Buvanestin® solution for injection 5 mg/ml

Buvanestin® solution for injection 5 mg/ml

International nonproprietary name

Bupivacaine

Pharmacological group

Local anesthetic drug

Composition

Active ingredient:
Bupivacaine hydrochloride monohydrate on 100% basis - 5 mg
Excipients:
amber acid - 8 mg
sodium chloride - 8 mg
sodium edetate dihydrate (Trilon B) - 0.5 mg
2 М sodium hydroxide solution - up to рН 4.0 - 6.0
water for injection - up to1 ml

Pharmacological action

Bupivacaine - is a long term amide local anesthetic agent 4 times stronger than lidocain. Revers-ibly blocks the pulse conductivity of the nerve fibers suppressing the sodium ion transportation through the membranes of nerve fibers. Similar effects can be observed on membranes of excita-ble brain cells and myocardium. Bupivacaine has hypotensive effect, slows heart rate.
Bupivacaine is particularly suitable for long-term epidural blockade. After single epidural ad-ministration in the concentration 5 mg/ml effective duration is 2 from 5 hours and up to 12 hours after peripheral nerve blockade.
Postsurgical analgesia is maintained during 7-14 hours with intercostal block.
The most significant property of bupivacaine is its effective duration. The difference between the effective duration of bupivacaine in combination with or without epinephrine is insignificant. Bupivacaine at low concentrations effects less on motor nerve fibers and has a shorter effective duration, which is useful for short-term pain relief, for example during labor or after surgery.

Pharmacokinetics

Bupivacaine has resolution factor rKa-8.2 346 (at 25°С in n-octanol/phosphate buffer medium of pH 7.4).
Bupivacaine is completely absorbed into the blood from the epidural space; the absorption is bi-phasic, the half-life for the phases is 7 minutes and 6 hours, respectively, and 50 minutes and 408 minutes (6.8 hours), respectively after intrathecal administration.
Total plasma clearance of bupivacaine is 0.58 l/min., volume of distribution at steady state is 73 l, the terminal half-life is 2.7 hours, intermediate hepatic extraction index is about 0.38 after in-travenous administration. Half-life in newborn babies in comparison with adults may be longer – up to 8 hours. Half-life in children at the age after three months is the same as in adults.
Bupivacaine is mainly bound with α1-acid plasma glycoproteins (binding to plasma proteins - 96%). After major surgery this protein level may increase and increase the plasma concentration of bupivacaine. However concentration of free bupivacaine is not changed. Therefore, the plasma concentration exceeding the toxic level can be well tolerated.
Bupivacaine clearance is almost entirely due to the drug metabolism in the liver and is more de-pendent on the liver enzyme system activity than on liver perfusion. Metabolite pharmacological activity is less than bupivacaine activity.
The plasma concentration of bupivacaine depends on the dose of bupivacaine, method of admin-istration, vascularization at the administration point.
After intercostal blocks the maximum plasma concentration of the drug (4 mg/L after administra-tion at dose 400 mg) is observed due to rapid absorption, while after subcutaneous administration in the abdomen reveals the plasma minimum concentration of the drug.
After intrathecal administration absorption from the subarachnoid space is slow, which, in com-bination with administration of lower dose required for spinal anesthesia, results in a relatively low maximum plasma concentration (4 mg/L for every 100 mg administered).
Slow absorption is a factor limiting the excretion rate of bupivacaine and causes longer half-life after epidural administration of the drug.
In children, rapid absorption and high plasma concentration are observed in cases of caudal blockade (about 1.0-1.5 mg/L after administration at dose 3 mg/kg of the body weight).
Crosses the placenta. Binding with plasma proteins in the fetus is lower than in the mother's body, the concentration of unbound fraction in the fetus and mother is the same.
Bupivacaine is metabolized in the liver mainly by aromatic hydroxylation to 4-hydroxy-bupivacaine and by N-dealkylation to 2,6-pipecyloxylidine (PPC). Both reactions occur with par-ticipation of CYP3A4 cytochrome isoenzyme. About 1% of bupivacaine is excreted unchanged by urine during one day after administration and approximately 5% in the form of PPC. PPC and 4-hydroxybupivacaine plasma concentration during and after prolonged bupivacaine administra-tion is low relative to the administered dose of the drug.
In patients with liver disease, especially in patients with severe liver dysfunctions increase the risk of toxic reactions after administration of local amide anesthetics.
In elderly patients the maximum analgesic and anesthetic effect occurs faster than in younger patients. Also in elderly patients a higher maximum plasma concentration of bupivacaine is ob-served. Total plasma clearance in these patients is lower.

