Longocaine®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LONOGAINE® (LONGOCAIN®)

Composition:

active substance: bupivacaine;

1 ml of solution contains bupivacaine hydrochloride (as bupivacaine hydrochloride monohydrate) 5 mg;

excipients: sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly yellowish solution.

Pharmacotherapeutic group. Local anesthetics. Amides. Bupivacaine.

ATC code N01B B01.

Pharmacological Properties

Pharmacodynamics

Longocaine® contains bupivacaine hydrochloride – 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 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 membranes. Sodium channels in nerve membranes contain receptors for binding local anesthetic molecules.

Similar effects may also occur on excitable membranes of 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 appear. Signs of central nervous system toxicity (see section "Adverse Reactions") typically precede cardiovascular effects, as central nervous system toxicity occurs at lower plasma concentrations of the drug. Direct cardiac effects of local anesthetics include slowed conduction, negative inotropy, and ultimately cardiac arrest.

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

Pharmacokinetics

The pKa of bupivacaine is 8.2, and its partition coefficient is 346 (25°C n-octanol/phosphate buffer at pH 7.4). The metabolites have pharmacological activity lower than that of bupivacaine.

Plasma concentrations of bupivacaine depend on the dose, route of administration, and vascularity of the injection site.

Bupivacaine is completely absorbed from the epidural space, followed by a biphasic elimination pattern: the initial half-life is 7 minutes, and the subsequent phase is 6 hours. Slow absorption is the rate-limiting factor for bupivacaine elimination and explains why the apparent terminal half-life is longer after epidural administration than after intravenous injection.

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. Plasma protein binding is approximately 96%, primarily to α1-acid glycoprotein. Bupivacaine clearance 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.

Increased total plasma concentrations of the drug have been observed during prolonged epidural infusions. This is associated with postoperative increases in α1-acid glycoprotein levels. However, the concentration of unbound (i.e., pharmacologically active) drug is similar before and after surgery.

Bupivacaine crosses the placental barrier and rapidly reaches equilibrium regarding unbound drug concentration. However, total plasma drug concentration is lower in the fetus than in the mother due to the fetus’s lower plasma protein binding capacity.

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

Clinical characteristics.

Indications.

Longocaine®, 0.5% solution, is indicated for local anaesthesia by transcutaneous infiltration, peripheral nerve block(s), and central neural block (caudal or epidural), i.e., it is used by a specialist when prolonged anaesthesia is required. Since sensory nerve block is more pronounced than motor block, Longocaine® is particularly effective in relieving pain, for example, during childbirth.

Contraindications.

Hypersensitivity to amide-type local anaesthetics or to any of the excipients of the medicinal product.

Bupivacaine should not be used for intravenous regional anaesthesia (Bier block).

Bupivacaine should not be used for epidural anaesthesia in patients with severe 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 such as 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; purulent skin 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.

Caution should be exercised when administering bupivacaine together with other local anaesthetics or medicinal products structurally similar to amide-type local anaesthetics, such as certain antiarrhythmic agents (e.g., lidocaine and mexiletine), since systemic toxic effects are additive.

Specific interaction studies between bupivacaine and Class III antiarrhythmic agents (e.g., amiodarone) have not been conducted; however, caution is recommended in such cases (see section "Special warnings and precautions for use").

Acute systemic toxicity

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

Toxic effects on the central nervous system manifest as a stepwise reaction, with symptoms and signs increasing in severity. Initial symptoms include mild dizziness, circumoral paraesthesia, tongue numbness, hyperacusis, tinnitus, and visual disturbances. Dysarthria, muscle rigidity, and tremor are more serious symptoms and may precede generalized seizures. These signs should not be mistaken for neurotic behaviour. Subsequently, loss of consciousness and grand mal epileptic seizures may occur, lasting from several seconds to several minutes. During seizures, increased muscular activity rapidly leads to hypoxia and hypercapnia, along with 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 central nervous system, followed by metabolism and excretion. Recovery may be rapid, except in cases where large amounts of the medicinal product have been administered.

In severe cases, toxic effects on the cardiovascular system may occur, and cardiovascular toxicity is generally preceded by signs of central nervous system 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 been observed without preceding CNS effects.

Treatment of acute toxicity

If signs of acute systemic toxicity occur, administration of the local anaesthetic must be immediately discontinued.

Management of a patient exhibiting signs of systemic toxicity should focus on rapidly terminating seizures and ensuring adequate ventilation, with oxygen supplementation as needed, to facilitate or control pulmonary ventilation.

Once seizures are controlled and adequate pulmonary ventilation is ensured, additional treatment is usually not required.

In case of cardiovascular depression (arterial hypotension, bradycardia), appropriate treatment should be considered, including intravenous fluid administration, 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, immediate initiation of cardiopulmonary resuscitation measures is essential. Maintaining adequate oxygenation, pulmonary ventilation, circulation, and treatment of acidosis are critically important.

Cardiac arrest caused by bupivacaine may be resistant to electrical defibrillation; therefore, resuscitation efforts must be actively continued for an extended 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 facilitate or control pulmonary ventilation.

Special precautions for use

There have been reports of cardiac arrest associated with the use of bupivacaine for epidural anesthesia or peripheral nerve blocks. In some cases, resuscitation was complicated and prolonged resuscitative measures were required before a positive response from the patient was achieved. Nevertheless, in some 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 its administration for local anesthesia results in high plasma concentrations. This is particularly relevant in cases of 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 available whenever local or general anesthesia is administered. The responsible physician must take necessary precautions to avoid intravascular injection (see section "Method of administration and dosage"). Prior to initiating any nerve block procedure, intravenous access must be established to allow administration of medications required for resuscitation. Physicians must have appropriate and sufficient training in performing the procedure and must be familiar with the diagnosis and management of adverse effects, systemic toxicity, or other complications (see sections "Overdose" and "Adverse reactions").

