Buvanestin^® (Solution) Instructions for Use

Marketing Authorization Holder

Biosintez, PJSC (Russia)

ATC Code

N01BB01 (Bupivacaine)

Active Substance

Bupivacaine (Rec.INN registered by WHO)

Dosage Form

Buvanestin®

Solution for injection 5 mg/1 ml: amp. 4 ml or 10 ml 5 or 10 pcs.

Dosage Form, Packaging, and Composition

Solution for injection in the form of a transparent, colorless or slightly yellowish liquid.

Excipients: succinic acid, sodium chloride, sodium edetate dihydrate (Trilon B), 2M sodium hydroxide solution, water for injection.

4 ml – glass ampoules (5) – contour cell packs (1) – cardboard boxes.
4 ml – glass ampoules (5) – contour cell packs (2) – cardboard boxes.
10 ml – glass ampoules (5) – contour cell packs (1) – cardboard boxes.
10 ml – glass ampoules (5) – contour cell packs (2) – cardboard boxes.

Clinical-Pharmacological Group

Local anesthetic

Pharmacotherapeutic Group

Local anesthetic agent

Pharmacological Action

Bupivacaine is a long-acting amide-type local anesthetic, four times more potent than lidocaine. It reversibly blocks impulse conduction along the nerve fiber by affecting sodium channels. It has a hypotensive effect and slows the heart rate. At a concentration of 5 mg/ml with a single epidural administration, the duration of action is from 2 to 5 hours, and up to 12 hours with peripheral nerve block. Using the solution at a concentration of 2.5 mg/ml has a lesser effect on motor nerves.

Pharmacokinetics

Bupivacaine has a pKa of 8.2 and a concentrated blood-plasma ratio of 0.73.

Bupivacaine is completely absorbed from the epidural space into the blood. Absorption is biphasic, and the half-life for these phases is 7 minutes and 6 hours.

Bupivacaine mainly binds to α1-acid glycoproteins in plasma (plasma protein binding – 92-96%). The plasma concentration of bupivacaine depends on the drug dosage, method of administration, and vascularization at the injection site. Bupivacaine is metabolized in the liver, mainly by aromatic hydroxylation to 4-hydroxybupivacaine and N-dealkylation to 2,6-pipecoloxylidine (PPX). The metabolites have less pharmacological activity than Bupivacaine. Both reactions occur with the participation of cytochrome P4503A4 enzymes. The clearance of bupivacaine is almost entirely due to drug metabolism in the liver and depends more on the activity of liver enzyme systems than on liver perfusion. About 1% of bupivacaine is excreted unchanged in the urine within 24 hours after administration, and approximately 5% as PPX. The concentration of PPX and 4-hydroxybupivacaine in plasma during and after prolonged administration of bupivacaine is low relative to the administered dose of the drug.

It crosses the placental barrier. Binding to fetal plasma proteins is lower than in the mother; the concentration of the unbound fraction is the same in the fetus and mother. Bupivacaine passes into breast milk in amounts not dangerous to the child.

Indications

Local anesthesia (pain relief for trauma, surgical interventions, including caesarean section, labor analgesia, performing painful diagnostic procedures)

• Local infiltration anesthesia;
• Conduction anesthesia (intercostal block, block of large and small nerves, block of nerves in the head and neck area);
• Caudal or lumbar epidural anesthesia;
• Retrobulbar (regional) anesthesia.

ICD codes

Dosage Regimen

For spinal nerve root block, Bupivacaine is administered into the epidural space. For infiltration anesthesia, Bupivacaine is injected into the tissues of a limited area (infiltration). For peripheral conduction anesthesia, pain syndrome therapy, and sympathetic block, the drug is administered locally, taking into account anatomical relationships.

The dose of the drug is selected individually in each specific case. In this case, the minimum dose that provides sufficient pain relief should be prescribed. The drug should be administered with caution to avoid the development of acute toxic reactions in case of accidental intravascular administration. It is recommended to carefully perform an aspiration test before and during administration. Weakened patients are prescribed lower doses. Epidural anesthesia can be carried out by continuous administration of 4-8 ml/hour of bupivacaine 2.5 mg/ml for lumbar segments and 2-4 ml/hour for thoracic segments. If a large dose is required, for example, for epidural anesthesia, preliminary administration of a test dose is recommended: 3-5 ml of bupivacaine with epinephrine. In case of accidental intravascular administration of the drug, transient tachycardia may occur, easily detected by the doctor. The main dose is administered slowly at a rate of 25-50 mg/min or fractionally as a bolus, constantly maintaining verbal contact with the patient. If signs of intoxication appear, administration of the drug should be stopped immediately.

Approximate doses for single administration for children from 12 years of age and adults of average height.

