Bupivacaine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BUPIVACAINE

Composition:

Active substance: bupivacaine hydrochloride;

1 ml of solution contains 5 mg of bupivacaine hydrochloride;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Local anesthetics. ATC code N01BB01.

Pharmacological properties.

Pharmacodynamics.

Bupivacaine hydrochloride is 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 of bupivacaine depend on the dose and site of administration.

Like other local anesthetics, bupivacaine reversibly blocks impulse conduction in nerve fibers by inhibiting sodium ion transport across nerve fiber cell membranes. Sodium channels in nerve membranes contain receptors for binding local anesthetic molecules.

Local anesthetics may exert similar effects on other excitable membranes, for example, in the brain and myocardium. When excessive amounts of the drug reach the systemic circulation, symptoms and signs of toxicity originating from the central nervous and cardiovascular systems may occur.

Signs of developing toxicity on the central nervous system (CNS) (see section "Adverse reactions") usually precede cardiovascular effects, as CNS toxicity signs occur at lower plasma drug concentrations. Direct cardiac effects of local anesthetics include slowed conduction, negative inotropism, and ultimately cardiac arrest.

Indirect cardiovascular effects (arterial hypotension, bradycardia) may develop after epidural blockade, depending on the degree of accompanying sympathetic blockade.

Pharmacokinetics.

The pKa of bupivacaine is 8.2, and the partition coefficient is 346 (25 °C n-octanol/phosphate buffer at pH 7.4). Metabolites possess pharmacological activity, but less than that of bupivacaine.

The plasma concentration of bupivacaine depends on the dose, route of administration, and vascularity of the injection site.

Bupivacaine shows complete and biphasic absorption from the epidural space, with half-lives of approximately 7 minutes and 6 hours, respectively. Slow absorption is a rate-limiting factor in the elimination of bupivacaine and explains why the apparent terminal half-life after epidural administration is longer than after intravenous administration.

The total plasma clearance of bupivacaine is 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 0.38 after intravenous administration. Bupivacaine is primarily bound in plasma to alpha-1-acid glycoprotein, with the bound fraction accounting for 96%. The clearance of bupivacaine is almost entirely dependent on hepatic metabolism and is more sensitive to changes in intrinsic hepatic enzyme activity than to hepatic perfusion.

Pediatric population

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

An increase in total plasma drug concentration has been observed during prolonged epidural infusion. This is associated with postoperative elevation of alpha-1-acid glycoprotein levels. The concentration of unbound (i.e., pharmacologically active) drug is similar before and after surgery.

Bupivacaine readily crosses the placenta and rapidly reaches equilibrium in terms of unbound drug concentration. The extent of plasma protein binding in the fetus is lower than in the mother, resulting in lower total drug concentrations in fetal plasma.

Bupivacaine is extensively metabolized in the liver, primarily via aromatic hydroxylation to 4-hydroxybupivacaine and N-dealkylation to PPX, both pathways being 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 infusion remain low compared to the concentration of the parent drug.

Clinical characteristics.

Indications.

Bupivacaine is used for local anaesthesia by cutaneous infiltration, peripheral nerve block(s), and central neural block (caudal or epidural), i.e., it is administered by a specialist in situations where prolonged anaesthesia is required. Since sensory nerve block is more pronounced than motor block, bupivacaine is particularly effective for pain relief, for example during labour.

Contraindications.

Hypersensitivity to amide-type local anaesthetics or to any of the excipients. Bupivacaine is not used for intravenous regional anaesthesia (Bier block). Bupivacaine is not used for epidural anaesthesia in patients with marked arterial hypotension, such as in cardiogenic or hypovolemic shock. Epidural anaesthesia, regardless of the local anaesthetic used, has its own contraindications, which include:

• active neurological diseases: meningitis, poliomyelitis, intracranial haemorrhage, subacute combined degeneration of the spinal cord due to pernicious anaemia, and tumours of the brain and spinal cord;
• spinal tuberculosis;
• skin abscess or other purulent 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.

Because systemic toxic effects are additive, bupivacaine should be used with caution in patients receiving other local anaesthetics or drugs structurally related to amide-type local anaesthetics, such as certain antiarrhythmic agents (e.g., lidocaine and mexiletine). Specific interaction studies between bupivacaine and class III antiarrhythmic agents (e.g., amiodarone) have not been conducted, but caution is recommended in such cases (see section "Special precautions for use").