Indications for Use

• surgical anesthesia in adults and in children at the age from 12 years old;
• acute pain in adults and in children at the age from 1 year old;
• infiltration anesthesia, when longer anesthetic effect is required, for example with postsurgical pain;
• nerve block anesthesia with prolonged effect or epidural anesthesia in the cases, when addition of epinephrine is contradicted and significant relaxation of muscles is undesirable;
• anesthesia in obstetrics.
Intrathecal administration
Spinal anesthesia for lower extremity surgery including hip surgery with duration of 3-4 hours and not requiring severe motor block.

Contraindications

• increased sensation to any components of the drug or to other local amide anesthetic agents;
• the central nervous system diseases (for epidural administration);
• severe arterial hypertension (cardiovascular or hypovolemic shock);
• pediatric use: less than12 years old for surgical anesthesia, less than1 year old under all indica-tions, with the exception of intrathecal anesthesia, at which the drug can be administered since the birth;
• intravenous nerve block anesthesia (Biru block) (accidental penetration of bupivacaine into the blood channels may cause acute systemic toxic response);
• paracervical block anesthesia in obstetrics (may cause the fetal death).
contradictions to epidural anesthesia:  coagulopathy;  anticoagulate therapy;  skin infections in the puncture area; intracranial hypertension;  hypovolemia; neurological disorders, for example, multiocular sclerosis, meningitis, tumors, poliomyelitis, tuberculosis;  cardiac diseases with fixed ejection (idiopathic hypertrophic subaortic stenosis, aortic stenosis, mitral stenosis, complete atrioventricular block and etc.);  spine anatomical anomaly; preventive administration of low doses of heparine.
contradictions for intrathecal administration:  acute diseases of the central nervous system, as meningitis, poliomyelitis, intracerebral bleeding, as well as neoplasms of the central nervous system;  spinal canal narrowing and spine disorders in the exacerbation phase (spondylitis, tumor) or recent spinal cord injury (fracture);  septicemia; pernicious anemia with subacute combined degeneration of spinal cord; pyodermatites at the place of proposed puncture or laced with the puncture place; in patients with severe arterial hypertension, such as cardiovascular or hypovolemic shock; blood clotting disorders or concomitant anticoagulate treatment.
With care
Cardiovascular inefficiency (possible progressive), cardiovascular dysfunction (after epidural anesthesia), in fragile and elderly patients (at the age from 65 years old) or in patients with severe associated diseases, such as the II and III degree atrioventricular block, severe hepatic or renal failure, inflammatory diseases or infection of the injection place (after infiltration anesthesia), cholinesterase deficiency, late pregnancy (the III trimester). The patients receiving antiarrhythmic drugs of the III class (for example, amiodarone) need careful ECG maintenance and monitoring due to possible development of the adverse cardiovascular effects (see section “Interaction with other drugs”).
Simultaneous administration of bupivacaine with other local anesthetic agents or the drugs which structure is similar to the amide local anesthetic agents, such as antiarrhythmic drugs of the Ib class (for example, lidocain) due to possible development of additive toxic effects.
For peridural administration (caudal or lumbal block anesthesia) - prior neurological disorders, septicaemia, puncture obstruction due to spinal deformity.
Intrathecal administration additionally:
Increased risk of high or complete spinal block in elderly patients and in patients during late pregnancy, therefore, reduced doses of the drug are recommended in these patients (see section “Posology and Administration methods”).
Precautions shall be taken for intrathecal anesthesia in patients with neurological disorders such as multiocular sclerosis, hemiplegia, paraplegia, and neuromuscular disorders, although it has not been proven that intrathecal anesthesia causes deterioration of these diseases. Prior to intrathecal anesthesia in such cases ensure that the potential benefit to the patient outweighs any potential risk.
Administration during pregnancy and lactation period
Bupivacaine shall be administered only when potential benefit to the mother outweighs any potential risk to the fetus.
Administration of bupivacaine is condradicted for paracervical block anesthesia (see section “Contradictions”), as bupivacaine may cause severe cardiovascular disorders, for example decreased heart rate/tachycardia.
Bupivacaine has been used in a large number of pregnant women and women at the childbearing age, until now no any specific changes in fertile function in women at the childbearing age and increased frequency of defect developmental in the fetus.
Epinephrine addition to bupivacaine may decrease the blood flow in the uterus and its labor, especially when the anesthetic solution is accidentally injected into the mother's vessels.
Bupivacaine shall not be administered intrathecally at early pregnancy terms, unless the benefit overweights the risk, and dose reduction is recommended in patients at late pregnancy terms (see section “Posology and Administration methods”, “Precautions”).
Like other local anesthetic agent bupivacaine penetrates into breast milk, but when administered at therapeutic doses the effect on the baby is insignificant.

