaine 5 mg/mL (75–150 mg bupivacaine hydrochloride).

For obstetrical anesthesia (e.g., epidural or caudal anesthesia during vaginal delivery or vacuum extraction), administer 6–10 mL of Bupivacaine 2.5 mg/mL (15–25 mg bupivacaine hydrochloride). These doses are initial; repeat administration may be performed every 2–3 hours if needed.

For epidural block (during cesarean section), administer 15–30 mL of Bupivacaine 5 mg/mL (75–150 mg bupivacaine hydrochloride).

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

During infusion, arterial pressure and heart rate should be monitored regularly, and the patient should be observed for possible signs of intoxication. If toxic effects occur, the infusion must be immediately stopped.

Maximum Recommended Doses

The maximum recommended single dose for one procedure is 2 mg/kg body weight. For adults, the maximum dose is 150 mg within 4 hours, equivalent to 30 mL of Bupivacaine 5 mg/mL (150 mg bupivacaine hydrochloride).

The maximum recommended daily dose is 400 mg. The total dose should be adjusted according to the patient’s age, general health, and other relevant factors.

Children

Bupivacaine is not recommended for use in children.

Overdose

Systemic toxic reactions involve the central nervous and cardiovascular systems. These reactions may result from high plasma concentrations of local anesthetic due to accidental intravascular injection, overdose, or unusually rapid absorption from highly vascularized tissues (see also section "Special Warnings and Precautions for Use"). Central nervous system (CNS) symptoms are similar for all amide-type local anesthetics, while cardiac symptoms vary among agents both quantitatively and qualitatively.

CNS toxicity usually precedes cardiovascular toxicity, except in patients under general anesthesia or receiving strong sedatives such as benzodiazepines or barbiturates, in which case CNS signs may be masked.

CNS Toxicity develops progressively with increasing severity of symptoms. Initial symptoms typically include mild dizziness, perioral numbness, tongue numbness, hyperacusis, tinnitus, and visual disturbances. Slurred speech, muscle twitching, or tremor are more serious symptoms that precede generalized seizures. These signs should not be interpreted as neurotic behavior. This may be followed by loss of consciousness and generalized tonic-clonic seizures lasting from several seconds to several minutes. During seizures, hypoxia and hypercapnia (elevated blood CO₂ levels) develop rapidly due to increased muscular activity and inadequate pulmonary gas exchange. In severe cases, apnea may also occur. Development of acidosis, hyperkalemia, and hypoxia exacerbates and prolongs the toxic effects of local anesthetics.

Recovery depends on the metabolism and redistribution of the local anesthetic away from the CNS. This occurs rapidly unless very large doses have been administered.

Cardiovascular Toxicity may occur in severe cases and is usually preceded by signs of CNS toxicity. In patients under deep sedation or general anesthesia, prodromal CNS symptoms may be absent. Hypotension, bradycardia, arrhythmias, and even cardiac arrest may result from high systemic concentrations of local anesthetics. However, rare cases of cardiac arrest without preceding CNS symptoms have been reported.

Treatment of Acute Toxicity

If signs of acute systemic toxicity occur, administration of the local anesthetic must be immediately discontinued.

Management of a patient exhibiting signs of systemic toxicity focuses on rapid control of seizures and ensuring adequate ventilation, with oxygen supplementation as needed to support or control pulmonary ventilation.

In the event of seizures, immediate treatment with intravenous thiopental (100–200 mg) or diazepam (5–10 mg) should be initiated. Prolonged seizures may compromise ventilation and oxygenation. If such a condition occurs, administration of a muscle relaxant (e.g., succinylcholine 1 mg/kg body weight) facilitates ventilation and allows control of oxygenation. In such cases, early endotracheal intubation should be considered.

After seizure control and adequate ventilation are achieved, further treatment is usually not required. However, in cases of hypotension, intravenous vasopressors with inotropic activity, such as ephedrine (15–30 mg intravenously), should be administered.

In cases of circulatory insufficiency (hypotension, bradycardia), appropriate treatment should include intravenous fluids, vasopressors, inotropic agents, and/or lipid emulsions.

In the event of cardiac arrest, immediate cardiopulmonary resuscitation (CPR) must be initiated. It is essential to maintain adequate oxygenation, ventilation, and circulation, while simultaneously correcting acidosis.

Prolonged resuscitation efforts may be necessary in cases of cardiac arrest.

Adverse reactions.

General description

Bupivacaine causes systemic toxicity similar to that observed with other local anesthetics. This is caused by high plasma concentrations resulting from administration of an excessive dose, rapid absorption, or, most commonly, accidental intravascular injection. Such reactions affect the central nervous system (CNS) and the cardiovascular system. CNS reactions are characterized by tongue numbness, dizziness, blurred vision, and muscle twitching, followed by drowsiness, seizures, unconsciousness, and possibly respiratory arrest. Cardiovascular reactions lead to depression of function and are characterized by hypotension and myocardial depression. These may result from hypoxia due to seizures and apnea, as well as from the direct adverse effect of the drug.

Adverse reactions caused by the drug may be difficult to distinguish from the physiological effects of nerve block (e.g., decreased blood pressure, bradycardia), phenomena caused by needle puncture—either directly (e.g., nerve injury) or indirectly (e.g., epidural abscess).

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

The frequency of adverse neurological reactions associated with the use of local anesthetics, including prolonged anesthesia, paresthesia, weakness, paralysis of the lower extremities, and loss of sphincter control, is very low. In rare cases, the use of local anesthetics has been associated with allergic reactions (in the most severe cases— anaphylactic shock).

For information on symptoms and treatment of acute systemic toxicity, see section "Overdose".

List of adverse reactions

* Hepatic injury with reversible increases in AST, ALT, ALP, and bilirubin levels has been observed following repeated injections and prolonged infusions of bupivacaine. If signs of liver dysfunction occur during treatment, this medicinal product should be discontinued (see section "Special precautions for use").

Children

Adverse reactions in children are similar to those in adults; however, early signs of local anesthetic toxicity may be difficult to detect in children when blocks are performed under sedation or general anesthesia.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is of great importance. It allows ongoing monitoring of the benefit-risk balance of the use of this medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

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

Keep out of reach and sight of children.

Incompatibilities.

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

Packaging.

10 ml in a vial. 5 vials in a blister pack, 1 blister pack in a carton.

Prescription status. Prescription only.

Manufacturer.

PJSC "Halychpharm".

Manufacturer's address and location of activity

6/8 Opryshkivska Street, Lviv, 79024, Ukraine.