Bupivacaine-isobar

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BUPINECAINE-ISOBAR (BUPINECAINE-ISOBAR)

Composition:

Active substance: bupivacaine hydrochloride;

1 ml of solution contains bupivacaine hydrochloride 5 mg;

Excipients: sodium chloride; hydrochloric acid, 1 M solution, or sodium hydroxide (in the form of 1 M solution of 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.

Bupinecain-Isobar contains bupivacaine, a long-acting amide-type local anesthetic with anesthetic and analgesic effects. When high doses are administered, surgical anesthesia is achieved, whereas lower doses result in sensory blockade (analgesia) accompanied by less pronounced motor blockade. The onset and duration of local anesthetic effect depend on the dose and 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, 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 model: the initial half-life is 7 minutes, and the subsequent half-life 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 compared to intravenous administration.

The volume of distribution at steady state is approximately 73 L, hepatic extraction ratio is approximately 0.4, total plasma clearance is 0.58 L/min, and 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 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-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 via N-dealkylation to pipecoloxylidine (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 the pregnant woman and the fetus. However, total plasma concentration is lower in the fetus due to lower plasma protein binding.

Clinical characteristics.

Indications.

Bupinecaine-isobar, 0.5% solution, is used to perform local anesthesia by means of percutaneous infiltration, peripheral nerve block(s), and central neural block (caudal or epidural), i.e., it is administered by a specialist in situations where prolonged anesthesia is required. Since sensory nerve block is more pronounced than motor block, Bupinecaine-isobar is particularly effective in relieving pain, for example, during childbirth.

Contraindications.

• Hypersensitivity to the active substance or to other components of the medicinal product, or to amide-type local anesthetics.
• Intravenous regional anesthesia (Bier block).
• Epidural anesthesia in patients with marked arterial hypotension, e.g., in cases of cardiogenic or hypovolemic shock.

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

• Diseases of the nervous system in the active stage, 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 tuberculosis;
• Purulent infection of the skin at or near the site intended for 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 studies on interactions between local anesthetics and class III antiarrhythmics (e.g., amiodarone) have not been conducted; therefore, caution should be exercised when these agents are used concomitantly.

Special precautions for use.

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

Cases of cardiac arrest and fatal outcomes have been reported with the use of bupivacaine for epidural anesthesia or peripheral nerve block. In the event of cardiac arrest, prolonged resuscitation efforts may be required to achieve a successful outcome. Sometimes resuscitation has been complicated or impossible despite adequate preparation and appropriate therapy.

Like all local anesthetics, bupivacaine may cause acute toxic effects on the central nervous and cardiovascular systems when high plasma concentrations of the drug are reached. This is particularly likely following accidental intravascular injection or injection into highly vascularized areas. Cases of ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse, and fatal outcomes have been reported in association with high systemic concentrations of bupivacaine.

Procedures involving regional or local anesthetics should always be performed with appropriate resuscitation equipment available. The responsible physician must take necessary safety precautions to avoid intravascular injection (see section "Method of administration and dosage"). Intravenous access should be established prior to performing any nerve blocks to allow for possible resuscitation. Physicians should have specialized training in performing these procedures and be familiar with the diagnosis and management of adverse effects, systemic toxicity, and other complications.

Large peripheral nerve blocks may require large volumes of local anesthetic administered in highly vascularized areas, often near major blood vessels, where there is an increased risk of accidental intravascular injection and/or systemic absorption of the anesthetic. This may lead to high plasma concentrations of the anesthetic.

Overdose or accidental intravenous injection may cause toxic reactions (see sections "Overdose" and "Adverse reactions").

Repeated injections of bupivacaine hydrochloride may lead to a significant increase in its blood concentration with each subsequent dose due to gradual accumulation of the drug. Tolerance to elevated plasma levels of the anesthetic depends on the patient's physical condition.