Cautions

Regional and intrathecal anesthesia shall be performed by experienced specialists in a properly equipped room. The equipment and preparations required for cardiac monitoring and resuscita-tion shall be available for immediate use. For large blocks prior to administration of a local anesthetic agent, an intravenous catheter is recommended to be installed. The personnel performing anesthesia shall undergo the appropriate training in the anesthesia technique and shall know the methods of diagnosis and treatment of possible adverse effects of the drug, systemic toxic reactions and other complications (see section “Overdose”).
Cardiac arrest or death during administration of bupivacaine for epidural anesthesia or peripheral blockade are reported. In some cases, resuscitation has been difficult or impossible, despite of adequate treatment.
The peripheral nerve block is associated with administration of a larger volume of local anesthetic agent into the high vascularization area, often close to large vessels with increased risk of unintentional intravascular injection of the local anesthetic agent or systemic absorption of a large dose of the drug, which in turn may cause high blood concentration of local anesthetic agent. Like other local anesthetic agents, bupivacaine may cause acute the central nervous and cardiovascular systems toxic reactions if its administration for local anesthesia increases blood concentration of the drug. The signs are most often appear after unintentional intravascular injection or high vascularization of the site of administration. Together with high plasma concentration of bupivacaine, cases of ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death were recorded. However, the doses normally used for intrathecal anesthesia do not result in high systemic concentration of the drug.
Certain types of blocks, regardless of the local anesthetic agent used, can be associated with serious adverse reactions, for example:
• epidural anesthesia, especially with hypovolemia, may cause the cardiovascular system depression. Care shall be taken in patients with cardiovascular diseases.
• Large peripheral blocks may require administration of large amount of local anesthetic agent at the high vascularization areas, often near the large vessels with increased risk of intravascular administration and/or systemic absorption, which may cause high plasma concentration of the drug.
• During retrobulbar administration the drug may accidently enter the cranial subarachnoid space, causing temporary blindness, apnea, convulsions, collapse and other adverse effects. These adverse reactions shall be immediately eliminated.
• Retrobulbar and peribulbar administration of local anesthetic agents causes a certain risk of persistent impairment of the eye muscles dysfunction. The main causes are trauma and/or local toxic effects on muscles and/or nerves. Severity of these tissue reactions depends on the injury severity, concentration of the local anesthetic agent and the tissue exposure duration with the local anesthetic agent. Therefore, the lowest effective concentration and dose of the drug should be used as for other local anesthetic agent administration. Vasoconstrictors may enhance the tissue reactions and shall be used only for the main indications.
• In case of unintentional intravascular injection into the head or neck area, the drug may enter the artery and in this case the drug may cause cerebral symptom, even at low doses.
• The cases of chondrolisis during postsurgical long-term intra-articular infusion of local anesthetic agents are reported. In most of the described cases, infusion into the shoulder joint was performed. The cause-and-effect relation to administration of anesthetic agents is not determined. Bupivacaine shall not be used for prolonged intra-articular infusion.
Severity of the adverse reactions described above is based on the injury size, the concentration of the local anesthetic agent and duration of its effect on the tissue, therefore, as for other local anesthetic agents, bupivacaine shall be administered at the lowest effective dose.
Special precautions shall be taken for regional anesthesia in the following groups of patients:
• Patients receiving the antiarrhythmic drugs of the class III (for example, amiodarone) shall be carefully monitored with continuous ECG monitoring since their cardiovascular effects can be summed up with those of bupivacaine.
• Elderly patients and patients with severe liver disease, severe renal failure or general unsatisfactory condition.
• Patients with atrioventricular block of the II and III degree, since local anesthetic agents can worsen the myocardial conductivity.
• Patients during late pregnancy.
Epidural anesthesia may cause blood pressure drop and decreased heart rate. These possible complications can be reduced by preliminary administration of crystalloid and colloidal solutions. In case of blood pressure drop, sympathomimetics shall be immediately administered intravenously (for example, 5-10 mg of ephedrine); if required, their administration shall be repeated.
The drug contains sodium, so in case of salt-free diet with limited salt intake, the sodium content shall be taken into account.
According to the postmarketing surveillance data, chondrolysis appeared in some patients receiv-ing the long-term administration of local anesthetic agents into the joint cavity after the surgery. In most cases, chondrolisis of the shoulder joint. The cause-and-effect relation to administration of bupivacaine has not been finally confirmed, chondrolysis may be caused by several factors. Contradictory data about this state onset mechanism are provided in the literature. Long-term intra-articular administration is not approved indication for the drug administration.
Children
Safety and efficiency of bupivacaine in children at the age less than 1 year have not been studied, only limited data are available.
Data on intra-articular block with bupivacaine in children at the age from 1 to 12 years old are not available.
Data on large nerve block with bupivacaine in children at the age from 1 to 12 years old are not available.
The drug for epidural anesthesia shall be administered slowly, based on the age and body weight, since severe hypotension and respiratory failure may especially develop after epidural anesthesia at the breast level.
For intrathecal administration
Spinal anesthesia may cause severe block and paralysis of the intercostal muscles and diaphragm, especially in pregnant women.
The risk of high or total spinal block, causing the blood circulation and respiration depression is increased in elderly patients and patients during late pregnancy. These patients shall receive lower doses.
Spinal anesthesia may cause blood pressure drop and decreased heart rate. This risk can be reduced with administration of crystalloid solutions. The blood pressure drop shall be immediately eliminated for example with intravenous administration of 5-10 mg of ephedrine.
Cases of arrhythmias, sudden cardiovascular collapse and death are possible. However, the doses normally used for intrathecal anesthesia do not increase the systemic concentration of the drug. A sudden severe blood pressure drop may appear during intrathecal anesthesia in patients with hypovolemia, regardless of its cause. Arterial hypotension, which usually occurs in adults after intrathecal block is rarely recorded in children at the age less than 8 years old.
Spinal anesthesia may be followed by intercostal paralysis, and therefore respiratory failure may appear in patients with pleural effusion. Septicemia may increase the risk of intraspinal abscess during the postsurgical period.
High or total spinal block, a cardiovascular system disorder in this condition, the respiratory muscles innervation and their signs may appear. Neurological complications are rare consequence of spinal anesthesia and may cause paresthesia, muscle weakness and paralysis. In some cases, these complications are permanent.
Care shall be taken for patients with multiple sclerosis, hemiplegia, paraplegia and neuromuscular disorders.
Before the treatment onset, the benefit and risk for the patient shall be correlated.
Buvanestin® contains no preservatives, so it shall be immediately administered after ampoule opening. Do not resterilize the drug. Remains of the solution shall be disposed.
Effects on ability to drive and use machines
Based on the dose and route of administration, local anesthetic agents may have a transient effect on motor function and movement coordination. During administration of the drug avoid driving and performing other potential hazardous activities requiring increased attention focusing and quick psychomotor reactions.

