Marcaine^® Adrenaline (Solution) Instructions for Use

Marketing Authorization Holder

Aspen Pharma Trading, Limited (Ireland)

Manufactured By

Recipharm Monts (France)

ATC Code

N01BB51 (Bupivacaine in combination with other drugs)

Active Substances

Bupivacaine (Rec.INN registered by WHO)

Epinephrine (Rec.INN registered by WHO)

Dosage Form

Marcaine® Adrenaline

Injection Solution 100 mg+100 mcg/20 ml: fl. 5 pcs.

Dosage Form, Packaging, and Composition

20 ml – vials (5) – cardboard packs.

Clinical-Pharmacological Group

Local anesthetic with a vasoconstrictor component

Pharmacotherapeutic Group

Local anesthetic agent + alpha- and beta-adrenomimetic

Pharmacological Action

A combined preparation consisting of a local anesthetic – bupivacaine and an alpha- and beta-adrenomimetic – epinephrine.

Bupivacaine is a long-acting amide-type anesthetic, 4 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.

With a single epidural injection, the duration of effect when using a concentration of 5 mg/ml is from 2 to 5 hours and up to 12 hours with peripheral blockade.

Using solutions at a concentration of 2.5 mg/ml has a lesser effect on motor nerves.

The addition of the vasoconstrictor epinephrine leads to a decrease in the rate of absorption of the anesthetic and, as a result, to an enhancement and prolongation of the drug’s action.

Pharmacokinetics

Bupivacaine has a pKa of 8.2 and a partition coefficient of 346 (at 25°C (77°F) in n-octanol/phosphate buffer pH 7.4 medium).

Bupivacaine is completely absorbed into the blood from the subarachnoid space; absorption is biphasic, the half-life for the two phases is 7 minutes and 6 hours, respectively. The slow elimination of bupivacaine is determined by the presence of a slow absorption phase from the epidural space, which explains the longer T_1/2 after epidural administration compared to intravenous administration.

The total plasma clearance of bupivacaine is 0.58 l/min, the volume of distribution at steady state is 73 l, the terminal T_1/2 is 2.7 hours, the intermediate hepatic extraction index is about 0.38 after IV administration. Bupivacaine is mainly bound to α1-acid glycoproteins in plasma (plasma protein binding – 96%). The clearance of bupivacaine is almost entirely due to the metabolism of the drug in the liver and depends more on the activity of hepatic enzyme systems than on liver perfusion. Metabolites have less pharmacological activity than Bupivacaine.

In children aged from 1 to 7 years, the pharmacokinetics of the drug are similar to those in adults.

It crosses the placenta. Binding to plasma proteins in the fetus is lower than in the mother, the concentration of the 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 N-dealkylation to pipecoloxylidine (PPX). Both reactions occur with the participation of cytochrome P4503A4 enzymes. 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-hydroxy-bupivacaine in plasma during and after prolonged administration of bupivacaine is low relative to the administered dose of the drug.

Indications

• Various types of local anesthesia (pain relief for trauma, surgical interventions, including caesarean section, labor analgesia, performing painful diagnostic procedures, for example, during arthroscopy);
• Local infiltration anesthesia, conduction anesthesia (including intercostal block, block of large and small nerves, block of nerves in the head and neck area), caudal or lumbar epidural block, retrobulbar (regional) anesthesia.

ICD codes

Dosage Regimen

Adults and children over 12 years

The table below is a guide for dosing the drug for the most commonly performed techniques. When calculating the required dose, it is important to base it on clinical experience and assessment of the patient’s physical status.

Dosage recommendations

The doses indicated in the table are considered necessary for successful blockade and should be considered as recommended doses for an average adult patient. As a rule, the dose of a local anesthetic containing Epinephrine is equal to the dose of the anesthetic without epinephrine.

There are large individual differences in the onset and duration of action, so exact doses cannot be established. When using other regional anesthesia techniques, reference data should be used.

When using a large volume of solution containing Epinephrine, the possibility of risk of developing systemic effects of epinephrine should be taken into account.

Note: When administering large volumes of solutions containing Epinephrine, there is a risk of developing systemic effects of epinephrine.

Maximum recommended dose: 30 ml (150 mg bupivacaine hydrochloride). The maximum recommended dose is determined based on the administration of 2 mg/kg body weight and is for adults 150 mg bupivacaine hydrochloride over a 4-hour period. The maximum allowable daily dose is 400 mg (80 ml Marcaine adrenaline). The drug should be administered with caution to avoid the development of acute toxic reactions in case of accidental intravascular administration of the drug. It is recommended to carefully perform an aspiration test before and during the administration of the drug. If a large dose is required, for example, during epidural block, 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, the administration of the drug should be stopped immediately.