Although regional anesthesia is often the optimal method of anesthesia, certain patient groups require special attention to reduce the risk of serious adverse effects:

• Patients receiving class III antiarrhythmic agents (e.g., amiodarone) should be under close observation and ECG monitoring, as the likelihood of additive negative cardiac effects increases;
• Elderly and debilitated patients should receive lower doses according to their physical condition;
• Patients with conduction disturbances, partial or complete heart block, as local anesthetics may depress myocardial conduction;
• Patients with progressive liver disease or severe renal impairment;
• Patients in late pregnancy.

Patients with allergy to ester-type local anesthetics (e.g., procaine, tetracaine, benzocaine) have not shown cross-sensitivity to amide-type local anesthetics such as bupivacaine.

Some types of local anesthesia may be associated with serious adverse reactions regardless of the local anesthetic used.

• Local anesthetics should be used with caution for epidural anesthesia in patients with cardiovascular dysfunction, especially in cases of concomitant hypovolemia, as the ability to compensate for functional changes caused by these drugs (e.g., prolonged AV conduction) may be reduced.
• Physiological effects due to central nervous blockade are more pronounced in the presence of arterial hypotension. In patients with hypovolemia from any cause, sudden and severe arterial hypotension may develop during epidural anesthesia. Therefore, epidural anesthesia should be avoided or used with caution in patients with untreated hypovolemia or significant impairment of venous return.
• In retrobulbar injections, the drug may very rarely reach the cranial subarachnoid space, causing temporary blindness, apnea, seizures, cardiovascular collapse, and other adverse effects. These complications must be promptly diagnosed and treated.
• Retrobulbar and peribulbar administration of local anesthetics carries a certain risk of persistent ocular muscle dysfunction. The main causes may include traumatic injury and/or local toxic effects on muscles and/or nerve fibers. The severity of such reactions depends on the extent of trauma, the concentration of the local anesthetic, and the duration of its tissue exposure. Therefore, as with all local anesthetics, the lowest effective concentration and dose should be used.
• Vasoconstrictors may enhance adverse tissue reactions and should be used only when indicated.
• When performing blocks in the head or neck area, including retrobulbar, dental blocks, and stellate ganglion block, accidental intra-arterial injection of local anesthetics—even in low doses—may lead to systemic toxicity and severe cerebral symptoms.
• Paracervical block may have a more unfavorable effect on the fetus than other nerve blocks used in obstetrics. Paracervical block may occasionally cause bradycardia or tachycardia in the fetus; therefore, fetal heart rate should be carefully monitored. Due to the systemic toxicity of bupivacaine, particular caution should be exercised when using bupivacaine for paracervical block.
• In the post-marketing period, cases of chondrolysis have been reported in patients who received prolonged intra-articular infusions of local anesthetics after surgical procedures. Most reported cases of chondrolysis were associated with the shoulder joint. Due to numerous contributing 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 bupivacaine.

Epidural anesthesia with any local anesthetic may lead to decreased arterial pressure and bradycardia, which should be anticipated and appropriate preventive measures taken. The risk of such outcomes can be reduced, for example, by pre-administration of intravenous crystalloid or colloid solutions. Decreased arterial pressure should be corrected immediately by intravenous administration of a sympathomimetic agent, such as ephedrine 5–10 mg, repeated as necessary. Severe arterial hypotension may result from hypovolemia due to bleeding or dehydration, or from aorto-caval compression in patients with massive ascites, large intra-abdominal tumors, or in late pregnancy. Significant arterial hypotension should be avoided in patients with heart failure.

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

Epidural anesthesia may cause paralysis of intercostal muscles, and in patients with pleural effusion, respiratory insufficiency may occur.

In patients with sepsis, the risk of intraspinal abscess formation is increased, especially in the postoperative period. Sepsis is a contraindication for epidural anesthesia.

When performing intra-articular injection with bupivacaine, caution is advised in suspected recent major intra-articular trauma or in the presence of large open joint surfaces created during surgical procedures, as this may accelerate absorption and lead to higher plasma concentrations of bupivacaine.

