Bupivacaine

BUPIVACAINE

Solution for injection 5 mg/ml 10 ml in ampoules No.10.

1 ml of the solution contains 5 mg of bupivacaine hydrochloride.

Drug of choice being used for epidural, conduction and infiltration anesthesia if a significant long-lasting effect is needed.

Marketing Authorization No. UA/13416/01/01

Composition

1 ml of the solution contains  5 mg of bupivacaine hydrochloride;

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

Pharmaceutical form

Solution for injection.

Pharmacotherapeutic group

Local anesthetics. АТС Code N01В В01.

Clinical performance

Indications.

Infiltration anesthesia if long-lasting effect is needed, for example, to eliminate post-operative pain.

Long-lasting conduction and epidural anesthesia when adrenaline administration is contraindicated or superpotent muscle relaxants are not recommended.

Contraindications

Hypersensitivity to the local anesthetics of amide type or to any other component of the product. Bupivacaine is not used for intravenous regional anesthesia (Bier block). Bupivacaine should not be used as epidural anesthetic by the patients having frank arterial hypotension, for example, at cardiogenic or hypovolemic shock.

Regardless any local anesthetic, epidural anesthesia has its own general contraindications, which include:

  • active central nervous system diseases, such as meningitis, poliomyelitis, intracranial hemorrhage, subacute compound degeneration of spinal cord caused by pernicious anesthesia and  brain or spinal tumors;
  • spinal tuberculosis;
  • pyogenic infection of the skin at or adjacent to the site of puncture;
  • coagulation diseases or ongoing anticoagulation treatment.

Posology and method of administration

Bupivacaine should be applied only by the doctors having the relevant experience in conduction anesthesia or under their control. Administer the minimum doses which enable to reach the proper degree of anesthesia. It is important to follow all necessary precaution measures, including careful aspiration, in order to avoid accidental intravascular injections.

In case of epidural anesthesia, the test dose of 3-5 ml of bupivacaine with adrenaline is administered, as intravascular injection with adrenaline can rapidly increase the cardiac rate.

For the next 5 minutes, a physician should maintain verbal contact with the patient and perform perioral monitoring of heart rhythm. Moreover, aspiration is needed before administration of the general dose. The general dose should be slowly administered at the rate of 25-50 mg/minute and ongoing contact with patient should be maintained. If intoxication symptoms occur, the product’s administration shall be immediately interrupted.  Below are the recommended doses for the patients; a dose should be adjusted taking into account the block grade and the general patient’s condition.

Infiltration anesthesia: 5-30 ml of bupivacaine, 5 mg/ml (25-150 mg of bupivacaine hydrochloride).

Intercostal block: 2-3 ml of bupivacaine, 5 mg/ml (10-15 mg of bupivacaine hydrochloride) per each nerve, 10 nerves total.

Block of large nerves (for example, epidural, sacral anesthesia and shoulder anesthesia): 15-30 ml of bupivacaine, 5 mg/ml (75-150 mg of bupivacaine hydrochloride).

Obstetric anesthesia (for example, epidural anesthesia, caudal anesthesia at vaginal delivery or vacuum extraction): 6-10 ml of bupivacaine, 5 mg/ml (30-50 mg of bupivacaine hydrochloride). If needed, these initial doses may be repeated each 2-3 hours.

Epidural block (caesarean section): 15-30 ml of bupivacaine, 5 mg/ml 975-150 mg of bupivacaine hydrochloride).

If product is used in combination with opiates, the dose of bupivacaine should be reduced.

In the course of the product’s administration, a physician should monitor the patient’s arterial pressure, heart rate and possible intoxication symptoms. If toxic effect occurs, infusion should be immediately interrupted.

Maximum recommended doses

The maximum recommended dose which is administered at the same case is calculated based on the rate of 2 mg/kg. For adult patients, the maximum dose should be 30 ml (150 mg of bupivacaine hydrochloride) within 4 hours.

The maximum recommended dose for adult patients should be 400 mg per day. The general dose can be adjusted based on patient’s age, body type and other important factors.