Dosing and Administration

Bupivacaine shall be administered only by doctors experienced in local anesthesia or under their supervision. To achieve the required anesthesia degree, the minimum possible dose shall be administered.
Under no circumstances accidental intravascular drug administration shall be allowed.
Careful aspiration sample is recommended before and during administration of the drug. If higher dose administration is required, for example for epidural block, previous test dose administration is recommended: 3-5 ml of bupivacaine with epinephrine.
The drug shall be administered slowly at the rate 25 50 mg/min. or at divided dose, maintaining continuous verbal contact with the patient and monitoring the heart rate.
Sudden intravascular administration of the drug may cause short-term increase in the heart rate, sudden random intrathecal administration may cause a spinal block. In case of intoxication signs, the drug shall be immediately withdrawn.
Adults and children at the age from 12 years old
The estimated doses to be adjusted based on the depth of anesthesia and the patient's condition are listed below. These doses are considered required for successful blockade and shall be considered as recommended for an average adult patient.
Dosage recommendations
Infiltration anesthesia: 5 60 ml of the drug at concentration 2.5 mg/ml (12.5 150 mg of bupivacaine) or 5 30 ml of the drug at concentration  5 mg/ml (25 150 mg of bupivacaine).
Diagnostic and therapeutic block: 1 40 ml of the drug at concentration 2.5 mg/ml (2.5 100 mg of bupivacaine), for example, trifacial block 1 5 ml of the drug (2.5 12.5 mg of bupivacaine) and stellate ganglion of the sympathetic trunk 10 20 ml of the drug (25 50 mg of bupivacaine).
Intercostal block: 2 3 ml of the drug at concentration 5 mg/ml (10 15 mg of bupivacaine) per one nerve, not exceeding the total number 10 nerves.
Large blocks (for example, epidural block, sacral plexus or brachial plexus block): 15 30 ml of the drug at concentration 5 mg/ml  (75 150 mg of bupivacaine).
Anesthesia in obstetrics (for example, epidural and caudal anesthesia during vaginal delivery: 6 10 ml of the drug at concentration 2.5 mg/ml (15 25 mg of bupivacaine) or 6 10 ml of the drug at concentration 5 mg/ml (30 50 mg of bupivacaine).
Repeated administration of the drug is allowed at initial dose after every 2-3 hours.
Epidural anesthesia for caesarian operation: 15 30 ml of the drug at concentration 5 mg/ml  (75 150 mg of bupivacaine).
Epidural analgesia in form of intermittent bolus dosing: initially 20 ml of the drug administered at concentration 2.5 mg/ml (50 mg of bupivacaine), then after every 4 6 hours based on the number of damaged segments and  the age of the patient 6 16 ml of the drug at concentration 2.5 mg/ml (15 40 mg of bupivacaine).
 
