Marcaine^® Spinal Heavy (Solution) Instructions for Use

Marketing Authorization Holder

Aspen Pharma Trading, Limited (Ireland)

Manufactured By

Cenexi, SAS (France)

ATC Code

N01BB01 (Bupivacaine)

Active Substance

Bupivacaine (Rec.INN registered by WHO)

Dosage Form

Marcaine® Spinal Heavy

Injection solution 20 mg/4 ml: amp. 5 pcs.

Dosage Form, Packaging, and Composition

4 ml – ampoules (5) – blister packs (1) – cardboard boxes.

Clinical-Pharmacological Group

Local anesthetic for spinal anesthesia

Pharmacotherapeutic Group

Local anesthetic agent

Pharmacological Action

Bupivacaine is a local anesthetic of the amide type.

When administered intrathecally, the effect occurs rapidly, and its duration varies from medium to long. The duration of the effect depends on the dose.

The drug solution is hyperbaric and its spread in the subarachnoid space is influenced by gravity.

A small volume of distribution in the intrathecal space leads to a lower average concentration and reduced duration of the drug’s effect compared to an isobaric solution. Solutions that do not contain dextrose provide a less predictable level of blockade.

The relative density at a temperature of 20°C (68°F) is 1.026 (which corresponds to 1.021 at a temperature of 37°C (98.6°F)). The pH of the solution is 4.0-6.0.

Bupivacaine reversibly inhibits the conduction of impulses along the nerve fiber by blocking the passage of sodium ions through the cell membrane.

Pharmacokinetics

Bupivacaine has a pKa of 8.2 and a partition coefficient of 346 (at 25°C (77°F) in an n-octanol/phosphate buffer pH 7.4 medium).

Bupivacaine is completely absorbed from the subarachnoid space; absorption is biphasic, with half-lives for the two phases being 50 and 408 minutes, respectively.

The slow elimination of bupivacaine is determined by the presence of a slow absorption phase, which explains the longer T_1/2 after subarachnoid administration compared to intravenous administration.

The plasma concentration of bupivacaine after intrathecal block is lower compared to other types of regional anesthesia, as intrathecal anesthesia requires smaller doses of the drug.

In general, the increase in the maximum plasma concentration of the drug is about 0.4 µg/ml for every 100 mg of the drug administered. This means that a dose of 20 mg creates a plasma concentration of approximately 0.1 µg/ml.

After intravenous administration, the total plasma clearance of bupivacaine is 0.58 l/min, the volume of distribution at steady state is 73 l, the terminal T_1/2 is 2.7 h, and the intermediate hepatic extraction index is about 0.38 after IV administration.

Bupivacaine is mainly bound to α1-acid glycoproteins in plasma (plasma protein binding – 96%). The clearance of bupivacaine is almost entirely due to the metabolism of the drug in the liver and depends more on the activity of the liver enzyme systems than on liver perfusion.

Bupivacaine crosses the placental barrier with rapid equilibration of the unbound fraction.

The degree of protein binding in the fetal bloodstream is lower than in the mother, leading to lower drug concentrations in fetal plasma compared to the total drug concentration in maternal plasma.

Bupivacaine passes into breast milk in amounts not dangerous to the infant.

Bupivacaine is metabolized in the liver, mainly by aromatic hydroxylation to 4-hydroxy-bupivacaine and N-dealkylation to PPX.

Both reactions occur with the participation of cytochrome P4503A4 enzymes. About 1% of bupivacaine is excreted unchanged in the urine within 24 hours after administration, and approximately 5% as PPX.

The plasma concentrations of PPX and 4-hydroxy-bupivacaine during and after prolonged administration of bupivacaine are low relative to the administered dose of the drug.

Indications

Intrathecal anesthesia (subarachnoid, spinal) for surgical and obstetric interventions:

• Surgical operations on the lower parts of the abdominal cavity (including cesarean section), on the lower extremities (including the hip joint);
• For urological operations lasting 1.5-3 hours (see section “Dosage and Administration”).

ICD codes

Dosage Regimen

Intrathecally

Adults

The following recommendations are indicative for an average adult.

When selecting the drug dose, one should be based on clinical experience taking into account the patient’s physical condition. It is necessary to use the smallest required dose for adequate anesthesia.

The duration of anesthesia depends on the dose, while the spread of the drug along the segments is difficult to predict, especially when using an isobaric (plain) solution.

Recommended doses for Marcaine^® Spinal Heavy

The recommended injection site is below L3.

In elderly patients and patients in late pregnancy, it is recommended to use a reduced dose of the drug.

Children (weighing up to 40 kg)

Marcaine^® Spinal Heavy can be used in children. The difference between children and adults is that in newborns and infants, the volume of cerebrospinal fluid is relatively large, so they require a higher dose per kg of body weight than adults to achieve the same level of blockade as in adults.

