Bupivacaine - instructions for use, dose, side effects, contraindications

Excipients: methylparahydroxybenzoate 1 mg, sodium chloride 8 mg, 0.1 M sodium hydroxide solution and / or 0.1 M hydrochloric acid solution until pH adjusted, water for injection up to 1 ml.

Description:

A clear, colorless solution.

Pharmacotherapeutic group:Local anesthetic

ATX: & nbsp

N.01.B.B.01 Bupivacaine

Pharmacodynamics:

Bupivacaine is a local anesthetic of a long-acting amide type. Reversibly blocks the impulse on the nerve fiber, disrupting the transport of sodium ions through the sodium channels. Has hypotensive effect, slows heart rate. May have a similar effect in the brain and myocardium.

Adding a vasoconstrictor of epinephrine leads to a decrease in the rate of absorption of anesthetic and, as a consequence, to an increase and prolongation of the action of the drug.

Pharmacokinetics:

The pKa value of bupivacaine is 8.2, the partition coefficient is 346 (at 25 ° C in n-octanol / phosphate buffer pH 7.4). The rate of absorption depends on the dose, route of administration and blood supply at the injection site.

With intercostal blockade due to rapid absorption, the maximum plasma concentration is 4 mg / l (with 400 mg), with subcutaneous injections in the abdomen, plasma concentrations are lower.

In children with caudal blockade, rapid absorption occurs, and a high concentration in the blood plasma is achieved - about 1-1.5 mg / l (with 3 mg / kg of body weight).

The equilibrium volume of bupivacaine distribution is 73 liters, the hepatic extraction coefficient is 0.4, the total plasma clearance is 0.58 liters per minute, and the half-life of plasma is 2.7 hours.

The half-life of newborns in comparison with adults may be longer - up to 8 hours. In children older than three months, the half-life is equal to that of adults.

The connection with plasma proteins is 96%, mainly with α₁acid plasma glycoproteins. After major surgery, the concentration of this protein can be increased, which can lead to a higher overall concentration of bupivacaine in the blood plasma. The free fraction of bupivacaine does not change. Therefore, the potentially toxic plasma concentration is well tolerated.

Bupivacaine is almost completely metabolized in the liver, mainly by aromatic hydroxylation to 4-hydroxybupivacaine and N-dealkylation to 2,6-pipecyloxylidine (PPC), both reactions are catalyzed by the cytochrome CYP3A4 isoenzyme. Thus, clearance depends on the hepatic blood flow and the activity of metabolizing enzymes.

Bupivacaine penetrates the placenta, the concentration of unbound bupivacaine in the fetus is equal to the maternal.In view of the lower association with plasma proteins in the fetus, the total plasma concentration is lower.

Indications:

Local anesthesia with:

- surgical operations;

- surgical operations in the oral cavity;

- diagnostic and therapeutic interventions;

- operations in obstetrics.

Contraindications:

- Hypersensitivity to any of the components of the drug or to other local anesthetics of the amide type;

- severe arterial hypotension (cardiogenic or hypovolemic shock);

- children's age till 12 years;

- intravenous regional anesthesia (Bira blockade) (accidental penetration of bupivacaine into the bloodstream can cause the development of acute systemic toxic reactions);

- paracervical blockade in obstetrics.

Carefully:

- AV blockade II and III degree;

- elderly age;

- severe liver disease, severe renal failure;

- weakened patients;

- use of antiarrhythmic drugs IIIth class (for example, amiodarone);

- simultaneous use of bupivacaine with other local anesthetics or preparations structurally similar to local anesthetic agents of the amide type, such as antiarrhythmic drugs Ib class (for example, lidocaine and mexiletine).

Pregnancy and lactation:

Data on adverse effects on pregnancy are absent. When used in pregnant animals in large doses, a decrease in the survival of offspring in rats and embryotoxic effects in rabbits were found. Concerning bupivacaine should not be used in the early stages of pregnancy, unless the benefits exceed the risks.

With paracervical blockade in obstetrics bupivacaine can cause fetal cardiovascular disorders, such as bradycardia / tachycardia. The use of bupivacaine as a means for paracervical blockade is contraindicated (see section "Contraindications").

Bupivacaine penetrates into breast milk, but when applied in therapeutic doses, the effect on the baby is negligible.

Dosing and Administration:

Intramuscularly or subcutaneously.

Local anesthesia should be carried out by experienced specialists in an appropriately equipped room with availability of ready-to-use equipment and preparations necessary for cardiac monitoring and resuscitation.Personnel performing anesthesia should be qualified and trained in the technique of performing anesthesia, should be familiar with the diagnosis and treatment of systemic toxic reactions, adverse events and reactions, and other complications.

