Bucaine

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

Composition:

Active substance: bupivacaine hydrochloride;

1 ml of solution contains bupivacaine hydrochloride 2.5 mg or 5.0 mg;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Local anesthetics. Amides. ATC code N01BB01.

Pharmacological Properties.

Pharmacodynamics.

Bucaïn contains bupivacaine, a long-acting amide-type local anesthetic.

Bupivacaine reversibly blocks impulse conduction along nerve fibers by inhibiting sodium ion transport across nerve fiber cell membranes. A similar effect may also occur at 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 fibers, shorter duration of action, and may be appropriate for prolonged analgesia, such as 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 concentration (4 mg/L after a 400 mg dose) due to rapid absorption, whereas subcutaneous injections in the abdominal area lead to the lowest plasma concentration. In children, rapid absorption and high plasma concentration 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 compared to intravenous administration.

The volume of distribution at steady state is approximately 73 L, hepatic extraction ratio is about 0.4, total plasma clearance is 0.58 L/min, and elimination half-life is 2.7 hours. The elimination half-life in neonates is up to 8 hours, which is longer than in 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 significant 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 the toxic threshold 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 pipecolyl xylidine (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. Free bupivacaine concentration is equal in pregnant women and fetus. However, total plasma concentration is lower in the fetus, which has a lower degree of protein binding.

Clinical characteristics.

Indications.

• Surgical anesthesia in adults and children over 12 years of age.
• Treatment of acute pain in adults and children from 1 year of age.

Infiltration anesthesia when a prolonged effect is required, e.g., in postoperative pain.

Long-acting nerve block or epidural anesthesia when addition of adrenaline is contraindicated and significant muscle relaxation is undesirable. Anesthesia in obstetrics.

Contraindications.

Hypersensitivity to the active substance, amide-type local anesthetics, or to any of the 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, including active-stage neurological diseases 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 administering bupivacaine together 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.

Procedures involving regional or local anesthetics, except for the simplest ones, should always be performed in the presence of equipment necessary for resuscitation. Intravenous catheters should be placed prior to the administration of local anesthetic when performing major nerve blocks.

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

Major peripheral nerve blocks may require large volumes of local anesthetic in highly vascularized areas, often near large blood vessels. In such cases, there is an increased risk of intravascular injection and/or systemic absorption, which may lead to high plasma concentrations of the drug.

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.

Some regional anesthetic techniques may be associated with serious adverse reactions, namely:

• Epidural anesthesia may cause cardiovascular depression, especially in the presence of concomitant hypovolemia. Caution should be exercised when administering the drug to patients with cardiovascular disorders.
• In isolated cases, retrobulbar injections may reach the cranial subarachnoid space and cause, for example, transient blindness, cardiovascular collapse, apnea, and seizures. These symptoms should be treated immediately.
• Retro- and peribulbar injections of local anesthetics may carry a certain 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 injection of local anesthetic. The extent of such complications depends on the degree of trauma, the concentration of the local anesthetic, and the duration of exposure. Therefore, the lowest effective dose should be selected. Accidental intravascular injection in the head and neck area may cause cerebral symptoms even at low doses.
• Paracervical block may occasionally cause bradycardia or tachycardia in the fetus; therefore, fetal heart rate must be carefully monitored.

Caution is advised in patients with second- or third-degree AV block, as local anesthetics may reduce myocardial conduction. Elderly patients, patients with severe liver disease or severe renal impairment, patients in late pregnancy, or patients in poor general condition also require special attention.

Patients receiving class III antiarrhythmic drugs (e.g., amiodarone) should be closely monitored. In addition, ECG monitoring should be considered in such patients, as the cardiovascular effects of bupivacaine and class III antiarrhythmic drugs may be additive.

Hepatic dysfunction with reversible elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and bilirubin has been reported rarely following repeated injections or prolonged infusions of bupivacaine. Rapid clinical improvement is possible after immediate discontinuation of bupivacaine. If signs of hepatic dysfunction occur during bupivacaine administration, the drug should be discontinued (see section "Adverse reactions").

