Bupivacaine spinal

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Bupivacaine Spinal (Bupivacaine Spinal)

Composition:

Active substance: bupivacaine hydrochloride;

1 ml of solution contains bupivacaine hydrochloride monohydrate 5.28 mg, equivalent to bupivacaine hydrochloride 5 mg;

Excipients: glucose monohydrate; 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.

Bupivacaine is a long-acting local anesthetic of the amide type. Bupivacaine Spinal causes moderate muscle relaxation of the lower limbs lasting 2–2.5 hours. The solution causes motor blockade of abdominal muscles and is suitable for use during abdominal surgery lasting 45–60 minutes.

Cardiovascular effects of the medicinal product Bupivacaine Spinal are similar to or less than those observed with other spinal agents. Bupivacaine 5 mg/mL with glucose 80 mg/mL is exceptionally well tolerated by all tissues with which it comes into contact.

Bupivacaine Spinal is hyperbaric, and its initial spread in the intrathecal space depends on gravity. Due to the small dose, intrathecal distribution results in a relatively low concentration, and the duration of action of the local anesthetic is usually relatively short.

Pharmacokinetics.

Bupivacaine has a pKa of 8.2 and a partition coefficient of 346 (25 °C n-octanol/phosphate buffer pH 7.4). The metabolites have lower pharmacological activity than bupivacaine.

Bupivacaine demonstrates complete and biphasic absorption from the subarachnoid space, with half-life periods of approximately 50 and 408 minutes for the two phases. The slow absorption phase is the rate-limiting factor for bupivacaine elimination, which explains why the terminal half-life is longer after subarachnoid administration than after intravenous administration.

Plasma concentrations of bupivacaine following intrathecal blockade are low compared to those after other regional anesthetic procedures, due to the small dose required for intrathecal anesthesia. Typically, the increase in maximum plasma concentration is approximately 0.4 mg/L for every 100 mg injected. This means that a 20 mg dose will produce plasma levels of approximately 0.1 mg/L.

After intravenous administration, the total plasma clearance of bupivacaine is 0.58 L/min, the steady-state volume of distribution is 73 L, the terminal half-life is 2.7 hours, and the hepatic extraction ratio is 0.38. Bupivacaine is primarily bound to alpha-1-acid glycoprotein in plasma (96%). Bupivacaine clearance is almost entirely dependent on hepatic metabolism and is more influenced by changes in hepatic enzyme activity than by hepatic perfusion.

Bupivacaine readily crosses the placenta, and equilibrium in unbound concentration is rapidly achieved. The degree of plasma protein binding in the fetus is lower than in the mother, resulting in lower total plasma concentrations in the fetus.

Bupivacaine is excreted in breast milk, but in such small amounts that there is no risk to the infant.

Bupivacaine is extensively metabolized in the liver, primarily via aromatic hydroxylation to 4-hydroxybupivacaine and N-dealkylation to pipecolylxylidine (PPX)—both pathways mediated by cytochrome P450 3A4. Approximately 1% of bupivacaine is excreted unchanged in urine within 24 hours, and about 5% as PPX. Plasma concentrations of PPX and 4-hydroxybupivacaine during and after prolonged bupivacaine administration are low compared to the parent compound.

Pediatric population. Pharmacokinetics in children is similar to that in adults.

Clinical characteristics.

Indications.

Bupivacaine Spinal is indicated in adults and children of various ages for intrathecal (subarachnoid) spinal anesthesia in 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 or to any of the excipients of the medicinal product.

Hypersensitivity to amide-type local anesthetics.

Bupivacaine must not be administered into inflamed or infected areas.

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

• active diseases of the central 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;
• increased intracranial pressure;
• spinal canal stenosis and active-stage diseases (e.g., spondylitis, tuberculosis, tumors) or recent trauma (e.g., spinal fracture);
• sepsis;
• purulent skin 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 agents (see also section "Special precautions for use").

Special precautions for use.

Spinal anesthesia should only be performed by clinicians with appropriate knowledge and experience.

Regional anesthesia procedures should always be carried out in properly equipped premises with trained personnel. Resuscitation equipment and medications must be readily available, and an anesthesiologist must be continuously present.