The dose of any local anesthetic depends on the analgesic procedure, the area to be anesthetized, the blood supply to the tissues, the depth of anesthesia and the degree of muscle relaxation required for the required duration of anesthesia, individual tolerability and the physical condition of the patient. To achieve the required degree of anesthesia, the minimum possible dose should be administered.

It should avoid the rapid introduction of a large volume of the drug. Under no circumstances should you allow accidental intravascular drug administration. It is recommended to perform an aspirate test before and during the administration of the drug. The drug should be administered slowly, at a rate of 25-50 mg / min or fractional, maintaining continuous verbal contact with the patient and controlling the heart rate.

The duration of anesthesia with bupivacaine is such that, for most indications, a single dose is sufficient.

Calculation of the maximum dose should be individual, you must take into account the physique and physical status of the patient, as well as the normal rate of systemic absorption at a particular injection site.

A single dose of bupivacaine up to 225 mg with epinephrine (1: 200,000) and 175 mg without epinephrine can be used depending on the individualization of each case. After every 3 hours, repeated administration of the drug at these doses is allowed.

The maximum recommended daily dose for healthy adult patients with a body weight of 70 kg is 400 mg. The dose should be reduced for children, elderly and weakened patients and patients with diseases of the cardiovascular system and / or liver.

Below are the approximate recommended doses for adult patients.

Type of blockade	Concentration,%	Dose		Motor blockade
		(ml)	(mg)
Local infiltration	0,25	Before the maximum	Before the maximum	From moderate to full
Blockade of peripheral nerves	0,5	5 to Max	25 to maximum	From moderate to full
	0,25	5 to Max	From 12.5 to the maximum
Sympathetic	0,25	20-50	50-125

During the surgical intervention, additional administration of the drug is possible.

With the simultaneous use of narcotic analgesics, the dose of bupivacaine should be reduced.

With prolonged administration of the drug, the patient should regularly monitor blood pressure, heart rate and other signs of potential toxicity. If toxic effects occur, the drug should be discontinued immediately.

Cooking method

The drug may be diluted only with compatible solvents, such as 0.9% sodium chloride solution, since dilution may alter the properties of the preparation and lead to the precipitation of bupivacaine. Dilution should be carried out only by qualified personnel with mandatory visual inspection for mechanical inclusions and discoloration prior to administration. It is possible to use only clear solutions without visible particles. The drug solution is intended for single use only.

Side effects:

The frequency of adverse reactions is determined by the following categories: very frequent (≥ 1/10), frequent (from ≥ 1/100 to <1/10), infrequent (from ≥ 1/1000 to <1/100), rare (from ≥ 1 / 10000 to <1/1000), very rare (<1/10000).

Undesirable drug-induced drug reactions can be difficult to distinguish from physiological manifestations of nerve blockade (eg, lowering blood pressure, bradycardia), reactions,directly caused by the introduction (eg, nerve damage).

Neurologic disorders are a rare, but well-known, undesirable drug response caused by local anesthesia. Symptoms and tactics of management of acute systemic toxicity are described in the section "Overdose".

Immune system disorders: rare - allergic reactions, anaphylactic shock.

Disturbances from the nervous system: frequent - paresthesia, dizziness; infrequent - signs of toxicity from the central nervous system: convulsions, paresthesia in the mouth, numbness of the tongue, hyperacusis, visual impairment, loss of consciousness, tremor, mild dizziness, tinnitus, dysarthria; rare - defeat of peripheral nerves, paraplegia, neuropathy, arachnoiditis, paresis.

Disturbances on the part of the organ of sight: rare - diplopia.

Heart Disease: frequent - bradycardia; rare - cardiac arrest, arrhythmia.

Vascular disorders: very frequent - lowering blood pressure; frequent - increased blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs: rare - respiratory depression.

Disorders from the gastrointestinal tract: very frequent - nausea; frequent - vomiting.

Disorders from the kidneys and urinary tract: frequent - urinary retention.

Undesirable reactions in children are similar to those in adults, however, early signs of local anesthetic toxicity in children are more difficult to recognize if the blockade is performed under sedation or anesthesia.

Overdose:

Acute systemic intoxication

Symptoms

Toxic reactions are manifested mainly from the central nervous and cardiovascular systems. They arise due to the high concentration of local anesthetic in the blood, which can be caused by accidental intravascular injection, overdose or extremely fast absorption from the area of highly vascularized tissues (see section "Special instructions").