Recommended doses of Marcaine Spinal Heavy in children

Adverse Reactions

Adverse reactions to Marcaine^® Spinal Heavy are similar to adverse reactions that occur with the intrathecal administration of other long-acting local anesthetics.

Adverse reactions caused by the drug itself are difficult to distinguish from the physiological manifestations of nerve blockade (e.g., arterial hypotension, bradycardia, temporary urinary retention), reactions caused directly (e.g., spinal hematoma) or indirectly (e.g., meningitis, epidural abscess) by needle insertion, or reactions associated with cerebrospinal fluid leakage (e.g., post-puncture headache).

Contraindications

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

General contraindications to intrathecal anesthesia should be taken into account

• Acute diseases of the central nervous system (CNS), such as meningitis, poliomyelitis, intracranial hemorrhage, as well as CNS neoplasms;
• Narrowing of the spinal canal and diseases of the spine in the acute phase (spondylitis, tumor) or recent spinal trauma (fracture);
• Septicemia;
• Pernicious anemia with subacute combined degeneration of the spinal cord;
• Pustular skin lesion at the intended puncture site or adjacent to the puncture site;
• Cardiogenic or hypovolemic shock;
• Blood clotting disorders or concomitant anticoagulant therapy.

With caution in debilitated elderly patients or patients with severe concomitant diseases, such as atrioventricular block II and III degree, severe hepatic or renal failure, however, regional anesthesia is more preferable for these groups of patients.

Patients taking class III antiarrhythmic drugs (e.g., amiodarone) require careful observation and ECG monitoring due to the possibility of developing adverse events from the cardiovascular system (see section “Drug Interactions”).

There is an increased risk of high or total spinal block in elderly patients and in patients in late pregnancy. Therefore, it is recommended to use reduced doses of the drug in such patients (see section “Dosage and Administration”).

Caution should be exercised when performing intrathecal anesthesia in patients with neurological diseases, such as multiple sclerosis, hemiplegia, paraplegia and neuromuscular disorders, although it has not been proven that intrathecal anesthesia leads to worsening of the condition in these diseases.

Before performing intrathecal anesthesia in such cases, it is necessary to ensure that the potential benefit to the patient outweighs the possible risk.

Bupivacaine should be used with caution in patients receiving other local anesthetics or drugs structurally similar to amide-type local anesthetics, such as antiarrhythmic drugs (e.g., lidocaine, mexiletine), due to the possibility of developing an additive toxic effect.

Use in Pregnancy and Lactation

Pregnancy

Bupivacaine has been used in a large number of pregnant women and women of childbearing age. No effect of the drug on reproductive function or an increase in the frequency of malformations has been noted (see section “Pharmacokinetics”).

In patients in late pregnancy, it is recommended to use reduced doses of the drug (see section “Dosage and Administration”).

Lactation

Bupivacaine passes into breast milk in amounts not dangerous to the infant.

Use in Hepatic Impairment

With caution severe hepatic impairment.

Use in Renal Impairment

With caution severe renal impairment.

Geriatric Use

With caution: debilitated elderly patients. There is an increased risk of high or total spinal block in elderly patients. Therefore, it is recommended to use reduced doses of the drug in such patients (see section “Dosage and Administration”).

Special Precautions

Intrathecal anesthesia should be performed only under the supervision of an experienced specialist in a properly equipped operating room.

Medicines and medical equipment for resuscitation should be prepared for use. Before starting intrathecal anesthesia, venous access must be provided, for example, in the form of a venous catheter.

The personnel performing anesthesia must be appropriately trained and educated in the diagnosis and treatment of possible side effects, systemic toxic reactions or other possible complications (see section “Overdose”).

Like other local anesthetics, Bupivacaine can cause acute toxic reactions from the central nervous and cardiovascular systems if its use for local anesthesia leads to a high concentration of the drug in the blood.

This may be particularly evident in the case of unintentional intravascular injection. Against the background of high plasma concentration of bupivacaine, cases of ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death have been recorded. However, the doses usually used for intrathecal anesthesia do not lead to high systemic concentration of the drug.

A rare, but at the same time serious adverse reaction that can develop during spinal anesthesia is high or total spinal block, leading to depression of the cardiovascular and respiratory systems.

Disorders of the cardiovascular system are caused by extensive sympathetic blockade, which can lead to hypotension, bradycardia and even cardiac arrest. Blockade of the innervation of the respiratory muscles, including the diaphragm, causes respiratory impairment. In patients with hypovolemia, pronounced arterial hypotension may develop during intrathecal anesthesia, regardless of the local anesthetic used. Arterial hypotension, which usually occurs in adults after intrathecal block, is rarely observed in children under 8 years of age.