Epidural analgesia in form of continuous infusion (for example, postsurgical pain):

Block type

Concentration

Volume

Dose

Epidural administration (at the lumbal level)

 

 

 

Bolus*

2.5 mg/ml

5 10 ml

12.5 25 mg

Infusion

2.5 mg/ml

5 7.5 ml/h

12.5 18.75 mg**

Epidural administration (at the chest level)

 

 

 

Bolus*

2.5 mg/ml

5 10 ml

12.5 25 mg

Infusion

2.5 mg/ml

2.5 5 ml/h

6.25 12.5 mg

Epidural administration (vaginal delivery)

 

 

 

Bolus*

2.5 mg/ml

6 10 ml

15 25 mg

Infusion

2.5 mg/ml

2 5 ml/h

5 12.5 mg

 
*If during the previous hour the drug was not administered bolus.
** Do not exceed the maximum recommended daily dose (see below).
Additional administration of the drug is possible during the surgery.
For simultaneous administration of narcotic analgesics bupivacaine dose shall be reduced.
In case of long-term administration of the drug, the patient blood pressure heart rate and other signs of potential toxicity shall be regularly monitored. In case of toxic effects, the drug shall be immediately withdrawn.
In case of prolonged blocks with prolonged infusion or divisional administration of the drug, possible increase of its plasma concentration up to toxic values or possible local injury of nerve fibers shall be considered. The experience to date shows that administration of 400 mg of the drug in adult patients within 24 hours is usually well tolerated.
Higher doses of bupivacaine can be used for caudal block. Recommended doses for required caudal block with administration of higher doses of bupivacaine as well as administration of bupivacaine in ophthalmosurgery are listed in the Table below.
Bupivacaine with concentration 5 mg/ml

Block type

Dose
Onset of action,
 minutes
Duration,
 hours
Indications

ml

mg

Retrobulbar

2-4

10-20

5

4-8

Ophthalmosurgery (see section Precautions)

Peribulbar

6-10

30-50

10

4-8

Ophthalmosurgery (see section Precautions)

Caudal

20-30

100-150

15-30

2-3

Intraoperative and postsurgical pain relief. Pain syndrome treatment and pain relief during diagnostic procedures (dose includes the test).
The anesthesia duration is based on the dose, while the drug distribution over the segments is difficult to predict, especially when using an isobaric (simple) solution.
Possible risk of systemic epinephrine effects shall be considered when using a large volume of the solution containing epinephrine.
Maximum recommended doses
Maximum recommended single dose calculated at 2 mg /kg body weight is 150 mg for adults during 4 hours. This is equivalent to 60 ml of the drug at concentration 2.5 mg/ml (150 mg of bupivacaine) or 30 ml of the drug at concentration 5 mg/ml (150 mg of bupivacaine).
Maximum recommended daily dose is 400 mg. Calculation of the total daily dose shall be based on the patient's age, physique and other significant conditions.
Children at the age from 1 to 12 years old
Nerve block anesthesia shall be performed by a doctor experienced in work with children and mastering the corresponding administration technique.
Doses for children listed in the table are reference. Variability is possible. Dose reduction is usually required for children with high body weight based on the ideal body weight. Generally accepted guidelines for anesthesia shall be applied when determining the anesthesia methods and based on the patient individual characteristics.
The minimum dose shall be administered to achieve the adequate anesthesia.

 

Concentration,
mg/ml
Volume,
ml/kg
Dose,
mg/kg
Onset of action, min.
Effective duration, min.