Symptoms of CNS damage for all local anesthetics of the amide type are similar, whereas the symptoms of cardiovascular damage differ qualitatively and quantitatively. Unintentional intravascular injection of a local anesthetic can lead to immediate toxic reactions (within a few seconds-minutes).Signs of systemic toxicity in case of an overdose appear later (15-60 minutes after administration), as the concentration of local anesthetic in the blood plasma increases slowly.

From the central nervous system

Intoxication of the central nervous system manifests itself gradually. The initial signs of intoxication, as a rule, are: dizziness, paresthesia around the mouth, numbness of the tongue, hyperacusis, tinnitus and visual impairment.

More serious manifestations are dysarthria and myofasciculation, which may precede the onset of generalized seizures. These phenomena should not be mistaken for a neurotic disorder. Following them, loss of consciousness and the development of a large convulsive fit lasting from a few seconds to several minutes are possible. In connection with increased muscular activity and insufficient ventilation (disruption of the normal breathing process), hypoxia and hypercapnia rapidly build up during seizures. In severe cases, breathing may stop. Concomitant acidosis increases the toxic effect of local anesthetics.

The resolution of symptoms is due to the metabolism of the local anesthetic and its redistribution from the central nervous system.The described phenomena quickly stop, if the overdose was not excessive.

From the side of the cardiovascular system

The defeat of the cardiovascular system, as a rule, indicates more severe intoxication. It is usually preceded by signs of central nervous system damage that can be erased if the patient is in anesthesia or deep sedation caused by drugs such as benzodiazepines or barbiturates. Due to the high concentration of local anesthetics in blood plasma, there may be a drop in blood pressure, bradycardia, arrhythmias and cardiac arrest.

Toxic manifestations of the cardiovascular system are often caused by myocardial depression and myocardial conduction disturbance, which cause a decrease in cardiac output, lowering of arterial pressure, atrioventricular blockade (AV blockade), bradycardia, ventricular arrhythmia, including ventricular tachycardia and ventricular fibrillation, cardiac arrest. These phenomena are often preceded by severe signs of damage to the central nervous system, including convulsions, but in rare cases, cardiac arrest occurs without concomitant signs from the central nervous system.After a very rapid intravenous injection, the concentration of bupivacaine in the blood plasma can be quite high. In this case, he quickly reaches the coronary arteries, and the symptoms of circulatory disorders occur earlier than signs of damage to the central nervous system. This mechanism causes myocardial depression and may be the first manifestation of intoxication.

When the blockade is performed under general anesthesia in children, the early signs of intoxication are difficult to detect, and careful monitoring is therefore required.

Treatment

If a spinal block arises, adequate ventilation should be provided (ensure airway patency, oxygen supply, if necessary, intubation and artificial ventilation). With a decrease in blood pressure and / or bradycardia, it is necessary to introduce a vasopressor with inotropic action.

When symptoms of acute systemic intoxication occur, the administration of the drug should be stopped immediately. It is necessary to ensure proper ventilation, oxygenation and maintain blood circulation.

In all cases, it is necessary to adjust the supply of oxygen, if necessary, intubation and controlled ventilation (in some cases with hyperventilation).

When convulsions are injected diazepam, with bradycardia - atropine. With circulatory failure - dobutamine intravenously, the administration of norepinephrine is allowed (starting from 0.05 μg / kg / min, if necessary, the dose is increased by 0.05 μg / kg / min every 10 minutes), in more severe cases, the dose is titrated according to the results of monitoring hemodynamics. The administration of ephedrine is possible. With severe damage to the cardiovascular system, resuscitation can continue for several hours. Any acidosis is subject to elimination.

When cupping systemic intoxication in children, the dose of the drug should be selected according to their age and body weight.

Interaction:

Caution should be exercised while using bupivacaine with other local anesthetics or antiarrhythmics Ib class (such as lidocaine and mexiletine), since they can enhance the toxic effects of each other.

A separate study of the interaction of local anesthetics and antiarrhythmics IIIth class (for example, amiodarone) was not performed, nevertheless it is recommended to use caution when they are used simultaneously (see section "Special instructions").

The alkalization can lead to precipitation, since the solubility of bupivacaine at pH> 6.5 decreases.

When preparing for the introduction, it is necessary to avoid prolonged contact of the drug with metal objects, since metal ions can cause reactions at the site of administration, manifested by soreness and edema.

