Bupinecaine-hyperbar

INSTRUCTIONS for medical use of the medicinal product BUPINECAINE-HYPERBAR (BUPINECAINE-HYPERBAR)

Composition:

Active substance: bupivacaine hydrochloride;

1 ml of the preparation contains 5 mg of bupivacaine hydrochloride;

Excipients: glucose monohydrate, hydrochloric acid 1 M solution or sodium hydroxide for pH adjustment, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Local anesthetics. ATC code N01BB01.

Pharmacological Properties.

Pharmacodynamics.

Bupivacaine is a long-acting amide-type local anesthetic. Bupivacaine reversibly blocks impulse conduction along nerve fibers by inhibiting sodium ion transport across neuronal membranes. Similar effects may also occur at excitable membranes of the brain and myocardium. It moderately relaxes muscles of the lower limbs and blocks contractile activity of the abdominal muscles.

The drug 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 depends on gravity.

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

Pharmacokinetics.

Bupivacaine is highly lipophilic, 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, which explains why the terminal half-life is longer after subarachnoid administration compared to intravenous administration.

After intravenous administration, the 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 pathways mediated by cytochrome P450 3A4. Therefore, its clearance depends on hepatic perfusion and metabolic enzyme activity.

Rapid onset and prolonged duration of action: at the T10–T12 segmental level, the duration of action is 2–3 hours.

Muscle relaxation of the lower limbs lasts 2–2.5 hours.

Abdominal muscle blockade lasts 45–60 minutes. The duration of abdominal muscle contractility blockade does not exceed the duration of analgesia.

Bupivacaine crosses the placental barrier. Free bupivacaine concentration is equal in pregnant women and 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 is similar to that in adults.

Clinical characteristics.

Indications.

The drug is indicated for intrathecal (subarachnoid) spinal anesthesia in adults and children of various ages undergoing 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, to any component of the drug, or to amide-type local anesthetics.

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

• 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 or spinal cord;
• spinal canal stenosis and active-stage diseases (e.g., spondylitis, tuberculosis, tumors) or recent trauma (e.g., fracture) of the spine;
• septicemia;
• skin abscess or other purulent infection at or near the site of lumbar puncture;
• 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 is advised when these agents are used concomitantly.

Special precautions for use.

Intrathecal anaesthesia should only be administered by a physician with the necessary level of knowledge and experience.

Regional anaesthetic procedures must always be performed in appropriately equipped and staffed facilities. Resuscitation equipment and appropriate medications must be immediately available, and an anaesthesiologist must be continuously present.

Prior to performing intrathecal anaesthesia, provision should be made for intravenous access, such as intravenous infusion. The physician responsible for administering anaesthesia must take necessary precautions to avoid intravascular injection of the drug and must be adequately trained and familiar with the diagnosis and treatment of adverse effects, systemic toxicity, and other complications. If signs of acute systemic toxicity or complete spinal block occur, administration of the local anaesthetic must be immediately discontinued.

It should be remembered that intrathecal anaesthesia may occasionally lead to high or complete block with paralysis of intercostal muscles and diaphragm, particularly in pregnant women.

Like all local anaesthetics, bupivacaine may cause acute toxic effects on the central nervous and cardiovascular systems when used for local anaesthesia resulting in high drug concentrations in the blood. This is especially true 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 due to high systemic concentrations of bupivacaine. In the event of cardiac arrest, prolonged resuscitation measures may be required to achieve a successful outcome. High systemic concentrations of the drug are not expected with doses typically used for intrathecal anaesthesia.

Intrathecal anaesthesia may cause paralysis of intercostal muscles, and patients with pleural effusion may develop respiratory insufficiency. Sepsis may increase the risk of developing intraspinal abscess in the postoperative period.

Neurological injury is a rare consequence of intrathecal anaesthesia and may lead to paraesthesia, anaesthesia, motor weakness, and paralysis. Occasionally, these effects may be irreversible.

Before initiating treatment, it must be determined whether the benefits of treatment outweigh the potential risks to the patient.

The drug should be used with caution in patients with second- or third-degree atrioventricular block, as local anaesthetics may reduce myocardial conduction. Elderly patients and patients with liver disease, severe renal impairment, or poor general condition also require special attention, although regional anaesthesia may be the optimal choice for surgical procedures in such patients.

Patients receiving class III antiarrhythmic drugs (e.g., amiodarone) should be closely monitored. ECG monitoring should be considered, as the cardiac effects of these drugs may be additive.

Intrathe cal anaesthesia may lead to the development of arterial hypotension and bradycardia. The risk of these effects can be reduced, for example, by injecting vasopressor agents. Arterial hypotension should be promptly treated with intravenous sympathomimetics, which may need to be repeated as necessary. Severe arterial hypotension may occur due to hypovolemia from bleeding or dehydration, or aortocaval occlusion in patients with massive ascites, large intra-abdominal tumours, or in late pregnancy. Significant arterial hypotension should be avoided in patients with cardiac decompensation.

Sudden and severe arterial hypotension may develop during intrathecal anaesthesia in patients with hypovolemia from any cause.