In patients with impaired liver or kidney function, the concentration of the drug in the blood may increase significantly, especially with repeated administrations. In this case, low doses of bupivacaine 2.5 mg/ml should be prescribed.

When using epidural anesthesia during labor, the dose of bupivacaine should be reduced by one third.

For children under 12 years of age, the dose calculation should be based on body weight – on average up to 2 mg/kg.

The addition of epinephrine increases the duration of anesthesia by 1.5-2 times.

Adverse Reactions

Adverse reactions caused by the drug itself are difficult to distinguish from physiological manifestations of nerve block (for example, arterial hypotension, bradycardia, temporary urinary retention), reactions caused directly (for example, spinal hematoma) or indirectly (for example, meningitis, epidural abscess) by needle insertion, or reactions associated with cerebrospinal fluid leakage (for example, post-puncture headache).

From the cardiovascular system decrease or increase in blood pressure, bradycardia, decreased cardiac output, blockade, ventricular arrhythmia, cardiac arrest.

From the gastrointestinal tract nausea, vomiting.

From the nervous system paresthesia, dizziness, convulsions, tongue numbness, visual disturbances, tremor, loss of consciousness, tinnitus, dysarthria, headache, unintentional total spinal block, paraplegia, paralysis, neuropathy, arachnoiditis, muscle weakness, low back pain.

From the genitourinary system urinary retention, urinary incontinence.

From the respiratory system respiratory depression.

General allergic reactions up to anaphylactic shock, chills.

Contraindications

• Hypersensitivity to any of the components of the drug or other amide-type local anesthetics;
• Diseases of the central nervous system (for epidural administration);
• Arterial hypotension;
• Children under 2 years of age.

The drug is not used for intravenous regional anesthesia (Bier’s block), as the penetration of bupivacaine into the bloodstream can cause the development of acute systemic toxic reactions.

With caution

Cardiovascular failure (possible progression), heart block, inflammatory diseases or infection of the injection site (for infiltration anesthesia), cholinesterase deficiency, renal failure, age over 65 years, general severe condition, decreased hepatic blood flow, simultaneous use of antiarrhythmic drugs (including beta-blockers), the need for paracervical anesthesia, children aged 5 to 12 years.

For epidural administration (caudal or lumbar anesthesia) – previous neurological diseases, septicemia, difficulties in performing puncture due to spinal deformity.

Bupivacaine should be used with caution in patients receiving other local anesthetics or drugs structurally similar to amide-type local anesthetics, such as antiarrhythmic drugs (for example, lidocaine, mexiletine).

Use in Pregnancy and Lactation

Bupivacaine should be used only if the expected benefit to the mother outweighs the potential risk to the fetus. No effect of bupivacaine on reproductive function or an increase in the frequency of fetal malformations has been previously noted. When epinephrine is added to bupivacaine, uterine blood flow and contractility may decrease, especially with accidental intravascular administration.

Side effects caused by bupivacaine in the fetus most often occur with paracervical block, since this anesthesia results in the highest concentrations of bupivacaine in the fetus.

Bupivacaine passes into breast milk in amounts not dangerous to the child.

Use in Hepatic Impairment

Use with caution in cases of decreased hepatic blood flow. In patients with impaired liver function, the concentration of the drug in the blood may increase significantly, especially with repeated administrations. In this case, low doses of bupivacaine 2.5 mg/ml should be prescribed.

Use in Renal Impairment

Use with caution in renal failure. In patients with impaired renal function, the concentration of the drug in the blood may increase significantly, especially with repeated administrations. In this case, low doses of bupivacaine 2.5 mg/ml should be prescribed.

Pediatric Use

Contraindicated in children under 2 years of age. Use with caution in children from 5 to 12 years of age. For children under 12 years of age, the dose calculation should be based on body weight – on average up to 2 mg/kg.

Geriatric Use

Use with caution in patients over 65 years of age.

Special Precautions

Regional and local anesthesia, except for minor procedures, should be performed by experienced specialists in an appropriately equipped room with equipment and drugs ready for immediate use necessary for cardiomonitoring and resuscitation. When performing large blocks, it is recommended to establish an intravenous catheter before administering the local anesthetic.

Performing peripheral nerve block involves injecting a larger volume of local anesthetic into an area of high vascularization, often close to large vessels, where the risk of unintentional intravascular injection of the local anesthetic or systemic absorption of a large dose of the drug increases, which in turn can lead to increased plasma concentration.

During retrobulbar injection, the drug may accidentally enter the cranial subarachnoid space, causing temporary blindness, apnea, convulsions, collapse and other side effects. Developed complications must be promptly diagnosed and managed.