Intravenous access, for example for intravenous infusion, must be established prior to initiating spinal anesthesia. The responsible clinician must take necessary precautions to avoid intravascular injection. He or she must also be adequately trained to diagnose and treat adverse effects, systemic toxicity, and other complications. If signs of acute systemic toxicity or complete spinal block appear, injection of the local anesthetic must be immediately discontinued; see sections "Adverse reactions" and "Overdose".

After injection of a local anesthetic, cardiovascular and respiratory vital signs and the patient's level of consciousness must be carefully monitored continuously, because sympathetic block resulting from spinal anesthesia may lead to peripheral vasodilation and hypotension. In addition, the level of anesthesia should be carefully monitored, as it is not always predictable with spinal techniques.

Like all local anesthetics, bupivacaine may cause acute toxic effects on the central nervous and cardiovascular systems if its administration for local anesthesia results in high drug concentrations in the blood. This particularly applies to cases of unintentional intravascular injection or injection into highly vascularized areas.

Cardiovascular toxicity is usually preceded by signs of central nervous system (CNS) toxicity. In patients under deep sedation or general anesthesia, prodromal symptoms from the CNS (CNS) may not occur.

Cases of ventricular arrhythmias, ventricular fibrillation, sudden cardiovascular collapse, and fatal outcomes have been reported in association with high systemic concentrations of bupivacaine. In case of cardiac arrest, prolonged resuscitation measures may be required. However, with doses usually used for intrathecal anesthesia, high systemic concentrations are not expected.

There is an increased risk of high or complete spinal block in elderly patients and in pregnant women in late pregnancy. Therefore, the dose should be reduced for these patients; see also section "Dosage and administration".

Spinal anesthesia with any local anesthetic may lead to hypotension and bradycardia. The risk of such effects may be reduced, for example, by injection of a vasopressor. Hypotension should be treated immediately with intravenous administration of sympathomimetics (repeated as necessary). Severe arterial hypotension may occur due to hypovolemia resulting from bleeding or dehydration, or aortocaval occlusion in patients with massive ascites, large intra-abdominal tumors, or late pregnancy. Pronounced hypotension should not be allowed in patients with cardiac decompensation.

In patients with hypovolemia from any cause, sudden severe hypotension may develop during spinal anesthesia.

Spinal anesthesia may cause intercostal paralysis, and patients with pleural effusion may experience respiratory difficulty.

Sepsis may promote the formation of intraspinal abscess in the postoperative period.

Before initiating treatment, the benefits and potential risks for the patient should be evaluated.

Patients with poor general condition due to age or other complicating factors, such as partial or complete cardiac conduction block, progressive liver or kidney dysfunction, require special attention, although regional anesthesia may be the optimal choice for surgical intervention in these patients.

Patients receiving class III antiarrhythmic drugs (e.g., amiodarone) must be under close surveillance. In addition, the need for ECG monitoring should be considered, as the cardiac effects of the drugs may be additive (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Spinal anesthesia is considered not to adversely affect neurological disorders such as multiple sclerosis, hemiplegia, paraplegia, and neuromuscular disorders, but caution is required. Before initiating treatment, the benefits and potential risks for the patient should be evaluated.

Use during pregnancy or breastfeeding.

Pregnancy. When bupivacaine is used for obstetric analgesia, it is important that the mother be placed on her side or tilted laterally to avoid aortocaval occlusion with subsequent maternal hypotension and acidosis.

The dose of the medicinal product must be reduced for pregnant women in late stages of pregnancy (see also section "Special precautions for use").

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

Ability to affect reaction speed when driving or operating machinery.

In addition to the direct anesthetic effect, local anesthetics may very mildly affect mental functions and coordination even in the absence of overt toxicity, and may temporarily impair motor activity and alertness.

Method of administration and dosage.

Dosage

Adults and children aged 12 years and older

The table below (Table 1) provides dosage recommendations for the most commonly used techniques in adults. The figures indicate the required average dose range. Standard dosage recommendations should be considered when factors affecting individual block techniques are present, and to meet individual patient needs.

Clinical experience and knowledge of the patient's physical condition are important for calculating the required dose.