After repeated injections or prolonged infusions of bupivacaine, liver function disturbances have been observed, including reversible increases in alanine aminotransferase (ALT), alkaline phosphatase, and bilirubin levels. Only a limited number of reports have been received regarding a possible association between bupivacaine use, particularly prolonged use, and drug-induced liver injury. Although the pathophysiology of this reaction remains unclear, immediate discontinuation of bupivacaine has resulted in rapid clinical improvement. If signs of liver dysfunction are observed, the drug should be discontinued.

Use during pregnancy or breastfeeding.

There is no evidence of adverse effects on pregnancy, but bupivacaine should not be used in 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. These effects may be related to high concentrations of anesthetic reaching the fetus (see section "Special precautions for use").

Bupivacaine passes into breast milk, but in such small amounts that the risk of affecting the infant when the drug is used at therapeutic doses is negligible.

Ability to affect reaction speed when driving or operating machinery.

Bupivacaine has a minor influence on the ability to drive vehicles or operate machinery. In addition to the direct anesthetic effect, local anesthetics may cause very slight effects on mental function and motor coordination, even in the absence of overt CNS toxicity, and may temporarily impair motor activity and attention.

Method of Administration and Dosage

Bupivacaine must be administered by physicians experienced in regional anesthesia, or the administration should be performed under the supervision of such a physician. The lowest effective doses required to achieve adequate anesthesia should always be used.

Extreme caution must be exercised to avoid accidental intravascular injection. Aspiration should be performed before administering the main dose and repeated during administration. The main dose should be injected slowly at a rate of 25–50 mg/min or in divided doses, maintaining constant verbal contact with the patient and monitoring heart rhythm.

For epidural administration, a test dose of 3–5 mL of bupivacaine with adrenaline should be administered first, as accidental intravascular injection may be recognized by a transient increase in heart rate, and accidental intrathecal injection by signs of spinal block. If symptoms of intoxication occur, administration of the drug must be stopped immediately.

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

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

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

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

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

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 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, i.e., 30 mL of Bupinecaine-Isobar 5 mg/mL (150 mg bupivacaine hydrochloride).

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

Bupinecaine-Isobar should not be used in children.

Overdose

Accidental intravascular injection of local anesthetics may cause immediate (within seconds to minutes) systemic toxic reactions. In cases of overdose, signs of systemic toxicity appear later (15–60 minutes after injection) due to the slower rise in plasma concentration of the local anesthetic.

Symptoms

Systemic toxic reactions primarily affect the central nervous system (CNS) and the cardiovascular system, and are caused by high plasma concentrations of local anesthetics due to accidental intravascular injection, overdose, or exceptionally rapid absorption from highly vascularized areas.

CNS reactions are similar for all amide-type local anesthetics, whereas cardiovascular reactions depend more on the specific drug, both quantitatively and qualitatively.

CNS toxicity develops progressively, with increasing severity of symptoms and reactions. Initial symptoms usually include mild dizziness, perioral paresthesia, tongue numbness, hyperacusis, tinnitus, and visual disturbances. Dysarthria and muscle twitching/tremor are more serious signs that precede generalized seizures. These signs should not be interpreted as neurotic behavior. Further progression may lead to loss of consciousness and generalized tonic-clonic seizures, lasting from several seconds to several minutes. During seizures, hypoxia and hypercapnia develop rapidly due to increased muscular activity combined with impaired respiration and inadequate pulmonary gas exchange. In severe cases, apnea may occur. Acidosis, hyperkalemia, and hypoxia enhance and prolong the toxic effects of local anesthetics.

Recovery occurs due to redistribution of the drug from the CNS, followed by further metabolism and excretion. Recovery may be rapid, except in cases of large-dose administration.

Cardiovascular toxic reactions may occur in severe cases and are usually preceded by signs of CNS toxicity. In patients under general anesthesia or deep sedation with benzodiazepines or barbiturates, prodromal CNS symptoms may be absent.

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.

Arterial hypotension, bradycardia, arrhythmias, and even cardiac arrest may result from high systemic concentrations of local anesthetics in the blood. However, in very rare cases, cardiac arrest has occurred without preceding CNS symptoms. Therefore, myocardial depression may develop even as the first sign of intoxication, without prior CNS effects.

