Novostezin

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

Composition:

Active substance: bupivacaine hydrochloride;

1 ml of solution contains bupivacaine hydrochloride equivalent to anhydrous substance 2.5 mg or 5 mg;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Local anesthetics. Amides.

ATC code N01BB01.

Pharmacological properties.

Pharmacodynamics.

The medicinal product contains bupivacaine, a long-acting amide-type local anesthetic with anesthetic and analgesic effects. When high doses are used, surgical anesthesia is achieved, whereas lower doses result in sensory blockade (analgesia) accompanied by less pronounced motor blockade. The onset and duration of the local anesthetic effect depend on the dose and the site of administration.

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 a shorter duration of action, and may 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 is completely absorbed from the epidural space, followed by a two-phase elimination pattern: 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 than after 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 is similar to that 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 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 mediated by cytochrome P450 3A4. Therefore, clearance depends on hepatic perfusion and the activity of the metabolizing enzyme.

Bupivacaine crosses the placental barrier. The concentration of free bupivacaine is equal in pregnant women and fetus. However, the total plasma concentration is lower in the fetus, which has a lower degree of plasma protein binding.

Clinical characteristics.

Indications.

For the performance of local anesthesia by transcutaneous infiltration, peripheral nerve block(s), and central neural block (caudal or epidural), i.e., used by a specialist in situations requiring prolonged anesthesia. Since sensory nerve block is more pronounced than motor block, bupivacaine is particularly effective in relieving pain, for example, during childbirth.

Contraindications.

• Hypersensitivity to any component of the medicinal product or to amide-type local anesthetics;
• intravenous regional anesthesia (Bier block), because accidental intravascular injection of bupivacaine may lead to the development of acute systemic toxic reactions;
• 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-stage neurological disorders 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.

Regional or local anesthetic procedures, except for the simplest ones, should always be performed with resuscitation equipment available. Intravenous catheters should be inserted before initiating local anesthetic administration when performing major nerve blocks.

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

Major peripheral nerve blocks may require large volumes of local anesthetic injected into highly vascular 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 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 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 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 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 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 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 closely 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 hepatic 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.

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, for example, 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 this medicinal product.

1 ml of the medicinal product contains 3.15 mg of sodium. This should be taken into account for patients on a strict low-sodium diet.

Use during pregnancy or breastfeeding.

There is no evidence of adverse effects on pregnancy in humans, but the drug should not be used during 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) due to the use of local anesthetics. Such effects may be caused by high concentrations of anesthetic reaching the fetus (see section "Special precautions for use").

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 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.

Administration and Dosage

Bupivacaine should be administered only by physicians experienced in performing 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 should be performed before and during administration of the total dose to detect intravascular placement. The total dose should be administered slowly at a rate of 25–50 mg/min, or in divided doses, with continuous verbal contact maintained with the patient and monitoring of cardiac rhythm.

For epidural administration, a test dose of 3–5 mL of the solution containing adrenaline (epinephrine) is recommended, as accidental intravascular injection may result in transient tachycardia, while accidental intrathecal injection may lead to spinal block. If signs of intoxication occur, administration must be immediately discontinued.

The recommended dosages are listed below. Dosage should be adjusted according to the degree of block required and the patient's overall condition.

For infiltration anesthesia, administer 5–30 mL of 5 mg/mL solution (25–150 mg bupivacaine hydrochloride).

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

For major nerve blocks (e.g., epidural, caudal, or brachial plexus anesthesia), administer 15–30 mL of 5 mg/mL solution (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 5 mg/mL solution (30–50 mg bupivacaine hydrochloride). These doses are initial; repeated administration may be performed every 2–3 hours as needed.

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

Table 1.

Dosage recommendations for 2.5 mg/mL bupivacaine hydrochloride solution in adults.

1 Dose includes test dose.

2 Total ≤400 mg/24 hours.

3 These solutions are often used for epidural administration in combination with appropriate opioid medicinal products for analgesia. Total ≤ 400 mg/24 hours.

4 When using bupivacaine with any other techniques for the same patient, the dosage should not exceed 150 mg.

5 In the post-marketing period, cases of chondrolysis have been reported in patients receiving prolonged intra-articular infusions of local anesthetics. Novostesin is not approved for this indication (see section "Special precautions").

6 Bupivacaine without adrenaline.

When used in combination with opioid drugs, 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 should 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, i.e. 30 ml of 5 mg/ml solution (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 status, and other significant factors.

Children. Do not use in this patient category.

Overdose.

Symptoms

Systemic toxic reactions involve the central nervous and cardiovascular systems. Such reactions may be caused by high blood concentrations of local anesthetic due to accidental intravascular injection, overdose, or unusually rapid absorption from highly vascularized tissues (see also section "Special precautions").

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

Accidental intravascular injections of local anesthetics may cause immediate (within several seconds to several minutes) systemic toxic reactions. In cases of overdose, systemic toxicity manifests later (15–60 minutes after injection) due to slower increase 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 paresthesia, 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. Thereafter, loss of consciousness and major epileptic seizure may occur, 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 develop. Acidosis enhances the toxic effects of local anesthetics.

Recovery depends on the metabolism and distribution of the local anesthetic outside the central nervous system. This occurs rapidly, except when doses of bupivacaine exceeding the maximum recommended doses have been administered.

Cardiovascular effects usually pose a more serious threat. These effects are often preceded by signs of central nervous system toxicity, which, however, may be masked by general anesthesia or deep sedation achieved with drugs such as benzodiazepines or barbiturates. As a result of high systemic concentrations of local anesthetics, arterial hypotension, bradycardia, arrhythmias, and even cardiac arrest are possible. 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. After very rapid intravenous bolus injection into coronary vessels, such high blood concentrations of bupivacaine may be achieved that circulatory effects occur independently or even before CNS effects develop. Due to this mechanism, myocardial depression may even develop as the first symptom of intoxication.

Treatment

In case of complete spinal block, adequate ventilation must be ensured (airway patency, oxygen supply, endotracheal intubation and artificial ventilation of the lungs if necessary). In case of arterial hypotension/bradycardia, a vasopressor agent with inotropic effect 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 immediately by ensuring optimal oxygenation/ventilation and administration of anticonvulsant agents.

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

In case of circulatory arrest, cardiopulmonary resuscitation should be initiated immediately. It is essential to maintain adequate oxygenation, ventilation, and circulation simultaneously with correction of acidosis.

Prolonged resuscitation measures may be required in case of circulatory 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 complications of regional, particularly epidural and spinal, anesthesia.

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze. Keep out of the reach of children.

Incompatibilities.

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

Packaging.

200 ml in bottles.

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

10 ml or 20 ml in vials; 5 vials in blister pack; 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Limited liability company "Novopharm-Biosyntez".

Manufacturer's address and location of activity.

38, Zhytomyrska Street, Zhytomyr Oblast, Zvyahel, 11700, Ukraine.