Blocks of large peripheral nerves may require large volumes of local anesthetic administered in highly vascularized areas, often near major blood vessels, where the risk of intravascular injection and/or systemic absorption is increased. 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 plasma levels with each subsequent dose. The drug's tolerability 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 reduced doses proportionate to their physical condition;
• 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 by medical staff, and ECG monitoring is recommended, 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.

• Caution should be exercised when using local anesthetics for epidural anesthesia in patients with cardiovascular impairment, as such patients have a reduced ability to compensate for functional changes associated with 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.

• Very rarely, retrobulbar injections may reach the cranial subarachnoid space and cause transient blindness, cardiovascular collapse, apnea, seizures, etc.

• Retro- and peribulbar injections of local anesthetics may pose a risk of persistent ocular muscle dysfunction. The main causes include traumatic nerve injury and/or local toxic effects of the injected anesthetic on muscles and nerves. The severity of such tissue reactions depends on the degree of trauma, the concentration of the local anesthetic, and the duration of exposure of tissues to the anesthetic. Therefore, as with all local anesthetics, the lowest effective concentration and dose of the local anesthetic should be used.

• Vasoconstrictor agents may intensify tissue reactions and should only be used when indicated.

• Unintentional intra-arterial injection of low doses of local anesthetics in the head and neck region, including retrobulbar, dental blocks, and stellate ganglion blocks, 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 required when using bupivacaine for paracervical block.

• Post-marketing reports have described cases of chondrolysis in patients who received prolonged intra-articular infusions of local anesthetics after surgical procedures. In most reported cases, chondrolysis affected the shoulder joint. Given multiple etiological factors and conflicting information in the scientific literature regarding the mechanism of action, a causal relationship has not been established. Prolonged intra-articular infusion is not an approved indication for the use of Longocaine®.

Epidural anesthesia with any local anesthetic may lead to arterial hypotension and bradycardia, which should be anticipated and appropriate preventive measures taken, including preloading with crystalloid or colloid solutions. Hypotension should be corrected immediately, for example, by intravenous administration of 5–10 mg ephedrine, repeated as necessary.

Severe arterial hypotension may occur due to hypovolemia from hemorrhage or dehydration, or 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.

During epidural anesthesia, sudden and severe arterial hypotension may develop in patients with hypovolemia from any cause.

Epidural anesthesia may cause paralysis of 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 large open surfaces are present in the joint 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 Longocaine® should not be used during early pregnancy except when the expected benefit outweighs the potential risks.

When performing paracervical block, there is an increased risk of adverse fetal reactions (such as bradycardia) due to the use of local anesthetics. These effects may be caused by 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 effects on the infant with therapeutic doses is negligible.

Ability to influence reaction speed when driving or operating machinery

Longocaine® has minimal impact on the ability to drive or operate machinery. Besides the direct effects of anesthetics, local anesthetics may have a very slight effect 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.

Dosage

Adults

The following table provides dosage guidelines for the drug in adult patients of average age, using the most commonly employed nerve block techniques. The figures indicate the expected range of average acceptable doses of the drug. Standard textbooks should be consulted when factors affecting specific block techniques are present, and to meet individual patient requirements.

Caution! 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 knowledge of the patient's physical condition are important factors in determining the required dose of the drug. The lowest dose necessary to achieve adequate anesthesia should be used. Individual variability may occur at the beginning and during anesthesia.

Dosage recommendations for adults – Table 1.

1. The dose includes the investigated dose.
2. The dose for blockade of large nerves should be adjusted depending on the site of administration and the patient's condition. When performing intercostal blockade or supraclavicular brachial plexus blockade, an increased incidence of serious adverse reactions may occur, regardless of the type of local anesthetic used; see also section "Special precautions for use".

In general, anesthesia for surgical intervention (e.g., epidural administration) requires higher concentrations and doses of the drug. When a less intense 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 anesthetic 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 fractional 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 recognized by transient tachycardia, and accidental intrathecal injection by signs of spinal block. If symptoms of intoxication occur, administration of the drug must 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.

Current clinical experience indicates that a dose of 400 mg administered over 24 hours is well tolerated in a healthy adult of average weight.

Children.

Lonkocaine® should not be used in children for these indications.

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 a slower rise in plasma 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 accompanied by apnea and severe arterial hypotension.

The adverse reaction profile of Longocaine® 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 arterial pressure, bradycardia), as well as phenomena directly (e.g., nerve trauma) or indirectly (e.g., epidural abscess) related to 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 prolonged in duration.

List of adverse reactions presented in tabular form.

The adverse reactions considered at least possibly related to treatment with Longocaine®, based on data obtained from clinical trials of the corresponding drugs and from the post-marketing period, are listed below by system organ classes and absolute frequency. Frequencies are 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 not evaluable with available data.

Adverse reactions following administration of the drug. Table 2.

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

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Do not freeze. Keep out of reach of children.

Incompatibility.

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

Packaging.

5 mL in ampoules.

5 ampoules in a blister pack, 2 blister packs in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address and location of its business activity.

108, Kobzarska St., Cherkasy, Cherkasy region, 18030, Ukraine. Tel.: (044) 281-01-01.