Nerve ending damage is a rare complication of intrathecal anesthesia and can lead to paresthesia, anesthesia, muscle weakness and paraplegia. Occasionally these disorders are permanent.

Marcaine^® Spinal Heavy does not contain preservatives, the ampoule is intended for single use. Residual solution must be discarded.

Since Marcaine^® Spinal Heavy contains dextrose, caramelization is possible during autoclaving, therefore, repeated sterilization is not recommended.

Overdose

Acute systemic toxicity

The use of Marcaine Spinal Heavy in accordance with the recommendations does not lead to such a plasma concentration of the drug at which systemic toxic manifestations may occur. However, when using Marcaine Spinal Heavy in combination with other local anesthetics, acute systemic toxicity may develop due to the summation of toxic effects.

Like other local anesthetics, Bupivacaine can cause acute toxic reactions from the central nervous and cardiovascular systems if its use for local anesthesia leads to a high concentration of the drug in the blood.

This may be particularly evident in the case of unintentional intravascular injection. Against the background of high plasma concentration of bupivacaine, cases of ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death have been recorded. However, the doses usually used for intrathecal anesthesia do not lead to high systemic concentration of the drug.

From the CNS

When using bupivacaine, intoxication manifests itself gradually in the form of signs and symptoms of impaired central nervous system function with increasing severity.

The initial manifestations of intoxication are: paresthesia around the mouth, dizziness, numbness of the tongue, pathologically increased perception of ordinary sounds and tinnitus. Visual impairment and tremor are more serious signs and precede the development of generalized convulsions. These phenomena should not be mistakenly regarded as neurotic behavior. Loss of consciousness and the development of major convulsive seizures, which can last from a few seconds to several minutes, may follow. Due to increased muscle activity, disruption of the normal breathing process after the onset of convulsions, hypoxia and hypercapnia quickly appear. In severe cases, apnea may develop. Acidosis enhances the toxic effect of local anesthetics.

These phenomena pass due to the redistribution of the local anesthetic from the central nervous system and the metabolism of the drug. Cessation of toxic phenomena can occur quickly, unless the anesthetic was administered in a very large amount.

Treatment of acute systemic toxicity

At the first signs of acute systemic toxicity or total spinal block, the administration of the drug should be stopped immediately and symptomatic therapy for cardiovascular and neurological (convulsions, CNS depression) disorders should be carried out.

In case of cardiac arrest, cardiopulmonary resuscitation should be initiated immediately. It is vital to maintain lung ventilation, circulation and adequate oxygenation, as well as to correct acidosis.

In case of depression of the cardiovascular system (arterial hypotension, bradycardia), intravenous administration of 5-10 mg of ephedrine is necessary, which can be repeated after 2-3 minutes if necessary. Children should be given a dose of ephedrine according to their age and weight.

If convulsions occur, therapy should be aimed at maintaining the activity of the cardiovascular system, ensuring adequate oxygenation and stopping convulsions. If necessary, oxygen supply and artificial lung ventilation (using an Ambu bag or tracheal intubation) should be provided. If convulsions do not stop on their own within 15-20 seconds, anticonvulsants should be used: sodium thiopental 1-3 mg/kg IV provides rapid relief of convulsions, 0.1 mg/kg of diazepam IV can be used (the effect develops more slowly compared to thiopental). Prolonged convulsions can interfere with ventilation and oxygenation. In such cases, to quickly stop convulsions, one can resort to tracheal intubation and administration of a muscle relaxant (e.g., succinylcholine 1 mg/kg).

Drug Interactions

Bupivacaine should be used with caution in patients receiving other local anesthetics or drugs that are structurally similar to amide-type local anesthetics, such as antiarrhythmic drugs (e.g., lidocaine, mexiletine), due to the possibility of developing an additive toxic effect.

The combined use of bupivacaine with class III antiarrhythmic drugs (e.g., amiodarone) has not been studied separately, however, caution is recommended when prescribing these drugs concomitantly (see also section “Special Precautions”).

When treating the injection site of a local anesthetic with disinfectant solutions containing heavy metals, the risk of developing a local reaction in the form of pain and swelling increases.

When used concomitantly with drugs that depress the central nervous system, local anesthetics enhance CNS depression.

MAO inhibitors or tricyclic antidepressants used concomitantly with bupivacaine increase the risk of a significant rise in blood pressure. The combination of bupivacaine with general inhalational halothane anesthesia increases the risk of arrhythmia.

Incompatibility

It is not recommended to mix solutions for intrathecal anesthesia with other drugs.

Storage Conditions

Store at a temperature of 2-25°C (-13°F). Do not freeze. Keep out of the reach of children. Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.