Treatment

If signs of acute systemic toxicity occur, administration of the local anesthetic must be stopped immediately.

Management of a patient with systemic toxicity involves seizure control and ensuring adequate pulmonary ventilation with oxygen; if necessary, assisted or controlled mechanical ventilation should be initiated.

If seizures occur, they should be treated immediately with intravenous administration of 1–3 mg/kg sodium thiopental or 0.1 mg/kg diazepam (the latter acts significantly slower). Prolonged seizures threaten the patient’s respiration and oxygenation. Injection of a muscle relaxant (e.g., succinylcholine 1 mg/kg) facilitates ventilation and creates better conditions for oxygenation control. In such situations, early endotracheal intubation and mechanical ventilation should be considered.

After seizures have ceased and adequate ventilation is ensured, further treatment is usually not required. However, if arterial hypotension is present, an intravenous vasopressor with inotropic activity should be administered, preferably ephedrine at a dose of 15–30 mg.

In the event of circulatory arrest, cardiopulmonary resuscitation must be initiated immediately. Maintaining optimal oxygenation, ventilation, circulation, and correcting acidosis are life-saving measures.

If cardiovascular depression (arterial hypotension, bradycardia) develops, appropriate treatment with intravenous fluids, vasopressors, inotropic agents, and/or lipid emulsion should be considered.

Cardiac arrest caused by bupivacaine may be resistant to electrical defibrillation and may require prolonged resuscitation efforts.

High or total spinal block during epidural anesthesia, leading to respiratory paralysis and arterial hypotension, should be treated by ensuring and maintaining airway patency, and providing adequate pulmonary ventilation with oxygen via assisted or controlled mechanical ventilation.

Adverse reactions.

Accidental subarachnoid injection of the drug may lead to very high spinal anaesthesia, possibly resulting in apnoea and severe arterial hypotension.

The adverse reaction profile of bupivacaine hydrochloride is similar to that of other long-acting local anaesthetics.

Adverse reactions caused by the drug itself may be difficult to distinguish from the physiological effects of nerve blockade (e.g. decreased blood pressure, bradycardia), from events directly caused by puncture (e.g. nerve injury), or indirectly related to puncture (e.g. epidural abscess).

Neurological injuries are rare but well-recognized consequences of regional, particularly epidural and spinal, anaesthesia, 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), administration of irritant substances (chemical injury due to preservatives (metabisulfite), detergents), or loss of sterility during the procedure. This may lead to the development of localized paraesthesia or anaesthesia, motor weakness, loss of sphincter control, or paraplegia. Sometimes these impairments may be permanent.

Immune system.

• Allergic reactions, anaphylactic reactions/anaphylactic shock.

Nervous system.

• Paraesthesia, dizziness;
• CNS toxicity symptoms (seizures, perioral paraesthesia, tongue numbness, hyperacusis, visual disturbances, loss of consciousness, tremor, dizziness, tinnitus, dysarthria);
• neuropathy, peripheral nerve injury, arachnoiditis, paresis, and paraplegia.

Eyes.

• Diplopia.

Cardiovascular system.

• Arterial hypotension;
• bradycardia, arterial hypertension;
• cardiac arrest, cardiac arrhythmias.

Respiratory system.

• Respiratory depression.

Gastrointestinal tract.

• Nausea;
• vomiting.

Urinary system.

• Urinary retention.

Hepatic dysfunction with reversible increases in AST, ALT, alkaline phosphatase, and bilirubin has been observed following repeated injections or prolonged infusions of bupivacaine. If signs of hepatic dysfunction occur, the drug should be discontinued.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization 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 via the national reporting system.

Shelf life.

2 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.

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

Packaging.

5 ml in ampoules. 5 ampoules in a blister. 2 blisters in a carton.

Prescription status. Prescription only.

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

Manufacturer's location and address of its place of business.

17 Myru Street, Kyiv, 03134, Ukraine.