A rare but serious adverse reaction following spinal anaesthesia is extensive or complete spinal block, leading to cardiovascular and respiratory depression. Cardiovascular depression caused by extensive sympathetic block may result in profound arterial hypotension and bradycardia or even cardiac arrest. Respiratory depression may be caused by blockade of nerves to respiratory muscles, including the diaphragm.

There is an increased risk of high or complete spinal block in elderly patients and in pregnant women in late pregnancy. Therefore, the dose of the drug should be reduced in these patients.

Intrathecal anaesthesia is generally considered not to adversely affect neurological disorders such as multiple sclerosis, hemiplegia, paraplegia, and neuromuscular disorders, but caution should be exercised. Before initiating treatment, it must be determined whether the expected benefit outweighs the potential risks to the patient.

Use during pregnancy or breastfeeding.

Pregnancy

There is no evidence of adverse effects of the drug on pregnancy. However, bupivacaine should not be used in early pregnancy except when the anticipated benefit to the mother outweighs the potential risk to the fetus.

The dose of the drug must be reduced in patients in late pregnancy.

Bupivacaine passes into breast milk in small amounts; therefore, the risk of effects on the infant following therapeutic doses of the drug is generally absent.

Ability to affect reaction speed when driving or operating machinery.

In addition to the direct anaesthetic effect, local anaesthetics may have a very mild effect on mental function and motor coordination, even in the absence of overt CNS toxicity, and may temporarily impair motor activity and alertness.

Administration and dosage.

Bupivacaine-Hyperbaric should be administered only by physicians experienced in regional anesthesia, or under their supervision, using the smallest possible doses that allow achieving an adequate level of anesthesia.

The recommended doses listed below should be considered as guidelines for administering the drug to adults; dosage should be individually adjusted for each patient.

The dose should be reduced for elderly patients and for patients in the later stages of pregnancy.

Table 1

The recommended injection site is below L3.

Currently, there is no clinical experience with doses exceeding 20 mg.

Spinal administration of the drug should be performed only after accurate 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 reduced 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

Bupivacaine-Hyperbar 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 requires administration of a relatively higher dose per kilogram of body weight to achieve the same level of block as in adults.

Regional anesthesia procedures in children should be performed by qualified physicians experienced in regional anesthesia techniques in pediatric patients and experienced in performing the specific anesthetic technique.

In pediatric practice, dosing should follow the recommendations provided in Table 2. Individual variability has been observed. Standard dosing recommendations should be considered when factors affecting specific block techniques are present, and to meet individual patient requirements.

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

Table 2

Dosing recommendations for neonates, infants, and children

The solution should be used as soon as possible after opening the ampoule. Any unused solution must be discarded.

Children.

Bupivacaine may be used in pediatric practice. For further information, see section "Posology and method of administration".

Overdose.

Acute systemic toxicity

Toxic effects on the central nervous and cardiovascular systems may occur when high doses of bupivacaine are administered, especially following accidental intravascular injection. However, a low dose is used in spinal anesthesia, making overdose unlikely.

When the drug is used concomitantly with other local anesthetics, systemic toxic reactions may occur, as toxic effects are additive.

Systemic adverse reactions are characterized by tongue numbness, dizziness, and tremor, followed by seizures and cardiovascular disturbances.

Treatment of acute systemic toxicity

In the event of total spinal block, adequate pulmonary ventilation should be ensured (airway patency, oxygen supply, intubation and artificial ventilation if required). 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 must be immediately discontinued. Treatment should focus on maintaining adequate pulmonary 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 is used; in case of bradycardia, atropine is administered. In the event 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), guided by hemodynamic monitoring in more severe cases, should be given. Ephedrine may also be used. Consideration should be given to intravenous administration of a 20% lipid emulsion.

In case of cardiac arrest, resuscitation measures may be required for several hours. Any acidosis should be corrected.

Adverse reactions.

The adverse reaction profile for bupivacaine hydrochloride is similar to that of other long-acting local anesthetics used for intrathecal anesthesia.

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

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

Neurological injury is a rare but well-recognized consequence of regional and, particularly, spinal anesthesia, which may be associated with a number of causes, such as direct trauma to the spinal cord or spinal nerves, anterior spinal artery syndrome (epidural hematoma), injection of irritating substances, or injection of non-sterile solution. This may result in the development of localized paresthesia or anesthesia, motor weakness, loss of sphincter control, or paraplegia. Occasionally, these impairments may be irreversible.

Reports of neurological complications of this type have been documented following the use of all local anesthetics for spinal anesthesia.

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

Adverse reactions are classified according to their frequency. Frequency is defined as follows: common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000).

Table 2

Children

Adverse reactions associated with the use of the drug in children are similar to those in adults. However, early signs of local anesthetic toxicity may be difficult to detect in children when the block is performed under sedation or general anesthesia.

Suspected adverse reactions reporting.

Reporting of suspected adverse reactions after drug registration is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.com.ua.

Shelf life.

2 years.

Storage conditions.

In the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibility. The addition of other substances to spinal solutions is not recommended.

Packaging.

4 ml in vials. 5 vials in a cassette. 1 cassette in a carton.

Prescription status. Prescription only.

Manufacturer. Public joint-stock company "Scientific and Production Center "Borshchahivskyy Chemical and Pharmaceutical Plant".

Manufacturer's address and location of its business activities.

17, Miru Street, Kyiv, 03134, Ukraine.