Application of the ampule

  1. Separate one ampoule from the block and shake the contents gently, holding the ampoule by its neck.
  2. Squeeze the ampoule in your hand (the product leakage shall not occur) and remove the cap by rotating it.
  3. Immediately put a syringe in the ampoule through the obtained hole.
  4. Turn the ampoule over and slowly suck the liquid in the syringe.
  5. Put a needle on the syringe.

Adverse reactions

Adverse reactions caused by the drug are difficult to distinguish from the physiological effects of the nerve block (e.g. decrease in blood pressure, bradycardia). Moreover, it is difficult to distinguish the events caused directly (e.g. nerve injury) or indirectly (e.g. epidural abscess) by needle puncture.

General disorders: nausea

Immune system disorders: allergic reactions, anaphylactic shock.

Cardiac disorders: arterial hypotension, bradycardia, arterial hypertension, cardiac arrest, arrhythmia.

Nervous system disorders: paresthesia, dizziness, central nervous system toxicity symptoms (convulsions, perioral paresthesia, tongue numbness, hyperacusia, vision disorder, faint, tremor, dizziness, tinnitus, dysarthria), neuropathy, peripheral nerves injury, arachnoidite, paresis and paraplegia.

Gastrointestinal disorders: vomiting.

Respiratory, thoracic and mediastinal disorders: respiratory depression

Renal and urinary disorders: urinary retention, urinary incontinence

Vision disorders: double vision.

Overdose

Symptoms

Systemic toxic  reactions are related to central nervous system and cardio-vascular system as well. Such reactions may be caused by high concentration of a local anesthetic in blood, which in its turn is caused by accidental vascular injection, overdose or rapid absorption from highly vascularized tissues.

The symptoms of the central nervous system disorders are similar for all anesthetics of amid type, while heart disorders symptoms vary for each product both qualitatively and quantitatively. Accidental intravenous injections of local anesthetics may cause immediate (from several seconds to several minutes) systemic toxic reactions. If product is overdosed, systemic toxicity can appear later (15-60 minutes after the injection) due to slow reduction of concentration of anesthetic in blood.

Central nervous system toxicity has gradual development and is characterized with increase of severity of its symptoms and reactions. The first symptoms are manifested in the form of  slight dizziness, perioral paresthesia, tongue numbness, hyperacusia, tinnitus and vision disorder. Difficulties with articulation, muscular convulsions or tremor are more serious symptoms which are followed by generalized convulsions.  Such symptoms should not be deemed as neurotic behavior. After that, a physician may observe faint and generalized epilepsy lasting from several seconds to several minutes. Due to the high muscle activity and insufficient ventilation, hypoxia and hypercapnia (increase of CO2 concentration in blood)may rapidly develop during  convulsions. In severe cases, apnea may develop. Acidosis can strengthen toxic effects of the local anesthetics.

The patient’s recovery depends on metabolism of the local anesthetic and it has rapid expansion beyond the central nervous system, except in cases where high doses of the product were administered.

Cardiovascular effects are usually more dangerous. These effects are usually preceded with the central nervous system toxicity. Toxic effects may be absconded with general anesthesia or deep sedation which is reached with the help of benzodiazepines and barbiturates. Due to the high systemic concentrations of the local anesthetics, a patient may face decrease of arterial pressure, bradycardia, arrhythmia and even cardiac arrest. Cardiovascular toxic effects are related to depression of the cardiac and myocardium conduction, which leads to decrease of cardiac output, arterial hypotension, AV-block, bradycardia and sometimes –to ventricular arrhythmia, including ventricular tachycardia, ventricular fibrillation and cardiac arrest. These symptoms are usually preceded with the symptoms of severe central nervous system toxicity, for example, convulsions, but sometimes cardiac arrest my occur without any effects of the central nervous system. A very rapid intravenous and painful injection into the coronary vessels may lead to such high concentration of bupivacaine in blood that impact in blood circulation system can be reached independently or prior to any effect from the central nervous system.


