Novostezin spinal heavy

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

Composition:

Active substance: bupivacaine hydrochloride;

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

Excipients: glucose monohydrate; sodium hydroxide or hydrochloric acid concentrated, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Local anesthetics. Amides.

ATC code N01BB01.

Pharmacological Properties.

Pharmacodynamics.

Bupivacaine is a long-acting amide-type local anesthetic. It reversibly blocks impulse conduction in nerve fibers by inhibiting sodium ion transport across neuronal membranes. Similar effects may also occur at excitable membranes of the brain and myocardium.

The medicinal product is intended for hyperbaric spinal anesthesia. The relative density of the injection solution is 1.026 at 20 °C (equivalent to 1.021 at 37 °C), and the initial distribution of the drug in the subarachnoid space is largely dependent on gravity.

When administered spinally, a low dose is used, resulting in relatively low plasma concentration and short duration of action.

Pharmacokinetics.

Bupivacaine is highly lipid-soluble, with an oil/water partition coefficient of 27.5.

Bupivacaine exhibits complete biphasic absorption from the subarachnoid space, with half-lives of approximately 50 and 400 minutes for the two phases, with considerable variability. The slow absorption phase is the rate-limiting factor for bupivacaine elimination, explaining why the terminal half-life is longer after subarachnoid administration compared to intravenous administration.

Absorption from the subarachnoid space is relatively slow. Together with the small dose required for spinal anesthesia, this results in a relatively low peak plasma concentration (approximately 0.4 mg/L for every 100 mg administered).

After intravenous administration, total plasma clearance of bupivacaine is approximately 0.58 L/min, the volume of distribution at steady state is 73 L, the terminal half-life is 2.7 hours, and the hepatic extraction ratio is 0.40. Bupivacaine is almost completely metabolized in the liver via aromatic hydroxylation to 4-hydroxybupivacaine and via N-dealkylation to pipecolylxylidine (PPX), both mediated by cytochrome P450 3A4. Therefore, its clearance depends on hepatic perfusion and metabolic enzyme activity. Bupivacaine crosses the placental barrier. The concentration of free bupivacaine is equal in the mother and the fetus. However, total plasma concentration is lower in the fetus, which has a lower degree of protein binding.

In children, the pharmacokinetics of the drug are similar to those in adults.

Clinical characteristics.

Indications.

Indicated for intrathecal (subarachnoid) spinal anesthesia in adults and children of various ages for surgery (urological procedures and lower limb surgeries lasting 2–3 hours, as well as abdominal surgeries lasting 45–60 minutes).

Contraindications.

Hypersensitivity to the active substance, other amide-type local anesthetics, or to any other component of the medicinal product.

Intrathecal anesthesia, regardless of the local anesthetic used, has its own contraindications, which include:

• active diseases of the central nervous system (CNS), 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 canal stenosis and active-stage diseases (e.g., spondylitis, tuberculosis, tumors) or recent spinal trauma (e.g., fracture);
• sepsis;
• skin abscess or other purulent infection at or near the lumbar puncture site;
• cardiogenic or hypovolemic shock;
• coagulation disorders or ongoing anticoagulant therapy.

Interaction with other medicinal products and other forms of interaction.

Since systemic toxic effects are additive, bupivacaine should be used with caution in patients receiving other local anesthetics or drugs structurally related to amide-type local anesthetics, such as certain class IB antiarrhythmic agents.

Specific interaction studies between bupivacaine and class III antiarrhythmic agents (e.g., amiodarone) have not been conducted; therefore, caution should be exercised when co-administering these drugs (see also section "Special precautions").

Special precautions for use.

Intrathecal anesthesia should only be administered by an experienced physician.

Procedures involving regional anesthetics must be performed in departments equipped with equipment for artificial ventilation of the lungs. Equipment for immediate resuscitation and appropriate medications must be readily available.

It should be remembered that intrathecal anesthesia may sometimes lead to extensive block with paralysis of intercostal muscles and the diaphragm, especially in pregnant women.

The drug should be used with caution in patients with second- or third-degree atrioventricular block, as local anesthetics may reduce myocardial conduction. Elderly patients and patients with liver disease, severe renal impairment, or poor general condition also require special attention.

Patients receiving class III antiarrhythmic drugs (e.g., amiodarone) should be under close monitoring. In addition, ECG monitoring should be considered, since cardiovascular effects of the drugs may be additive.

Intrathecal anesthesia may lead to the development of arterial hypotension and bradycardia. The risk of such effects can be reduced, for example, by administration of vasoconstrictor drugs. Hypotension should be treated immediately with intravenous sympathomimetics, which may be repeated as necessary.

Like all local anesthetics, bupivacaine, when used for local anesthesia resulting in high drug concentrations in the blood, may cause acute toxic effects on the central nervous and cardiovascular systems. This particularly applies to cases occurring after accidental intravascular injection or injection into highly vascularized areas.

Cases of ventricular arrhythmias, ventricular fibrillation, sudden cardiovascular collapse, and fatal outcomes have been reported in association with high systemic concentrations of bupivacaine. However, high systemic concentrations of the drug are not expected with doses usually used for intrathecal anesthesia.

A rare but serious adverse effect of intrathecal anesthesia is extensive or complete spinal block, leading to depression of cardiovascular and respiratory function. Cardiovascular depression caused by extensive sympathetic blockade may result in hypotension and bradycardia, and even cardiac arrest. Respiratory depression may result from blockade of nerve fibers innervating respiratory muscles, including the diaphragm.