Acute systemic toxicity

Systemic toxic reactions primarily involve the CNS and cardiovascular system. These reactions are caused by high concentrations of local anaesthetics in the blood, which may result from (accidental) intravascular injection, overdose, or extremely rapid absorption from highly vascularized areas (see section "Special precautions for use"). CNS reactions are similar for all amide-type local anaesthetics, whereas cardiovascular reactions depend more on the type of agent, both quantitatively and qualitatively.

Central nervous system (CNS) toxicity manifests as a progressive sequence of signs and symptoms with increasing severity. Initial symptoms include mild dizziness, perioral paraesthesia, tongue numbness, hyperacusis, tinnitus, and visual disturbances. Dysarthria, muscle rigidity, and tremor are more serious symptoms and may precede the onset of generalized seizures. These signs should not be mistaken for neurotic behaviour. This may be followed by loss of consciousness and a major epileptic seizure lasting from several seconds to several minutes. During seizures, increased muscular activity rapidly leads to hypoxia and hypercapnia, accompanied by respiratory impairment and possible worsening of airway function. In severe cases, apnoea may develop. The development of acidosis, hyperkalaemia, and oxygen deficiency increases and prolongs the toxic effects of local anaesthetics.

Recovery occurs due to redistribution of the local anaesthetic away from the CNS, followed by metabolism and excretion. Recovery may be rapid, except when large doses of the drug have been administered.

In severe cases, cardiovascular toxicity may occur. Typically, cardiovascular toxicity is preceded by signs of CNS toxicity. Prodromal CNS symptoms may not occur in patients under the influence of strong sedatives or receiving general anaesthesia. High systemic concentrations of local anaesthetics may lead to arterial hypotension, bradycardia, arrhythmia, and even cardiac arrest; however, in rare cases, cardiac arrest has occurred without preceding CNS effects.

Treatment of acute toxicity

When signs of acute systemic toxicity occur, administration of the local anaesthetic should be immediately discontinued.

Management of a patient showing signs of systemic toxicity should focus on rapid termination of seizures and ensuring adequate ventilation with oxygen supplementation, as needed, to assist or control lung ventilation.

Once seizures are controlled and adequate lung ventilation is ensured, further treatment is usually not required.

In case of cardiovascular depression (arterial hypotension, bradycardia), appropriate treatment should be considered, including intravenous fluids, vasopressors, inotropes, and/or lipid emulsion. When treating toxicity symptoms in children, age- and body weight-appropriate doses should be used.

In case of circulatory arrest, cardiopulmonary resuscitation should be initiated immediately. Maintaining adequate oxygenation, lung ventilation, and circulation, as well as treating acidosis, are life-saving measures.

Cardiac arrest caused by bupivacaine may be resistant to electrical defibrillation; therefore, resuscitation efforts must be actively continued for a prolonged period.

Manifestations of extensive or complete spinal block leading to respiratory paralysis and arterial hypotension during epidural anaesthesia should be managed by ensuring and maintaining airway patency, and oxygen should be administered to assist or control lung ventilation.

Special precautions for use

There have been reports of cardiac arrest associated with the use of bupivacaine for epidural anesthesia or peripheral nerve block. In some cases, resuscitation was complicated and required prolonged resuscitative efforts before a positive response was achieved. In certain instances, resuscitation failed despite apparently adequate preparation and appropriate therapy.

Like all local anesthetics, bupivacaine may cause acute toxic effects on the central nervous and cardiovascular systems when used for local anesthesia in such a way that high plasma concentrations are achieved. This is particularly relevant in cases following 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.

Appropriate resuscitation equipment must always be readily available when performing local or general anesthesia. The responsible physician must take necessary precautions to avoid intravascular injection (see section "Dosage and administration"). Prior to initiating any nerve block procedure, intravenous access for administration of resuscitation medications must be secured. Physicians performing these procedures must have adequate and appropriate training and must be familiar with the diagnosis and management of adverse effects, systemic toxicity, and other complications (see sections "Overdose" and "Side effects").

Blocking large peripheral nerves may require large volumes of local anesthetic administered in highly vascularized areas, often near major blood vessels, increasing the risk of intravascular injection and/or systemic absorption. This may lead to high plasma concentrations of the drug.

Overdose or accidental intravenous injection may result in toxic reactions.

Due to the slow accumulation of bupivacaine hydrochloride, repeated doses may lead to a significant increase in blood levels with each subsequent dose. Drug tolerance varies depending on the patient's condition.