Treatment of complications

In case of acute systemic toxicity, immediately discontinue the use of local anesthetics. The treatment should be aimed at maintenance of the proper ventilation, oxygenation and blood circulation. Always ensure proper oxygen delivery and controlled ventilation, if needed. Should convulsions last more than 15-20 seconds, inject 1-3 mg/kg of thiopental sodium in order to facilitate ventilation, or  0.1 mg/kg of diazepam (which has much slower effect). Long-lasting convulsions carry a threat for normal respiration and oxygenation. Injection of neuromuscular blockers (e.g. succinylcholine 1mg/kg) helps to ensure lung ventilation and oxygenation, however, it requires the relevant experience in tracheal intubation and  controlled ventilation.

Hypotension/bradycardia should be treated with  vasopressors (e.g. ephedrine 10–15 mg intravenously, if needed, repeated the injection 2-3 minutes later).  Circulatory arrest should be immediately treated with cardiopulmonary measures. Among with the acidosis elimination, it is vital to ensure blood oxygenation, respiration and blood circulation.

In case of treatment of systemic toxicity in children, use the doses based on  children’s age and body weight.

Cardiac arrest should be treated with long-lasting resuscitation measures.

Pregnancy and lactation

There is no evidence of untoward effects in human pregnancy. However, bupivacaine should not be used for women with early pregnancy, except when benefit overweighs the risks.

Adverse reactions in foetus  caused by local anesthesia, such as bradycardia, are mostly demonstrated during the paracervical block anesthesia. Such effects could be caused by high concentration of anesthetic which reaches the foetus (see. the section “Special warnings and precautions for use”).

Bupivacaine enters the mother's milk, but in such small quantities that there is generally no risk of affecting the child at therapeutic dose levels.

Children

Based on the indications for use, Bupivacaine may not be used in children

Special warnings and precautions for use

Before conducting the treatment, sensitivity test is required.

Regional or local anesthetic procedures should always be performed in a properly equipped and staffed area.

When performing the large blockades, intravenous catheters should be put before administration of the local anesthetics.

It has been reported about cardiac arrest and death which were caused by bupivacaine for epidural anesthesia and peripheral nerves’ blockade. In some cases resuscitation measures were complicated or impossible, even when adequate therapy was performed.

Large blockades of peripheral nerves may require large volumes of the local anesthetics applied on highly vascularized areas, mostly close to the large vessels. Thus, there is a high risk of intravascular injection and/or systemic absorption which may lead to the high concentrations in plasma.

Like all local anesthetic drugs, bupivacaine may cause acute toxicity effects on the central nervous and cardiovascular systems. This is especially the case after unintentional intravascular administration.

Some method of regional anesthesia may be related to severe adverse reactions:

  • epidural anesthesia can cause depression of the cardiovascular function, especial at concurrent hypovolemia. Patients with cardiovascular dysfunction should administer the product with due caution;
  • in some cases retrobulbar injections may reach cranial subarachnoid cavity and cause temporary blindness, cardiovascular failure, apnea and convulsions. These symptoms should be treated immediately;
  • retro- and peribulbar injections of local anesthetics can bring the risk of ocular dysfunction;
  • it has been reported about the possibilities of chondrolysis which occurred after surgical intervention among the patients who received long-lasting intra-articular infusions of local anesthetics. In general, chondrolysis affects shoulder joint. With account to the various etiological factors and inconsistency of literature data regarding influence mechanisms, cause-effect relationship was not detected. With the aim of surgical interventions, bupivacaine is not used as the long-lasting intra-articular infusion.

The main reasons are nerve injuries and/or local toxic effects of local anesthetic to muscle and nerves. Therefore, the lowest effective dose should be administered by the patients.

Accidental intravascular administration into the neck or head area may cause cerebral symptoms even in low doses.

Special precaution should be kept in cases when patients have AV-block of II or III grade, because local anesthetics can reduce the myocardium conductivity. Elderly patients, patients having severe liver and kidney disorders or patients in poor general condition also need special attention.