Severe pain

Caudal epidural anesthesia

2.5

0.6 0.8

1.5 2

20 30

2 6

Lumbal epidural anesthesia

2.5

0.6 0.8

1.5 2

20 30

2 6

Thoracic epidural anesthesia*

2.5

0.6 0.8

1.5 2

20 30

2 6

*For thoracic epidural anesthesia the drug is administered at rising doses until the required anesthesia level is achieved. Dose for children shall be calculated based on 2 mg per one kg of the body weight.
To prevent the drug from entering the blood flow, the aspiration test shall be conducted before and during administration of the main dose. The drug shall be administered slowly, dividing the total dose into several injections, especially for lumbar and thoracic epidural anesthesia, continuously monitoring the vital organ indications.
Peritonsillar infiltration anesthesia in children from 2 years old: at dose 7.5 mg and 12.5 mg per amygdale at bupivacaine concentration 2.5 mg/ml.
Ilioinguinal/iliohypogastric nerve block in children from 1 year old: 0.1 0.5 mg/kg at bupivacaine concentration 2.5 mg/ml, which is equivalent to 0.25 1.25 mg/kg.
The drug can be administered at bupivacaine concentration 5 mg/ml at dose 1.25-2 mg/kg in children at the age from 5 years old.
Penis block: 0.2 0.5 mg/kg at bupivacaine concentration 5 mg/ml, which is equivalent to 1.0 2.5 mg/kg.
Information about epidural anesthesia in children (bolus or continuous administration) is limited.
The drug can be diluted only with compatible solvents such as 0.9 saline solution because dilution may change the drug properties and cause bupivacaine precipitation. The drug shall be diluted only by qualified personnel with mandatory visual supervision for mechanical inclusions before administration.
Use only clear solutions without visible particles.
The drug solution is intended only for single administration.
For intrathecal administration
The drug dilution for intrathecal administration (spinal anesthesia) is not recommended.
Bupivacaine shall be administered only by doctors experienced in local anesthesia or under their supervision. To achieve the required anesthesia degree, the minimum possible dose shall be administered.
The doses listed below are used for adult patients. Dose titration shall be individual.
Dose shall be reduced for elderly patients and patients during the late pregnancy.

Indications

Concentration, mg/ml

Dose

Onset of action, min.
Effective duration, hours
ml

mg

Lower extremity surgery including hip surgery

5.0

2 4

10 20

5 8

1.5 4

The recommended injection site is below L3.
Clinical experience of administration of the dose exceeding 20 mg is not available. Intravenous access shall be provided prior to the drug administration.
The drug shall be administered only after confirmation of entry into the subarachnoid space (clear cerebrospinal fluid flow out of the needle or during aspiration).
In case of unsuccessful attempt only one additional attempt of administration in another place shall be made and in less volume. Poor distribution of the drug in the subarachnoid space can be one of the causes of the lack of effect, which can be eliminated by changing the patient's position.
Lower dose of the drug shall be used in elderly patients and patients during the late pregnancy.
Children with body weight less than 40 kg
Bupivacaine solution for injection 5 mg/ml is allowed to be used in children.
The main difference between adults and children is that the volume of cerebrospinal fluid in newborns and infants is greater, that requires relatively high dose per kilogram of body weight in comparison with adults to achieve the same degree of block.
Nerve block anesthesia shall be performed by a doctor experienced in work with children and mastering the corresponding administration technique.
Doses for children listed in the table are reference. Variability is possible. Generally accepted guidelines for anesthesia shall be applied when determining the anesthesia methods and based on the patient individual characteristics. The minimum dose shall be administered to achieve the adequate anesthesia.
Body weight, kg
Dose, mg/kg
< 5
0.4 0.5
5 15
0.3 0.4
15 40
0.25 0.3
 

