Marcaine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MARCAIN (MARCAIN®)

Composition:

Active substance: bupivacaine;

1 ml of solution contains 5 mg of bupivacaine hydrochloride calculated as bupivacaine hydrochloride monohydrate;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Local anesthetics. Amides.

ATC code N01BB01.

Pharmacological Properties.

Pharmacodynamics.

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

Bupivacaine reversibly blocks impulse conduction in nerve fibers by inhibiting sodium ion transport across nerve fiber cell membranes. Similar effects 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 epinephrine and without epinephrine is relatively small. Bupivacaine is particularly suitable for prolonged epidural blockade. Lower concentrations have less effect on motor nerve fibers and produce a shorter duration of action, making them suitable for prolonged 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 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 in 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, the hepatic extraction ratio is approximately 0.4, total plasma clearance is 0.58 L/min, and the elimination half-life is 2.7 hours.

The elimination half-life in newborns 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 are similar to those in adults.

Plasma protein binding is approximately 96%, primarily to α1-acid glycoprotein. After major surgical procedures, 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 pathways being mediated by cytochrome P450 3A4. Therefore, clearance depends on hepatic perfusion and metabolizing enzyme activity.

Bupivacaine crosses the placental barrier. Free bupivacaine concentrations are equal in the mother and fetus. However, total plasma concentration is lower in the fetus due to its lower degree of protein binding.

Clinical characteristics.

Indications.

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

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, which include: active 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 warnings and precautions for use").

Special precautions for use.

Procedures involving regional or local anesthetics, except for the simplest ones, should always be performed with resuscitation equipment available. Intravenous catheters should be inserted before starting local anesthetic administration when performing major blocks.

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

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

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 injections into highly vascularized areas.

Some regional anesthesia 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 impairment;
• In isolated cases, retrobulbar injections may reach the intracranial subarachnoid space and cause, for example, temporary 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 dysfunction of ocular muscles. The main causes include traumatic nerve injury and/or local toxic effects on muscles and nerves due to local anesthetic administration. 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 injections in the head and neck area may cause cerebral symptoms even at low doses;
• Paracervical block may occasionally cause fetal bradycardia or tachycardia; therefore, fetal heart rate should be carefully monitored.

Caution should be exercised 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 stages of 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 cardiac effects of bupivacaine and Class III antiarrhythmic drugs may be additive.

Cases of liver dysfunction with reversible increases in aspartate aminotransferase (AST), alanine aminotransferase (ALAT), alkaline phosphatase (ALP), and bilirubin have been reported rarely following repeated injections or prolonged infusions of bupivacaine. Rapid clinical improvement is possible after immediate discontinuation of bupivacaine. If signs of liver 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 can be reduced, for example, by injecting vasoconstrictor agents. Decreased arterial pressure should be corrected immediately, e.g., by intravenous administration of sympathomimetics, repeated as necessary.

In the post-marketing period, cases of chondrolysis have been reported 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 Marcaine.

This medicinal product contains 4.6 mmol (or 105 mg) of sodium per dose. Caution should be exercised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy

There is no evidence of adverse effects on pregnancy in humans, but Marcaine should not be used in early pregnancy except when the benefit is considered to outweigh the risks.

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"). Close monitoring of fetal heart rate is recommended.

Breastfeeding

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 dose and route of administration, bupivacaine may have a temporary effect on movement and coordination.

Administration and Dosage

Marcaine should 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 injections. Aspiration should be performed before and during administration of the total dose to rule out intravascular placement. 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 cardiac rhythm.

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

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, 5–30 mL of Marcaine 5 mg/mL (25–150 mg of bupivacaine hydrochloride) should be administered.

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

For blockade of major nerves (e.g., epidural, sacral, or brachial plexus anesthesia), 15–30 mL of Marcaine 5 mg/mL (75–150 mg of bupivacaine hydrochloride) should be administered.

For obstetrical anesthesia (e.g., epidural or caudal anesthesia during vaginal delivery or vacuum extraction), 6–10 mL of Marcaine 2.5 mg/mL (15–25 mg of bupivacaine hydrochloride) should be administered. These doses are initial doses and may be repeated as needed every two to three hours.

For epidural block during cesarean section, 15–30 mL of Marcaine 5 mg/mL (75–150 mg of bupivacaine hydrochloride) should be administered.

When 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 stopped immediately.

Maximum Recommended Doses

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

Marcaine should not be used in children.

Overdose

Symptoms

Systemic toxic reactions affect the central nervous and cardiovascular systems. These reactions may result from high plasma concentrations of local anesthetic caused by accidental intravascular injection, overdose, or unusually rapid absorption from highly vascularized tissues (see also section "Special Precautions").

Central nervous system (CNS) symptoms are similar for all amide-type local anesthetics, whereas cardiac symptoms differ among agents both quantitatively and qualitatively.

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

CNS toxicity develops progressively with increasing severity of symptoms and reactions. Initial symptoms typically include mild dizziness, perioral numbness, tongue numbness, hyperacusis, tinnitus, and visual disturbances. Slurred speech, muscle twitching, or tremors 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 CO₂ levels in blood) develop rapidly due to increased muscular activity and inadequate pulmonary gas exchange. In severe cases, apnea may also occur. Acidosis potentiates the toxic effects of local anesthetics.

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

Cardiovascular effects are usually more life-threatening. These effects are often preceded by signs of CNS toxicity, although these may be masked by general anesthesia or deep sedation induced by drugs such as benzodiazepines or barbiturates. High systemic concentrations of local anesthetics may lead to decreased arterial pressure, bradycardia, arrhythmias, and even cardiac arrest. Cardiovascular toxicity is frequently associated with depression of the cardiac conduction system and myocardium, resulting in 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 prior to CNS effects. Due to this mechanism, myocardial depression may even be the first sign of intoxication.

Treatment

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

If signs of acute systemic toxicity occur, administration of local anesthetics must be stopped immediately, and CNS symptoms (seizures, CNS depression) should be treated promptly by ensuring optimal oxygenation/ventilation and administering anticonvulsant drugs.

If circulatory insufficiency occurs (hypotension, bradycardia), appropriate treatment should be initiated, including intravenous fluid administration, vasopressors, inotropic agents, and/or lipid emulsions.

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

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

Adverse Reactions

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

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

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

*Liver injury with reversible elevations of AST, ALT, alkaline phosphatase, and bilirubin 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 "Dosage and Administration").

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions through the national reporting system.

Shelf life.

3 years. The solution should be used as soon as possible after opening the vial.

Storage conditions.

Store out of reach and sight of children, at a temperature not exceeding 25 °C. Do not freeze.

Incompatibilities.

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

Packaging.

20 ml in a vial. 5 vials in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Recipharm Monts, France.

Manufacturer's address and place of business.

18, Rue de Montbazon, 37260 MONTS, France / 18 rue de Montbazon, MONTS, 37260, France.