Epidural anesthesia may lead to decreased arterial pressure and bradycardia. This risk may be reduced, for example, by injection of vasoconstrictor agents. Hypotension should be corrected immediately by intravenous administration of sympathomimetics, repeated as necessary.

Post-marketing reports have described cases of chondrolysis in patients who received 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 information in the scientific literature regarding the mechanism of action, a causal relationship has not been established. Prolonged intra-articular infusions are not an approved indication for the use of the medicinal product Bucaine.

Pediatric population

The safety and efficacy of the medicinal product Bucaine in children under 1 year of age have not been established. Only limited data are available. The use of bupivacaine for intra-articular blocks in children aged 1 to 12 years has not been established.

The use of bupivacaine for major nerve blocks in children aged 1 to 12 years has not been established.

When administering epidural anesthesia to children, the drug should be used in gradually increasing doses according to age and body weight, as epidural anesthesia, particularly at the thoracic level, may cause severe arterial hypotension and respiratory disturbances.

The medicinal product Bucaine contains 0.136 mmol/mL (or 3.147 mg/mL) of sodium; therefore, caution should be exercised when administering it to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy

There is no evidence of adverse effects of the medicinal product Bucaine on pregnancy in humans; however, it should not be used in early pregnancy except when the expected benefit outweighs the possible risk.

When performing paracervical block, there is an increased risk of adverse reactions in the fetus (such as bradycardia and tachycardia) due to the use of local anesthetics. Such effects may be due to high concentrations of anesthetic reaching the fetus (see section "Special precautions for use"). Careful monitoring of fetal heart rate is recommended.

Breastfeeding period

Bupivacaine passes into breast milk, but the risk of effects on the infant when the drug is used at therapeutic doses is unlikely.

Ability to affect reaction speed when driving or operating machinery.

Depending on the dose and route of administration, bupivacaine may have a temporary effect on motor function and coordination.

Method of Administration and Dosage

Bukain must be administered only by physicians experienced in regional anesthesia, or under their supervision. The lowest effective doses required to achieve adequate anesthesia should be used.

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

For epidural administration, a test dose of 3–5 mL of Bukain with adrenaline should be administered first, as accidental intravascular injection may cause, for example, transient tachycardia, and 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 overall condition.

For infiltration anesthesia, administer 5–60 mL of Bukain 2.5 mg/mL (12.5–150 mg bupivacaine hydrochloride) or 5–30 mL of Bukain 5 mg/mL (25–150 mg bupivacaine hydrochloride).

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

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

For obstetric anesthesia (e.g., epidural or caudal anesthesia during vaginal delivery or vacuum extraction), administer 6–10 mL of Bukain 2.5 mg/mL (15–25 mg bupivacaine hydrochloride). These doses are initial doses and may be repeated as needed every 2–3 hours.

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

For continuous epidural anesthesia by intermittent bolus dosing, an initial dose of 20 mL of Bukain 2.5 mg/mL (50 mg bupivacaine hydrochloride) is used, followed by 6–16 mL of Bukain 2.5 mg/mL (15–40 mg bupivacaine hydrochloride) every 4–6 hours, depending on the desired number of anesthetized segments and the patient’s age.

Table 1

For continuous epidural administration (e.g., postoperative analgesia)

1. If an appropriate bolus dose has not been administered within one hour.
2. The maximum recommended daily dose must not be exceeded (see below).

The dose administered during surgery must also be taken into account.

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

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

Maximum recommended doses

The maximum recommended dose for a single procedure is calculated at 2 mg/kg body weight; for adults, the maximum dose is 150 mg within 4 hours.

Bucaïn 2.5 mg/mL: 60 mL (150 mg bupivacaine hydrochloride).
Bucaïn 5 mg/mL: 30 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 significant factors.

