Bupivacaine-zn

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

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-ZN contains bupivacaine, an amide-type local anesthetic with prolonged duration of action. 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 between bupivacaine administered with epinephrine versus without epinephrine is relatively small. Bupivacaine is particularly suitable for prolonged epidural blockade. Lower concentrations have less effect on motor nerve fibers 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 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 elimination half-lives of approximately 7 minutes and a subsequent half-life of 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, 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, longer than in adults. In children aged 3 months and older, the elimination 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 pathways being mediated by cytochrome P450 3A4. Thus, clearance depends on hepatic perfusion and the activity of metabolizing enzymes.

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

Clinical characteristics.

Indications.

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

Prolonged nerve block or epidural anesthesia in cases where the addition of adrenaline is contraindicated and the 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, including: active-stage diseases of the nervous system 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 studies on interactions 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.

Prior to initiating treatment, a sensitivity test for individual responsiveness should be performed.

Procedures involving regional or local anesthetics, except for the most simple ones, should always be conducted in the presence of equipment necessary for resuscitation. Intravenous catheters should be inserted prior to the administration of local anesthetic when performing major blocks.

Cases of cardiac arrest and death have been reported following the use of bupivacaine for epidural anesthesia or peripheral nerve blocks. Sometimes 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 the potential for cardiac complications.

Major peripheral nerve blocks may require large volumes of local anesthetic administered to highly vascularized 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 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 tissues.

Certain regional anesthesia techniques may be associated with serious adverse reactions:

• 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 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 dysfunction of the ocular muscles;
• 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 most commonly 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 include traumatic nerve injury and/or local toxic effects on muscles and nerves due to the administration 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 administration in the head and neck area may cause cerebral symptoms even at low doses.

Caution should be exercised in patients with second- and third-degree AV block, as local anesthetics may reduce myocardial conduction. Elderly patients, patients with severe liver disease, severe renal impairment, and those in poor general health 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 developing intraspinal abscesses is increased, particularly in the postoperative period.

Use during pregnancy or breastfeeding.

There is no evidence of adverse effects on pregnancy in humans; however, bupivacaine should not be used during early pregnancy except when the expected benefit outweighs the potential 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 motor function 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 for blood should be performed before and during administration of the total dose. When high doses are administered epidurally, a test dose of 3–5 mL of bupivacaine with adrenaline should be given first, as accidental intravascular injection may cause, for example, transient tachycardia, while accidental intrathecal injection may result in spinal block. The patient should remain in verbal contact and heart rate should be monitored periodically for at least 5 minutes after administration of the test dose. Furthermore, 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 portions, maintaining continuous verbal contact with the patient. If signs of intoxication occur, administration of the drug must be stopped immediately.

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

For infiltration anesthesia, 25–150 mg of bupivacaine hydrochloride should be administered.

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

For major nerve blocks (e.g., epidural, caudal, or brachial plexus anesthesia), 75–150 mg should be administered.

For obstetric anesthesia (e.g., epidural or caudal anesthesia during vaginal delivery or vacuum extraction), 30–50 mg of bupivacaine hydrochloride should be administered. These are initial doses; repeat administration may be necessary every two to three hours if required.

For epidural block (during cesarean section), 75–150 mg of bupivacaine 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 signs of toxic effects occur, the infusion must be stopped immediately.

Maximum Recommended Doses

The maximum recommended dose administered during 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 plasma concentrations of local anesthetic 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 systemic toxic reactions (within seconds to minutes). In cases of overdose, systemic toxicity manifests later (15–60 minutes after injection) due to slower increases in plasma 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, heightened hearing, tinnitus, and blurred vision. More severe manifestations include tremors or clonic movements preceding generalized seizures. These signs should not be mistaken for neurotic behavior. Further progression may lead to loss of consciousness and generalized tonic-clonic seizures lasting from one minute to several minutes. Following seizures, hypoxia and hypercapnia rapidly develop due to intense muscular activity and inadequate pulmonary gas exchange. In severe cases, apnea may occur. Acidosis potentiates the toxic effects of local anesthetics. The resolution of toxicity depends on the rate of elimination of the drug from the CNS and its metabolism. This occurs rapidly, except when very large amounts of the drug have been administered.

Cardiovascular Effects are usually more life-threatening. These effects are typically preceded by signs of CNS toxicity, although they may be masked by general anesthesia or deep sedation induced by agents 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 appear. Due to this mechanism, myocardial depression may even be the first sign of intoxication.

Treatment

In the case of total spinal block, adequate pulmonary ventilation must be ensured (airway patency, oxygen supply [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 stopped immediately. 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 should be given intravenously (this agent acts significantly more slowly). Prolonged seizures threaten the patient’s respiration and oxygenation. Injection of a muscle relaxant (e.g., succinylcholine 1 mg/kg) may facilitate 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 mcg/kg/min, increased by 0.05 mg/kg/min every 10 minutes if 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 must be initiated.

It is essential to maintain adequate oxygenation of respiration 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) or phenomena directly caused by needle puncture (particularly nerve injury).

Neurological damage is rare, but a 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 has low solubility 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, Kulikovskaya Street, building 41.