The smallest dose necessary to achieve adequate anesthesia should be used. Onset and duration of anesthesia may vary among patients, and the extent of spread of anesthesia may be difficult to predict, but will depend on the volume of the administered drug.

Table 1

Pregnant women: 2–2.5 ml (10–12.5 mg of bupivacaine hydrochloride).

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

Newborns, infants, and children weighing up to 40 kg

Bupivacaine Spinal can be used in pediatric practice.

One of the differences between children and adults is the relatively larger volume of cerebrospinal fluid in infants and newborns, which requires administration of a relatively higher dose per kg of body weight to achieve the same level of block compared to adults.

Regional anesthesia procedures in children should be performed by qualified physicians experienced in administering regional anesthesia to children and in the specific anesthetic technique.

The doses listed in Table 2 should be considered as guidelines when using the medicinal product in pediatric practice. Cases of individual variability have been observed. Standard dosing recommendations should be taken into account when factors affecting specific block techniques are present, and to meet individual patient needs.

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

Table 2

Dosage recommendations for newborns, infants, and children

The spread of anesthesia after administration of Bupivacaine Spinal depends on several factors, including the volume of the solution and the patient's position during and after injection.

When administered into the L3–L4 intervertebral space with the patient in a sitting position, 3 mL of Bupivacaine Spinal typically spreads to spinal segments T7–T10. When the patient receives the injection in a lateral horizontal position and then turns onto the back, the block spreads to spinal segments T4–T7. It should be understood that the level of spinal anesthesia achieved with any local anesthetic may be unpredictable in an individual patient.

The recommended injection site is below L3.

Children.

Bupivacaine Spinal can be used in pediatric practice. For further details, see section "Dosage and administration".

Overdose.

Acute systemic toxicity

If Bupivacaine Spinal is used according to recommendations, it is unlikely that sufficiently high blood levels will be reached to cause systemic toxicity.

However, when the drug is used concomitantly with other local anesthetics, systemic toxic reactions may occur, since the toxic effects are additive.

Systemic toxicity is rarely associated with spinal anesthesia but may occur following accidental intravascular injection. Systemic adverse reactions are characterized by tongue numbness, dizziness, and tremors, followed by seizures and cardiovascular disturbances.

Treatment of acute systemic toxicity

If signs of acute systemic toxicity or total spinal block appear, injection of the local anesthetic should be immediately discontinued, and CNS symptoms (convulsions, CNS depression) should be immediately treated with appropriate airway/breathing support and anticonvulsant drugs.

In case of circulatory arrest, immediate initiation of cardiopulmonary resuscitation is required. Optimal oxygenation, ventilation, circulatory support, and treatment of acidosis are vital.

If cardiovascular depression (arterial hypotension, bradycardia) occurs, appropriate treatment with intravenous fluids, vasopressors, and/or inotropic agents should be considered. Doses for children must be adjusted according to age and body weight.

Adverse reactions

The adverse reaction profile of the medicinal product Bupivacaine Spinal is similar to that of other long-acting local anesthetics used for intrathecal anesthesia.

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

Prolonged spinal anesthesia may lead to paralysis of all respiratory muscles.

Neurological damage is a rare but well-known consequence of regional, particularly spinal, anesthesia. Causes include direct injury to the spinal cord or spinal nerves, anterior spinal artery syndrome, injection of an irritant substance, or injection of a non-sterile solution. This may result in localized areas of paresthesia or anesthesia, motor weakness, loss of sphincter control, and paraplegia. Sometimes these impairments are irreversible. Neurological complications of this type have been reported following the use of all local anesthetics employed for spinal anesthesia.

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

Table 3

Adverse drug reactions

Pediatric population

Adverse reactions to the use of the drug in children are similar to those in adults; however, the first signs of local anesthetic toxicity may be difficult to detect in children if the block is performed under sedation or general anesthesia.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance associated with the use of this medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua .

Shelf life. 3 years.

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

Keep out of the reach of children.

Incompatibilities. Addition of other substances to spinal solutions is not recommended.

Packaging. 4 ml in a vial. 5 vials in a blister pack. 1 blister pack in a carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Galychpharm".

Manufacturer's address and location of its business activity.

6/8 Opryshkivska Street, Lviv, 79024, Ukraine.