Side effect

Adverse effects caused by the drug itself can be difficult to distinguish from the physiological signs of nerve block (for example, arterial hypotension, decreased heart rate, temporary urinary retention), reactions caused directly (for example, spinal hematoma) or indirectly (for example, meningitis, epidural abscess) by needle insertion, or reactions associated with leakage of cerebrospinal fluid (for example, post-puncture headache). The following adverse effects may develop:
Adverse immune system effects:
rare (>1/10 000, <1/1000) – allergic reactions, anaphylactic shock.
Adverse cardiovascular effects:
very common (>1/10) – arterial hypertension,
common (frequent) (>1/100, <1/10) – decreased heart rate, blood pressure increase,
rare (>1/10 000, <1/1000) – heart arrest, arrhythmia.
Adverse gastrointestinal effects:
very common (>1/10) – nausea,
common (>1/100, <1/10) – vomiting.
Adverse central nervous system effects:
common (>1/100, <1/10) – paresthesia, dizziness,
uncommon (infrequent) (>1/1000, <1/100) – the central nervous system signs of toxicity: convulsions, paresthesia around the mouth, numbness of tongue, hyperacusia, mild dizziness, visual disturbances, unconsciousness, tremor, tympanophony and ringing in the ears, dysarthria),
rare (>1/10 000, <1/1000) – unintentional total spinal block, peripheral nerve damage, paraplegia, paresis, paralysis, neuropathy, arachnoiditis. Adverse urinary system effects:
common (frequent) (>1/100, <1/10) – urine retention, urinary incontinence.
Adverse respiratory system effects:
rare (>1/10 000, <1/1000) – respiratory depression.
Adverse visual organ effects:
rare (>1/10 000, <1/1000) – diplopy.
For intrathecal administration:
Adverse immune system effects:
rare (>1/10 000, <1/1000) – allergic reactions, anaphylactic shock in the most severe cases.
Adverse cardiovascular effects:
very common (>1/10) – arterial hypertension, decreased heart rate,
rare (>1/10 000, <1/1000) – heart arrest.
Adverse gastrointestinal effects:
very common (>1/10) – nausea,
common (>1/100, <1/10) – vomiting.
Adverse central nervous system effects:
common (frequent) (>1/100, <1/10) – spinal headache,
uncommon (infrequent) (>1/1000, <1/100) – paresthesia, paresis, dysesthesia,
rare (>1/10 000, <1/1000) – total spinal block, paraplegia, paresis, paralysis, neuropathy, arachnoiditis.
Adverse urinary system effects:
common (frequent) (>1/100, <1/10) – urine retention, urinary incontinence.
Adverse locomotor apparatus effects:
uncommon (infrequent) (>1/1000, <1/100) – muscular weakness, back ache.
Adverse respiratory system effects:
rare (>1/10 000, <1/1000) – respiratory depression.
Adverse effects in children are similar with the adverse effects in adults but early signs of local anesthetic agent toxicity in children may be more difficult to recognize if the block is performed under sedation or anesthesia conditions.
Overdose
Acute systemic intoxication
Buvanestin® administration in accordance with recommendation does not cause the plasma concentration resulting in systemic toxic signs. However, when the drug is used in combination with other local anesthetic agents, acute systemic toxicity can develop with additional toxic effects.
Toxic reactions are mainly developed in the central nervous and cardiovascular systems. These reactions are caused with high local anesthetic agent concentrations in the blood which can arise as a result of accidental intravascular administration, overdose or extremely high absorption from the region of high vascularization (see. “Precautions”). Together with high plasma concentration of bupivacaine, cases of ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death were recorded. However, the doses normally used for intrathecal anesthesia do not result in high systemic concentration of the drug.
The central nervous system reactions are similar for all local amide anesthetic agents, while the cardiovascular system signs are different for different drugs. Sudden intravascular administration of local anesthetic agent may cause an immediate toxic reaction (within a few seconds-minutes). While overdose signs of systemic toxicity develop later, from15 to 60 minutes after the injection, due to slow increase in the plasma concentration of the drug.
Adverse the central nervous system effects:
Intoxication signs appear gradually in the form of signs and symptoms of the central nervous system dysfunction with increasing severity degree. Initial signs of intoxication include: paresthesia around the mouth, dizziness, numbness of tongue, pathologic increased perception of ordinary sounds, tympanophony. Vision dysfunction and tremor are the most serious signs and precede development of generalized convulsions. These events shall not be mistakenly considered as neurotic behavior. They may followed by unconsciousness and development of large convulsive attacks, which may last from a few seconds to several minutes. Due to increased muscular activity and abnormal respiratory process, hypoxia and hypercapnia quickly appear after the convulsion onset. Respiratory failure may occur in severe cases. Associated acidosis increases the toxic effect of local anesthetic agents.
These events are caused by redistribution of local anesthetic agent from the central nervous system and the drug metabolism. The described events quickly corrected, if the anesthetic agent was not administered in excessive amounts.
Adverse cardiovascular effects:
Cardiovascular toxicity signs may cause the most severe consequences and usually precedes the central nervous system toxic reactions, which may be masked with general anesthesia or deep sedation after administration the drugs such as benzodiazepines or barbiturates.
High plasma concentration of local anesthetic agents may cause arterial hypotension, decreased heart rate, arrhythmias and, in some cases, cardiac arrest.
Cardiovascular toxicity signs are often caused by myocardial depression and myocardial conduction disturbance, which may cause decrease in cardiac minute output, blood pressure drop, atrioventricular block, decreased heart rate and in some cases ventricular arrhythmia, including tachycardia and ventricular fibrillation, cardiac arrest. These toxic signs often precede the central nervous system acute toxicity symptoms, for example, in the form of convulsions, but in rare cases, cardiac arrest may occur without the previous the central nervous system signs.
In case of sudden rapid intravenous bolus administration in the coronary vessels, high plasma concentration of bupivacaine may be observed affecting the blood circulation and causing independent cardiotoxic effects or preceding the central nervous system toxic effects. The caused myocardial depression signs may appear as initial intoxication symptoms.
In case of block with general anesthesia in children, the early intoxication signs are difficult to detect and therefore careful monitoring is required. Treatment of acute intoxication
In case of general intoxication signs or total spinal block, the drug shall be immediately withdrawn and expectant therapy of cardiovascular and neurological disorders (convulsions, the central nervous system depression) is required. In case of cardiac arrest, cardiopulmonary resuscitation shall immediately be applied.
The therapy shall be aimed at maintaining ventilation, convulsions arresting and blood circulation maintenance.
In all cases, the oxygen supply shall be recovered, if required, intubation and controlled ventilation (in some cases with hyperventilation). Convulsions recover require the therapy aimed at maintaining the cardiovascular system, adequate oxygenation and convulsions arrest. If required, oxygen supply and artificial ventilation shall be provided (using an Ambu bag or trachea intubation). If convulsions do not stop on their own within 15 to 20 seconds, then anti-seizure medications shall be administered intravenously: 0.1 mg/kg of diazepam. Long convulsions can interfere with ventilation and oxygenation. In such cases, for rapid arrest of convulsions, trachea intubation and administration of a muscle relaxing agent can be applied (for example, succinylcholine 1 mg/kg).
In case of insufficient blood circulation, dobutamine shall be administered intravenously, norepinephrine can be administered starting from 0.05 μg/kg/min, if required, the dose can be increased by 0.05 mg/kg/min per every 10 minutes. In more severe cases, the dose is titrated based on the hemodynamics monitoring results.
In case of obvious cardiovascular system depression (blood pressure drop and decreased heart rate), 5-10 mg of ephedrine shall be administered intravenously and if required after 2 to 3 minutes the administration shall be repeated. Children shall receive a dose of ephedrine in accordance with their age and weight.
In case of cardiac arrest, cardiopulmonary resuscitation shall be applied immediately. Oxygenation improvement and ventilation and circulation support along with acidosis correction are vital, since hypoxia and acidosis will intensify the systemic toxic effects of the local anesthetic agent. Epinephrine (adrenaline) shall be administered as soon as possible (intravenous or intracardiac administration of 0.1 - 0.2 mg) if required the administration shall be repeated. Also the need for appropriate therapy with intravenous solutions and the use of fat emulsions shall be considered.
Cardiac arrest may require prolonged resuscitation measures.
Dosing regimen in children shall be based on the age and body weight.
Doses appropriate to the body weight of the child shall be used for treatment of systemic toxic reactions in children.
Special attention should be paid to the early signs of intoxication development in children, since have the most severe block in this group of patients is achieved the most often after the onset of anesthesia.

