Bupivacaine-m

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

Composition:

Active substance: bupivacaine;

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

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Local anesthetics. Amides.

ATC code N01BB01.

Pharmacological properties.

Pharmacodynamics. Bupivacaine-M contains bupivacaine, a long-acting amide-type local anesthetic. Bupivacaine reversibly blocks impulse conduction in nerve fibers by inhibiting sodium ion transport across nerve 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 of effect 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 and a shorter duration of action, and may therefore be 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 with caudal blockade (approximately 1.0–1.5 mg/L after a dose of 3 mg/kg).

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

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

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

Plasma protein binding is approximately 96%, primarily to α1-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 toxic levels may still be well tolerated.

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

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

Clinical characteristics.

Indications.

Infiltration anesthesia in cases where a prolonged duration of effect is required, for example, for relief of postoperative pain.

Prolonged nerve block or epidural anesthesia in cases where addition of adrenaline is contraindicated and use of potent muscle relaxants is undesirable. Anesthesia in obstetrics.

Contraindications.

Hypersensitivity to amide-type local anesthetics or to any of the excipients of the drug.

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 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; however, caution is recommended in such cases.

Special precautions for use.

Before starting treatment, a sensitivity test should be performed.

Procedures involving regional or local anesthetics, except for the simplest ones, should always be carried out in the presence of equipment for resuscitation. Intravenous catheters should be inserted before administering local anesthetic 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 complicated or impossible despite adequate therapy.

Patients receiving Class III antiarrhythmic agents (e.g., amiodarone) must be under close medical supervision; ECG monitoring is required due to possible cardiovascular complications.

Major peripheral nerve blocks may require large volumes of local anesthetic administered in highly vascularized areas, often near large 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 at 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 anesthesia techniques may be associated with severe adverse reactions:

• Epidural anesthesia may cause cardiovascular depression, especially in the presence of concomitant hypovolemia. Caution should be exercised when using the drug in patients with cardiovascular impairment;
• In isolated cases, retrobulbar injections may reach the cranial 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 carry a certain risk of developing persistent ocular muscle dysfunction;
• In the post-marketing period, cases of chondrolysis have been reported in patients receiving prolonged intra-articular infusions of local anesthetics after surgical procedures. Chondrolysis mostly 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 this drug.

The main causes are traumatic nerve injury and/or local toxic effects on muscles and nerves due to the injection of the local 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.

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

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, severe renal impairment, and patients in poor general condition also require special attention.

Epidural anesthesia may lead to decreased arterial pressure and bradycardia. This risk can be reduced by intravenous administration of crystalloid or colloid solutions. Decreased arterial pressure should be corrected immediately, for example, by intravenous administration of 5–10 mg ephedrine, repeated as necessary. Ephedrine should be administered to children in doses appropriate to age and body weight.

Epidural anesthesia may cause paralysis of intercostal muscles and impaired respiration in patients with pleural effusion. In patients with sepsis, the risk of intraspinal abscesses is increased, especially in the postoperative period.

Use during pregnancy or breastfeeding.

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

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

Ability to affect the speed of reactions when driving or operating machinery.

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

Method of Administration and Dosage

Bupivacaine should be administered by a physician experienced in regional anesthesia, or under the supervision of such a physician. 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. For high-dose epidural administration, a test dose of 3–5 mL of bupivacaine with adrenaline should be administered, as accidental intravascular injection may cause, for example, transient tachycardia, while accidental intrathecal injection may result in spinal block. Verbal contact with the patient should be maintained and periodic checks of heart rate should be performed for 5 minutes after administration of the test dose. In addition, aspiration should be performed before administration of the full dose, which should be injected slowly at a rate of 25–50 mg/min in incremental doses, with continuous verbal contact maintained with the patient. If signs of intoxication occur, administration of the drug should 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 25–150 mg of bupivacaine hydrochloride.

For intercostal block, administer 10–15 mg per nerve up to a total of 10 nerves.

For major nerve blocks (e.g., epidural, sacral, or brachial plexus anesthesia), administer 75–150 mg.

For obstetric anesthesia (e.g., epidural or caudal anesthesia during vaginal delivery or vacuum extraction), administer 30–50 mg of bupivacaine hydrochloride. These doses are initial doses and may be repeated as needed every two to three hours.