Patients treated with anti-arrhythmic drugs class III (e.g. amiodarone) should be kept under close surveillance and ECG monitoring considered, since cardiac effects may be additive.

Epidural anesthesia may lead to arterial pressure reduction and bradycardia. Such risk may be reduced through intravenous injection of crystalloid and colloid or solution. Low pressure should be treated immediately, for example through intravenous administration of ephedrine 5-10 mg, which may be repeated if needed.

Epidural anesthesia may cause paralysis of intercostal muscles and respiratory impairment among the patients having pleural exudate. Patients with septic disease have a risk of intraspinal abscess, especially at post-operative period.

Paracervical block anesthesia may sometimes cause bradycardia/tachycardia of fetus. Thus, fetus heart rhythm should be carefully observed.

Effects on ability to drive and use machines

Depending on dose and administration mode, bupivacaine may have temporary effect on body movements and coordination.

ЗаголовокInteraction with other medicinal products and other forms of interaction

Bupivacaine should be used with caution in patients receiving other products structurally similar to local anesthetics, for example, anti-arrhythmic products of IB class, since their effects are additive.

Specific interaction studies with local anesthetics and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution is advised

Pharmacological properties

Pharmacodynamic properties. Bupivacaine is  the long acting local anesthetic of amide type.

Bupivacaine has revertible action and blocks the impulses which  pass through nerve fibers by  inhibiting the transport of sodium ions through neural membranes. Similar affects may be observed in activated membranes of the brain and cardiac muscle.

The most important quality of bupivacaine is its long-lasting effect. There is a slight  difference between bupivacaine effect in combination with adrenaline and without it. Bupivacaine is specially suitable for the long-lasting epidural block. Low concentrations have lower influence upon motor nerves and have lower duration and may be suitable for the long-lasting pain control, for example during labors  or post-operative period.

Pharmacokinetic properties. Absorption rate depends on dosage, administration mode and perfusion on the administration area. Intercostal block leads to the higher concentrations in plasma (4 mg/l after administration of 400 mg) due to the fast absorption, while injections into the abdominal region lead to lower concentrations in plasma. In children patients, fast absorption and high concentrations in plasma happen during caudal block (approximately 1.0-1.5 mg after administration of 3 mg/kg dose).

Bupivacaine demonstrates full and double-phase absorption from epidural area, half-life period is nearly 7 minutes and 6 hours for fast and slow phases respectively. Slow absorption  limits recovery of bupivacaine and this is the reason why half-life after epidural application requires more time than intravenous injection.

Steady state volume distribution is approximately 73 l, liver extraction ratio is 0.4, general plasma clearance is 0.58 l/min and half-life period is 2,7 hours.

Half-life period in newborns is 8 hours longer that in adults. Children of 3 months and older have the same half-life period as adults.

Binding with plasma proteins is approximately 96%, bupivacaine usually binds with α1-glucoprotein. After significant surgical intervention, the above protein may increase and cause larger plasma concentration of bupivacaine. However, concentration of unbound proteins remains unchanged. That is why there is a good tolerance to plasma concentrations which are above the toxic levels.

Bupivacaine is almost completely metabolized in liver mostly through aromatic hydroxylation to 4-hydroxybupivacaine and N-dealkylation to PPX. Moreover, those two ways are mediated with cytochrome P450 3A4. Thus, clearance depends on liver perfusion and metabolizing ferment activity.

Bupivacaine passes the placental barrier. Concentration of free bupivacaine is the same in mother and fetus. However, the general plasma concentration is lower in fetus having the lower degree of binding with the proteins.

Incompatibilities

Alkalization may cause precipitate, since bupivacaine is slightly soluble at pH over 6.5.

Shelf life

2 years.

Storage conditions

Store in original package at the temperature not above 25°C. Keep away from children. Do not freeze.

Package

10 ml in ampules  No. 10, No.20, No.50.

Prescription category

Following the  doctor’s prescription.

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