Interaction with other medicines

Bupivacaine shall be administered with care in patients receiving other local anesthetic agents or drugs which structure is similar to amide local anesthetic agents, such as antiarrhythmic drugs (for example, lidocain, mexiletine), since they may enhance each other's toxic effects.
Combined administration of bupivacaine with antiarrhythmic drugs of the III class (for example amiodarone) was not studied individually, but care shall be taken when prescribing these drugs at the same time (see section “Precautions”).
Inhibitor of monoamine oxidase or tricyclic antidepressants increase the risk of severe blood pressure increase. When such simultaneous therapy is required, careful monitoring of the patient shall be provided.
Simultaneous administration with vasopressor and uterotonic agents (ergot derivatives) may cause persistent blood pressure increase with possible cardiovascular and cerebrovascular system complications.
Combination with total inhalation anesthesia with halothane increases the risk of arrhythmia. Phenothiazine and butyrophenone derivatives may reduce or reverse the pressor effect of epi-nephrine.
When preparing for administration avoid long contact of metal parts with the drug (for example, when treatment of the site of the local anesthetic agent administration with disinfectant solutions, containing heavy metals), as this increase the risk of local reactions as pain or edema.
The dugs which structure is similar to local anesthetic agents, for example, tocaine, increases the risk of additive toxic effects.
Combined administration of local anesthetic agents with the drugs depressing the central nervous system increase the central nervous system depression.
Solubility of bupivacaine decreases at pH>6.5, this shall be taken into account when adding alka-line solutions since precipitate may develop. Incompatibility Solutions for intrathecal anesthesia are not recommended to be mixed with other drugs.

Form release

Storage conditions

In a dry, dark place at temperature maximum 25 °С. Do not freeze.

Expiration date

2 years