With retrobulbar and peribulbar administration of local anesthetics, there is a small risk of persistent impairment of eye muscle function. The main causes are trauma and/or local toxic effects on the muscles and/or nerves. The severity of such tissue reactions depends on the degree of injury, the concentration of the local anesthetic and the duration of tissue exposure to the local anesthetic. Therefore, as with the use of other local anesthetics, the lowest effective concentration and dose of the drug should be used. Vasoconstrictors and other additives may enhance tissue reactions and should be used only when indicated. For injections in the neck or head area, the drug may accidentally enter an artery, and in these cases, even with the use of low doses, serious adverse reactions may develop.

Paracervical block sometimes leads to the appearance of bradycardia/tachycardia in the fetus, so careful monitoring of the fetal heart rate is mandatory. The solution does not contain preservatives and should be used immediately after opening the ampoule.

Effect on ability to drive vehicles and operate machinery

In addition to the direct anesthetic effect, local anesthetics can have a depressant effect on cognitive functions, coordination of movements and cause temporary impairment of motor function.

During the period of drug use, one should refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Acute systemic intoxication

In case of accidental intravascular administration, a toxic reaction appears within 1-3 minutes, while in case of overdose, maximum plasma concentrations of the drug can be reached within 20-30 minutes depending on the injection site, with signs of intoxication appearing slowly. Toxic reactions manifest mainly from the central nervous and cardiovascular systems. Against the background of high plasma concentrations of bupivacaine, cases of ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death have been recorded.

From the central nervous system

Intoxication manifests gradually in the form of signs and symptoms of impaired central nervous system function with increasing severity. The initial manifestations of intoxication are: paresthesia around the mouth, dizziness, tongue numbness, pathologically increased perception of ordinary sounds and tinnitus. Visual impairment and tremor are the most serious signs and precede the development of generalized convulsions. These phenomena should not be mistakenly regarded as neurotic behavior. Following them, loss of consciousness and the development of major convulsive seizures are possible, which can last from a few seconds to several minutes. Due to increased muscle activity and disruption of the normal breathing process after the onset of convulsions, hypoxia and hypercapnia quickly appear. In severe cases, apnea may develop. Acidosis enhances the toxic effect of local anesthetics.

These phenomena pass due to the redistribution of the local anesthetic from the central nervous system and the metabolism of the drug.

Treatment of acute intoxication

If signs of general intoxication appear, administration of the drug must be stopped immediately. Therapy should be aimed at maintaining lung ventilation, stopping convulsions and maintaining circulation. Oxygen should be used and, if necessary, artificial ventilation of the lungs should be performed. If convulsions do not stop on their own within 15-20 seconds, anticonvulsant drugs should be administered intravenously. Intravenous administration of 100-150 mg of sodium thiopental quickly stops convulsions; alternatively, 5-10 mg of diazepam can be administered intravenously, although it acts more slowly. Suxamethonium quickly stops muscle cramps, however, its use requires tracheal intubation and artificial ventilation of the lungs. With severe depression of the cardiovascular system, intravenous administration of 5-10 mg of ephedrine is necessary, which can be repeated after 2-3 minutes if necessary. Optimization of oxygenation and ventilation along with correction of acidosis is vital, since hypoxia and acidosis will enhance the toxic effects of bupivacaine. If necessary, epinephrine is administered (0.1-0.2 mg intravenously or intracardially). In case of cardiac arrest, prolonged resuscitation may be required.

Drug Interactions

Bupivacaine should be used with caution in patients receiving other local anesthetics or drugs that are structurally similar to amide-type local anesthetics, such as antiarrhythmic drugs (for example, lidocaine, mexiletine), due to the possibility of developing an additive toxic effect. The combined use of bupivacaine with class III antiarrhythmic drugs (for example, amiodarone) has not been studied separately, however, caution is recommended when prescribing these drugs simultaneously (see also the “Special Precautions” section).

It is not recommended to mix solutions for spinal anesthesia with other drugs.

MAO inhibitors or tricyclic antidepressants increase the risk of developing a pronounced increase in blood pressure.

Drugs containing oxytocin or ergotamine contribute to the development of a sustained increase in blood pressure with possible complications from the cardiovascular and cerebrovascular systems.

Combination with general inhalation anesthesia with halothane increases the risk of arrhythmia.

When treating the local anesthetic injection site with disinfectant solutions containing heavy metals, the risk of developing a local reaction in the form of soreness and swelling increases.

Drugs structurally similar to local anesthetics, for example, tocainide, increase the risk of developing an additive toxic effect.

When used concomitantly with drugs that depress the central nervous system, local anesthetics enhance central nervous system depression.

The solubility of bupivacaine decreases at pH>6.5; this should be taken into account if alkaline solutions are added, as a precipitate may form.

Storage Conditions

In a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.