In elderly patients and in women in late stages of pregnancy, there is an increased risk of developing extensive or complete spinal block. Therefore, the dose of the drug should be reduced for these patients.

Neurological injuries are a rare consequence of intrathecal anesthesia and may lead to the development of paresthesia, anesthesia, motor weakness, and paralysis. Intrathecal anesthesia is considered not to have a negative impact on neurological disorders such as multiple sclerosis, hemiplegia, paraplegia, and neuromuscular disorders, but caution should be exercised.

The solubility of bupivacaine decreases at pH > 6.5; therefore, this should be taken into account when mixing with alkaline solutions.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no known risks to the fetus associated with use during pregnancy.

It should be noted that the dose of the drug should be reduced in women in late pregnancy (see also section "Special precautions for use").

Breastfeeding.

Bupivacaine passes into breast milk, but the risk of effects on the infant following therapeutic doses of the drug is unlikely.

Ability to influence reaction speed 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.

The medicinal product should be administered only by physicians experienced in performing regional anesthesia or under their supervision, using the lowest doses sufficient to achieve an adequate degree of anesthesia.

The dosages of the medicinal product indicated below should be considered as a guideline for administration to average adult patients; dosage adjustment should be performed individually for each patient.

Dosage should be reduced for elderly patients and for pregnant women in late stages of pregnancy.

Table 1

The recommended injection site is below L3.

There is currently no clinical experience with doses higher than 20 mg.

Spinal administration of the drug should be performed only after clear identification of the subarachnoid space by lumbar puncture (until clear cerebrospinal fluid is obtained either through the lumbar puncture needle or by aspiration). In case of ineffective anesthesia, a repeat attempt to administer the drug should be performed only at another level and with a smaller volume of anesthetic. One of the reasons for insufficient effect may be incorrect distribution of the drug within the intrathecal space. In such cases, adequate effect can be achieved by changing the patient's body position.

Neonates, infants, and children with body weight up to 40 kg.

The medicinal product can be used in pediatric practice.

One of the differences between children and adults is the relatively higher volume of cerebrospinal fluid in infants and neonates, which necessitates the use of a relatively higher dose of the medicinal product per kilogram of body weight to achieve the same level of blockade compared to adults.

Regional anesthesia procedures in children should be performed by qualified physicians who have appropriate experience in administering regional anesthesia to children, as well as experience in performing the anesthetic technique.

The doses listed in Table 2 should be considered as recommended for use of the medicinal product in pediatrics. Individual variability has been observed. Standard dosage recommendations should be taken into account in the presence of factors affecting specific blockade techniques and to meet individual patient requirements.

The lowest effective dose required to achieve adequate anesthesia should be used.

Table 2

Dosage of the medicinal product for neonates, infants, and children

The solution should be used as soon as possible after the vial has been opened. Any remaining solution should be discarded.

Children.

The medicinal product can be used in pediatric practice. For further details, see section "Dosage and administration".

Overdose.

Acute systemic toxicity.

Toxic effects on the central nervous and cardiovascular systems may occur following administration of high doses of bupivacaine, particularly with intravascular injection. However, a low dose is used in spinal anesthesia, thus making overdose unlikely. When the drug is used concomitantly with other local anesthetics, systemic toxic reactions may occur, since toxic effects are additive.

Treatment.

In the event of total spinal block, adequate pulmonary ventilation should be ensured (airway patency, oxygen supply, intubation and artificial ventilation of the lungs, if necessary). In case of decreased arterial pressure/bradycardia, a vasoconstrictor (preferably with inotropic effect) should be administered.

If signs of acute systemic toxicity occur, administration of local anesthetics should be immediately discontinued. Treatment should focus on maintaining adequate ventilation, oxygenation, and circulation.

Oxygen should always be administered, and artificial ventilation (possibly with hyperventilation) should be performed if necessary. In case of seizures, diazepam should be administered; in case of bradycardia—atropine. In case of circulatory shock, intravenous fluids, dobutamine, and, if necessary, noradrenaline (initially 0.05 mcg/kg/min, increasing the dose by 0.05 mcg/kg/min every 10 minutes as needed) should be administered, guided by hemodynamic monitoring results in more severe cases. Ephedrine may also be used. Consideration should be given to intravenous administration of 20% lipid emulsion. Resuscitation measures may be required for several hours in case of cardiac arrest. Any acidosis should be corrected.

Adverse reactions.

Adverse reactions caused by the medicinal product itself are difficult to distinguish from the physiological effects associated with blockade of nerve fibres (e.g., decreased arterial pressure, bradycardia, transient urinary retention), conditions directly caused by the procedure (e.g., spinal haematoma), or indirectly by needle puncture (e.g., meningitis, epidural abscess), as well as from conditions related to cerebrospinal fluid leakage (e.g., post-dural puncture headache).

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

Pediatric population.

Adverse reactions observed with the use of the medicinal product in children are similar to those in adults. However, the initial signs of toxicity from local anesthetics may be difficult to recognize in children if the block is performed under sedation or general anesthesia.

Suspected adverse reactions reporting.

Reporting of suspected adverse reactions after medicinal product registration is important. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should 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 reach of children.

Incompatibilities.

The addition of other medicinal products is not recommended.

Packaging.

4 ml in vials; 5 vials in a blister pack; 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Limited liability company "Novopharm-Biosynthesis".

Manufacturer's address and location of its business activities.

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