Children aged 1 to 12 years

Regional anesthesia in children should be performed by physicians experienced in treating this patient population and familiar with the appropriate techniques.

The table below provides recommended doses for use in children. Individual variations exist. In children with increased body weight, dosage should often be gradually reduced based on ideal body weight. Standard reference guides should be consulted when factors affecting specific blockade techniques are present, and to meet individual patient requirements.

The lowest effective dose required to achieve adequate anesthesia should be used.

Table 2

Dosing recommendations for children aged 1 to 12 years

a) The onset time and duration of peripheral nerve block depend on the type of block and the dose administered.

b) Thoracic epidural block should be performed by gradually increasing the dose until the desired level of anesthesia is achieved.

For children, the dose should be calculated according to body weight at up to 2 mg/kg.

To prevent accidental intravascular injections, aspiration should be performed before and during administration of each dose of the drug. The drug should be administered slowly, with gradual dose escalation, especially during lumbar and thoracic epidural infusions, with continuous careful monitoring of the patient's vital functions.

Peritonsillar infiltration has been performed in children aged 2 years and older using bupivacaine 2.5 mg/mL at a dose of 7.5–12.5 mg per tonsil.

Femoral nerve blocks and ilioinguinal/iliohypogastric nerve blocks are performed in children aged 1 year and older using bupivacaine 2.5 mg/mL at a dose of 0.1–0.5 mL/kg, equivalent to 0.25–1.25 mg/kg. Children aged 5 years and older received bupivacaine 5 mg/mL at a dose of 1.25–2 mg/kg.

For penile blocks (dorsal nerves of the penis), bupivacaine 5 mg/mL is used at total doses of 0.2–0.5 mL/kg, equivalent to 1–2.5 mg/kg.

The safety and efficacy of Bucaine with and without adrenaline in children under 1 year of age have not been established. Only limited data are available.

The safety and efficacy of intermittent epidural bolus injections or continuous infusions have not been established. Only limited data are available.

Children.

For administration of the medicinal product in children, see section "Dosage and method of administration".

Overdose.

Acute systemic toxicity

Symptoms

Systemic toxic reactions involve the central nervous system and cardiovascular system. These reactions may result from high concentrations of local anesthetic in the blood due to accidental intravascular injection, overdose, or unusually rapid absorption from highly vascularized tissues (see also section "Special precautions for use").

CNS symptoms are similar for all amide-type local anesthetics, whereas cardiac symptoms differ among various agents both quantitatively and qualitatively.

Accidental intravascular injections of local anesthetics may cause immediate (within seconds to minutes) systemic toxic reactions. In cases of overdose, systemic toxicity manifests later (15–60 minutes after injection) due to slower increases in blood concentration of the local anesthetic.

CNS toxicity develops progressively, with increasing severity of symptoms and reactions. Initial symptoms usually present as mild dizziness, perioral numbness, tongue numbness, hyperacusis, tinnitus, and visual disturbances. Slurred speech, muscle twitching, or tremor are more serious symptoms preceding generalized seizures. These signs should not be interpreted as neurotic behavior. Subsequently, loss of consciousness and generalized tonic-clonic seizures may occur, 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 develop. Acidosis potentiates the toxic effects of local anesthetics.

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

Cardiovascular effects usually represent a more serious threat. These effects are often preceded by signs of CNS toxicity, which, however, may be masked by general anesthesia or deep sedation induced by agents such as benzodiazepines or barbiturates. High systemic concentrations of local anesthetics may result in decreased arterial blood pressure, bradycardia, arrhythmias, and even cardiac arrest. Cardiovascular toxic effects are often associated with depression of the cardiac conduction system and myocardium, leading to reduced cardiac output, arterial hypotension, AV block, bradycardia, and sometimes ventricular arrhythmias, including ventricular tachycardia, ventricular fibrillation, and cardiac arrest. These conditions are often preceded by signs of severe CNS toxicity, such as seizures; however, cardiac arrest rarely occurs without prior CNS effects. Following very rapid intravenous bolus injection into coronary vessels, blood concentrations of bupivacaine may become so high that cardiovascular effects occur independently or even before CNS effects appear. Due to this mechanism, myocardial depression may even be the first symptom of intoxication.