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

• Elderly patients and those with compromised general health require dose reduction commensurate with their physical status.
• Patients with partial or complete heart block – because local anesthetics may depress myocardial conduction.
• Patients with progressive liver disease or severe renal dysfunction.
• Patients in late stages of pregnancy.
• Patients receiving Class III antiarrhythmic agents (e.g., amiodarone) should be closely monitored, including ECG monitoring, as the cardiac effects of these drugs may be additive.

Patients with allergic reactions to ester-type local anesthetics (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to amide-type agents such as bupivacaine.

Some procedures involving local anesthesia may lead to serious adverse reactions, regardless of the type of local anesthetic used.

• Local anesthetics should be used with caution for epidural anesthesia in patients with impaired cardiovascular function, as such patients have limited ability to compensate for functional changes related to prolonged atrioventricular conduction caused by these drugs.
• Physiological effects resulting from central neural blockade are more pronounced in the presence of arterial hypotension. Sudden and severe arterial hypotension may develop during epidural anesthesia in patients with hypovolemia from any cause. Therefore, epidural anesthesia should be avoided or used with caution in patients with untreated hypovolemia or significant impairment of venous return.
• In very rare cases, retrobulbar injections may reach the intracranial subarachnoid space and cause transient blindness, cardiovascular collapse, apnea, and seizures.
• Retro- and peribulbar injections of local anesthetics may pose a risk of persistent dysfunction of the extraocular muscles. The main causes include traumatic nerve injury and/or local toxic effects of the anesthetic on muscles and nerves. The severity of tissue reactions depends on the degree of trauma, concentration of the local anesthetic, and duration of tissue exposure. Therefore, as with all local anesthetics, the lowest effective concentration and dose should be used.
• Vasoconstrictors may potentiate tissue reactions and should be used only when indicated.
• Accidental intra-arterial injection of low doses of local anesthetics in the head and neck region, including retrobulbar, dental blocks, and stellate ganglion block, may lead to systemic toxicity.
• Paracervical block may have a greater adverse effect on the fetus than other types of regional anesthesia used in obstetrics. Due to the systemic toxicity of bupivacaine, particular caution is advised when using bupivacaine for paracervical block.
• Cases of chondrolysis have been reported in patients who received prolonged intra-articular infusions of local anesthetics in the postoperative period. In most cases, chondrolysis involved the shoulder joint.

Due to multiple contributing factors and conflicting scientific data on the mechanism of action, a causal relationship has not been established. Prolonged intra-articular infusion is not an approved indication for this drug.

Epidural anesthesia with any local anesthetic may lead to arterial hypotension and bradycardia. These effects should be anticipated, and appropriate preventive measures taken, which may include preloading with crystalloid or colloid solutions. If hypotension occurs, a vasoconstrictor such as ephedrine should be administered intravenously at a dose of 10–15 mg. Severe arterial hypotension may result from hypovolemia due to bleeding or dehydration, or from aortocaval compression in patients with massive ascites, large intra-abdominal tumors, or in late pregnancy. Significant hypotension should be avoided in patients with cardiac decompensation.

Epidural anesthesia in patients with hypovolemia from any cause may lead to sudden and severe arterial hypotension.

Epidural anesthesia may paralyze intercostal muscles, and patients with pleural effusion may develop respiratory insufficiency. Sepsis may increase the risk of intraspinal abscess formation in the postoperative period.

When administering bupivacaine via intra-articular injection, caution is advised in cases of suspected recent extensive intra-articular trauma or when extensive open joint surfaces are present due to surgical procedures, as this may accelerate absorption and lead to elevated plasma concentrations.

Use during pregnancy or breastfeeding

There is no evidence of adverse effects on pregnancy in humans, but bupivacaine should not be used during early pregnancy except when the potential benefit outweighs the risk.

Adverse effects on the fetus due to local anesthesia, such as fetal bradycardia, have been most clearly observed following paracervical block. These effects may be due to high concentrations of anesthetic reaching the fetus (see section "Special precautions for use").

When used in therapeutic doses, bupivacaine passes into breast milk in such small amounts that there is no risk of affecting the infant.

Effect on ability to drive or operate machinery

Bupivacaine has minimal effect on the ability to drive or operate machinery. Besides the direct effects of anesthesia, local anesthetics may have a very slight effect on mental function and motor coordination, even in the absence of overt CNS toxicity, and may cause temporary impairment of motor activity and attention.