For epidural block (during cesarean section), administer 75–150 mg of bupivacaine.

When used in combination with opioid medications, 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 signs of toxic effects occur, the infusion should be immediately discontinued.

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.

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

Children

Bupivacaine is not indicated for use in children.

Overdose

Symptoms: Systemic toxic reactions primarily affect the central nervous system (CNS) and the cardiovascular system. These reactions may result from high concentrations of local anesthetic in the blood due to accidental intravascular injection, overdose, or particularly rapid absorption from highly vascularized areas.

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

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 a slower rise in blood concentration of the local anesthetic.

CNS Toxicity develops progressively with increasing severity of symptoms and reactions. Initial symptoms typically include mild dizziness, perioral numbness, tongue numbness, hyperacusis, auditory hypersensitivity, tinnitus, and blurred vision. More severe disturbances manifest as tremors or clonic movements preceding generalized seizures. These signs should not be mistaken for neurotic behavior. Subsequently, loss of consciousness and generalized tonic-clonic seizures may occur, lasting from one minute to several minutes. Following seizures, hypoxia and hypercapnia rapidly develop due to increased muscular activity and inadequate pulmonary gas exchange. In severe cases, apnea may occur. Acidosis potentiates the toxic effects of local anesthetics. The rate of recovery from toxicity depends on the speed of elimination of the drug from the CNS and its metabolism. Recovery is usually rapid, except when very large amounts of the drug have been administered.

Cardiovascular Effects are generally more life-threatening. These effects are usually preceded by CNS toxicity symptoms, which may, however, 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 hypotension, bradycardia, arrhythmias, and even cardiac arrest. Cardiovascular toxicity is often associated with depression of the cardiac conduction system and myocardium, resulting in reduced cardiac output, 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 convulsions; however, in rare cases, cardiac arrest has occurred without prior CNS effects. Following very rapid intravenous injection, such high blood concentrations of bupivacaine may be achieved in the coronary vessels that cardiovascular effects may occur independently or even before CNS effects. Given this mechanism, myocardial depression may even be the first sign of intoxication.

Treatment

In the case of total spinal block, adequate pulmonary ventilation should be ensured (airway patency, oxygen supplementation [oxygenation], intubation, and mechanical ventilation if necessary). In cases of arterial hypotension/bradycardia, a vasopressor with inotropic effect should be administered.

If signs of acute systemic toxicity occur, administration of local anesthetics must be immediately discontinued. Treatment should focus on maintaining adequate pulmonary ventilation, oxygenation, and circulation. Mechanical ventilation should be performed if necessary. If seizures do not stop spontaneously within 15–20 seconds, 1–3 mg/kg of sodium thiopental should be administered intravenously to facilitate ventilation, or 0.1 mg/kg diazepam intravenously (this agent acts significantly more slowly). Prolonged seizures threaten the patient’s respiration and oxygenation. Injection of muscle relaxants (e.g., succinylcholine 1 mg/kg) may facilitate adequate ventilation and oxygenation but requires experience in endotracheal intubation and mechanical ventilation. Atropine should be administered in cases of bradycardia.

In cases of circulatory depression, intravenous fluids should be administered, along with dobutamine, and, if necessary, noradrenaline (initially 5 µg/kg/min, increasing by 0.05 mg/kg/min every 10 minutes as needed), with hemodynamic monitoring in more complex cases. Trial administration of ephedrine may also be considered.

In the event of circulatory arrest, immediate cardiopulmonary resuscitation should be initiated.

It is essential to maintain adequate oxygenation of respiration and circulation while simultaneously correcting 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 arterial pressure, bradycardia) and phenomena directly caused by needle puncture (particularly nerve injury).

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

Shelf life. 3 years.

Storage conditions.

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

Incompatibility.

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

Packaging.

5 ml in a vial; 10 vials in a cardboard box;

5 ml in a vial; 5 vials in a blister pack; 2 blisters in a cardboard box.

Prescription status. By prescription only.

Manufacturer.

Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorovye Naroda".

Address.

Ukraine, 61002, Kharkiv region, city of Kharkiv, Kuilikivska street, building 41.