When epinephrine is added to a solution of a local anesthetic, it is necessary, if possible, to avoid their simultaneous use with monoamine oxidase inhibitors or tricyclic antidepressants, since it is possible to develop a persistent increase in blood pressure. If such simultaneous therapy is necessary for patients, careful monitoring must be established.

Simultaneous use with vasopressor and uterotonic agents (ergot derivatives) can lead to a persistent increase in blood pressure and cerebrovascular complications.

The derivatives of phenothiazine and butyrophenone can reduce or reverse the pressor effect of epinephrine.

Special instructions:

Personnel performing anesthesia should be qualified and trained in the technique of performing anesthesia, should be familiar with the diagnosis and treatment of systemic toxic reactions, adverse events and reactions, and other complications.

The drug contains methyl parahydroxybenzoate as a preservative. Local anesthetics containing preservatives should not be used for epidural or caudal anesthesia, since safety has not been established for intrathecal administration, or the intentional or unintentional administration of such preservatives.

The introduction of local anesthetics should be carried out in close proximity to resuscitation equipment.

Before starting large blockages, it is necessary to provide venous access.

Blockade of the main peripheral nerves may require the introduction of large amounts of local anesthetics into the well-blood-supplying areas of the body, often near large blood vessels. In such cases, the risk of intravascular bupivacaine or systemic absorption increases, which can lead to a high concentration of local anesthetic in the blood.

Like other local anesthetics, bupivacaine can cause acute toxic reactions from the central nervous and cardiovascular systems, if during the procedure of local anesthesia there is a high concentration in the blood. Most often this is manifested in the case of unintentional intravascular injection or with a good blood supply to the site of administration.

Certain types of local anesthesia, regardless of the local anesthetic used, can cause the development of serious adverse reactions, for example:

- With retrobulbar injection, the drug can occasionally enter the cranial subarachnoid space, causing temporary blindness, apnea, seizures,collapse and other undesirable reactions. The coping of these reactions must be carried out immediately.

- With retrobulbar and peribulbar injection of local anesthetics, there is a certain risk of a persistent impairment of the function of the eye muscles. The main causes are trauma and / or local toxic effects on muscles and / or nerves.

- If unintentional intravascular injection into the head or neck area, even at low doses, the drug is able to cause cerebral symptoms.

The severity of the undesirable reactions described above depends on the size of the injury, the concentration of the local anesthetic and the duration of its effect on the tissue. Therefore, as with other local anesthetics, it is necessary to administer the lowest effective dose of bupivacaine.

- Care should be taken in patients with AV blockade II and III degree, as local anesthetics can disrupt intracardiac patency.

- Care should be taken when administering the drug to elderly patients and patients with severe liver disease, severe renal failure, or a general unsatisfactory condition.

- It is necessary to carry out careful monitoring and continuous monitoring of ECG in patients receiving antiarrhythmic drugs IIIth class (for example, amiodarone), since the summation of their cardiovascular effects with those of bupivacaine is possible.

According to the post-registration data, in some patients who received long-term local anesthetic injections into the joint cavity after the operation, chondrolisis arose. In most cases, chondrolisis of the shoulder joint. The causal relationship with the administration of bupivacaine has not been conclusively confirmed, perhaps chondrolisis is due to several factors. Contradictory data on the mechanism of the onset of this state are described in the literature. Prolonged intra-articular injection is not an approved indication for the use of the drug. Remains of the solution are subject to destruction.

The drug contains sodium, so in the case of a salt-free diet with a limited consumption of it, you should take into account the sodium content in the preparation.

Children

The use of bupivacaine in children younger than 12 years is not recommended due to limited experience in controlled clinical trials, the literature describes an increased risk of toxicity,associated with the use of bupivacaine in children under 12 years.

Effect on the ability to drive transp. cf. and fur:

Depending on the dose and route of administration, local anesthetics can have a transient effect on motor function and movement coordination.

Form release / dosage:

Solution for injection, 5 mg / ml.

Packaging:

To 20 ml in a bottle of colorless glass type I, corked with a rubber stopper and closed with an aluminum cap with a tear-off lid of the "flip-off" type.

For 1 bottle in a cardboard pack together with instructions for use.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003433

Date of registration:02.02.2016

Expiration Date:02.02.2021

The owner of the registration certificate:Korgem Pharmaceuticals Private Limited Korgem Pharmaceuticals Private Limited India

Manufacturer: & nbsp

CLARIS LIFESCIENCES, Ltd. India

Representation: & nbspClarice LifeSinceys LimitedClarice LifeSinceys Limited

Information update date: & nbsp12.03.2017

Illustrated instructions

Instructions

Bupivacaine (Bupivacaine)