Administration and Dosage

Dosage

Adults

Table 1 provides guidance on dosage of the drug in average-aged adults using the most commonly employed blockade techniques. The figures indicate the expected range of average acceptable doses of the drug. Standard textbooks should be consulted when factors affecting specific blockade techniques are present, and to meet individual patient requirements.

Note: When performing prolonged blocks, either via continuous infusion or repeated bolus administration, consider the risk of achieving toxic plasma concentrations of the drug or the risk of local nerve injury.

The physician's experience and patient's physical condition are important factors in determining the required dose of the drug. The lowest doses sufficient to achieve adequate anesthesia should be used. Individual variability has been observed both at the onset and during anesthesia.

Table 1

Recommended dosage guidelines for adults

1. The dose includes the studied dose.
2. The dose for blockade of large nerves should be adjusted according to the site of administration and the patient's condition. Increased frequency of serious adverse reactions may occur with intercostal and supraclavicular brachial plexus blocks, regardless of the type of local anesthetic used (see also section "Special precautions").

In general, higher concentrations and doses of the drug are required for surgical anesthesia (e.g., for epidural administration). When less intensive blockade is required (e.g., for labor pain relief), lower concentrations of the drug are indicated. The volume of the administered drug will influence the extent of anesthesia spread.

To avoid intravascular injection, aspiration should be performed before and repeated during administration of the total dose, which should be administered slowly or in divided doses at a rate of 25–50 mg/min, with continuous careful monitoring of vital functions and maintenance of verbal contact with the patient. Accidental intravascular injection may be detected by transient increase in heart rate, and accidental intrathecal injection by signs of spinal block. If symptoms of intoxication occur, administration of the drug should be immediately discontinued (see section "Adverse reactions"). When bupivacaine is used with any other techniques in the same patient, the dosage should not exceed 150 mg.

Available experience to date indicates that a dose of 400 mg administered over 24 hours is well tolerated in a healthy adult.

Handling the ampoule

1. Detach one ampoule from the pack and shake it by holding the neck (Fig. 1).
2. Squeeze the ampoule in the hand (no leakage of the solution should occur) and twist to break off the top (Fig. 2).
3. Immediately connect the syringe to the ampoule through the opening formed (Fig. 3).
4. Invert the ampoule and slowly draw the contents into the syringe (Fig. 4).
5. Attach the needle to the syringe.

Fig. 1     Fig. 2     Fig. 3     Fig. 4

Children

Bupivacaine is not indicated for use in children.

Overdose

Accidental intravascular injections of local anesthetics may cause immediate (within seconds to minutes) systemic toxic reactions. In cases of overdose, systemic toxicity appears later (15–60 minutes after injection) due to slower rise in blood concentration of the local anesthetic (see section "Adverse reactions").

Adverse reactions.

Accidental intrathecal administration of the drug may lead to the development of a very high degree of spinal anesthesia, possibly resulting in apnea and severe arterial hypotension.

The adverse reaction profile of Bupivacaine is similar to that of other long-acting local anesthetics. Adverse reactions caused directly by the drug are difficult to distinguish from the physiological effects of nerve fiber blockade (e.g., decreased blood pressure, bradycardia), as well as from phenomena caused directly (e.g., nerve trauma) or indirectly (e.g., epidural abscess) by needle puncture.

Neurological injuries are rare but well-known consequences of regional, particularly epidural and spinal, anesthesia. These may be associated with several causes, such as direct trauma 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 paresthesia or anesthesia in localized areas, motor weakness, loss of sphincter control, and paraplegia. Sometimes these effects are long-lasting.

Adverse reactions are listed below by system organ classes and absolute frequency. Frequency is defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), and frequency not known (cannot be estimated from available data).

Table 2

Adverse reactions occurring during administration of the drug

After repeated injections or long-term infusions of bupivacaine, cases of hepatic dysfunction have been reported, with reversible increases in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin levels. If signs of hepatic dysfunction occur during treatment with bupivacaine, the drug should be discontinued.

Reporting of suspected adverse reactions

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

Shelf life. 2.5 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, 10 ml in polyethylene ampoules, pack of 10.

Prescription status. Prescription only.

Manufacturer.

LLC "FARMASEL".

Manufacturer's address and location of business operations.

3, Prorizna Street, Kvitneve, Brovary District, Kyiv Oblast, 07408, Ukraine.