Particular attention should be paid to early signs of toxicity in children, as children usually do not receive large nerve blocks before the onset of general anesthesia.

Treatment

In case of complete spinal block, adequate ventilation must be ensured (airway patency, oxygen supply, and if necessary, intubation and mechanical ventilation). In case of arterial hypotension/bradycardia, a vasopressor agent with inotropic effect should be administered.

Upon appearance of signs of acute systemic toxicity, administration of local anesthetics must be immediately discontinued, and CNS symptoms (seizures, CNS depression) should be promptly treated by optimal oxygenation/ventilation and administration of anticonvulsant agents.

If circulatory insufficiency occurs (arterial hypotension, bradycardia), appropriate treatment should be initiated, including intravenous fluid administration, vasopressors, inotropic agents, and/or lipid emulsions. When treating systemic toxicity in children, doses should be adjusted proportionally to age and body weight.

In case of circulatory arrest, immediate cardiopulmonary resuscitation must be initiated. It is essential to maintain adequate oxygenation, ventilation, and circulation, while simultaneously correcting acidosis. Prolonged resuscitation efforts may be required in cases of circulatory arrest.

Adverse Reactions

Adverse reactions caused directly by the drug may be difficult to distinguish from the physiological effects of nerve block (e.g., decreased arterial pressure, bradycardia), effects directly caused by needle puncture (such as nerve injury), or complications indirectly resulting from needle puncture (such as epidural abscess).

Neurological injuries are rare but well-known consequences of regional anesthesia, particularly epidural and spinal anesthesia.

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

The adverse reactions listed below are categorized according to the following frequency classification: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data).

Immune system disorders: rare – allergic reactions, anaphylactic reactions/shock.

Nervous system disorders: common – paraesthesia, dizziness; uncommon – symptoms of CNS toxicity (seizures, perioral paraesthesia, tongue numbness, hyperacusis, visual disturbances, loss of consciousness, tremor, mild dizziness, tinnitus, dysarthria); rare – neuropathy, peripheral nerve injury, arachnoiditis, paresis, paraplegia.

Eye disorders: rare – diplopia.

Cardiac disorders: common – bradycardia; rare – cardiac arrest, cardiac arrhythmia.

Vascular disorders: very common – arterial hypotension; common – arterial hypertension.

Respiratory, thoracic and mediastinal disorders: rare – respiratory depression.

Gastrointestinal disorders: very common – nausea; common – vomiting.

Renal and urinary disorders: common – urinary retention.

Hepatobiliary disorders: frequency not known – liver function abnormalities/increased levels of ALT and AST*.

*Liver injury with reversible increases in AST, ALT, ALP and bilirubin levels have been observed following repeated injections and prolonged infusions of bupivacaine. If signs of liver function impairment 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, in children it may be difficult to detect early signs of local anesthetic toxicity when the block is performed under sedation or general anesthesia.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and 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. 2 years. The solution should be used as soon as possible after opening the bottle/vial.

Storage conditions. Store at a temperature not exceeding 25 °C, in a place inaccessible to children. Do not freeze.

Incompatibilities.

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

Packaging. For dosage 2.5 mg/mL: 100 mL, 200 mL in bottles.

For dosage 5 mg/mL: 5 mL, 20 mL in glass vials, 5 glass vials in a blister pack, 1 blister pack in a cardboard box;

5 mL, 10 mL in glass vials, 5 glass vials in a blister pack, 2 blister packs in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Private Joint Stock Company "Infuziya".

Manufacturer's address and location of its business activity.

84A Nemirivske Highway, Vinnytski Khotory, Vinnytsia district, Vinnytsia region, 23219, Ukraine.