For children under 12 years, the dose should be calculated taking into account body weight (on average up to 2 mg/kg), for lumbosacral – 1.5-2 mg/kg body weight, for thoracolumbar -1.5- 2.5 mg/kg body weight. The addition of epinephrine increases the duration of the block by 50-100%.

Usage recommendations. The solution does not contain preservatives and should be used immediately after opening the container. The solution is for single use only. Residual solution should be discarded.

Due to the instability of epinephrine, solutions containing it should not be sterilized.

Avoid prolonged contact between solutions of local anesthetic containing adrenaline (low pH value) and metal surfaces (e.g., needles or metal parts of a syringe), due to the possibility of developing allergic reactions at the injection site, and possible acceleration of epinephrine decomposition.

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

Adverse Reactions

Adverse reactions to Marcaine are similar to adverse reactions that occur with intrathecal administration of other long-acting local anesthetics. Adverse reactions caused by the drug itself are difficult to distinguish from physiological manifestations of nerve block (e.g., arterial hypotension, bradycardia, temporary urinary retention), reactions caused directly (e.g., spinal hematoma) or indirectly (e.g., meningitis, epidural abscess) by needle insertion, or reactions associated with cerebrospinal fluid leakage (e.g., post-puncture headache).

Contraindications

• Children’s age (up to 2 years);
• Diseases of the CNS, septicemia, pustular skin lesions at the injection site (as with epidural administration of other local anesthetics);
• Hypersensitivity to any of the components of the drug (for example, methylparahydroxybenzoate) or to amide-type local anesthetics;
• Hypersensitivity to sodium metabisulfite, which is part of solutions containing Epinephrine.

The drug is not used for epidural anesthesia in patients with severe arterial hypotension, such as cardiogenic or hypovolemic shock.

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

With caution cardiovascular failure (possible progression), AV block II and III degree, inflammatory diseases, cholinesterase deficiency, renal failure, elderly age (over 65 years), late stage of pregnancy (III trimester), general severe condition, reduced hepatic blood flow (e.g., in chronic heart failure, liver diseases), simultaneous administration of antiarrhythmic agents (including beta-blockers), the need for paracervical anesthesia, children’s age (up to 12 years);

for peridural administration (caudal and lumbar anesthesia) – previous neurological diseases, deformity or other changes of the spine. 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 (e.g., lidocaine, mexiletine). Solutions containing Epinephrine should be used with caution in patients with severe or untreated arterial hypertension, poorly controlled thyrotoxicosis, coronary heart disease, AV block, cerebrovascular accident, complicated diabetes or other conditions that may be exacerbated by the influence of epinephrine. Caution should be exercised in cases of peripheral administration of the drug in areas with reduced blood circulation (such as fingers and toes).

Use in Pregnancy and Lactation

With caution: late stage of pregnancy (III trimester).

The drug should be used only if the expected benefit to the mother outweighs the possible risk to the fetus.

Bupivacaine has been used in a large number of pregnant women and women of childbearing age, however, no specific changes in reproductive function, for example, an increase in the frequency of developmental defects, have been noted to date.

The addition of epinephrine to bupivacaine may reduce uterine blood flow and contractility, especially if the anesthetic solution is accidentally injected into maternal vessels. Side effects caused by the action of the local anesthetic on the fetus, such as bradycardia, are most often found with paracervical block (the anesthetic reaches the fetus in high concentration).

Like other local anesthetics, Bupivacaine can pass into breast milk in insignificant amounts that do not pose a danger to the newborn.

There are no data on the passage of epinephrine into breast milk, the likelihood of impact on the newborn is extremely low.

Use in Hepatic Impairment

With caution: reduced hepatic blood flow (e.g., in chronic heart failure, liver diseases).

Use in Renal Impairment

With caution: renal failure.

Pediatric Use

Contraindicated in children under 2 years of age. With caution: from 2 to 12 years.

Geriatric Use

With caution: elderly age (over 65 years).

Special Precautions

There have been reports of cardiac arrest or death during the use of bupivacaine for epidural anesthesia or peripheral block. In some cases, resuscitation was difficult or impossible, despite undoubtedly good preparation and anesthesia.

Like other local anesthetics, Bupivacaine can cause acute toxic reactions from the central nervous and cardiovascular systems if its use for local anesthesia leads to a high concentration of the drug in the blood. This most often occurs in the case of unintentional intravascular injection or when the injection site is highly vascularized. Against the background of high plasma concentration of bupivacaine, cases of ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death have been recorded.

Regional and local anesthesia, with the exception of 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. Staff should be appropriately trained in anesthesia techniques and should be familiar with the diagnosis and treatment of the drug’s side effects, systemic toxic reactions and other complications (see the “Overdose” section).

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

When performing regional anesthesia, special attention should be paid to the following groups of patients

• Patients receiving class III antiarrhythmic drugs (e.g., amiodarone) should be under close observation due to the possible risk of developing complications from the Cardiovascular system
• Elderly patients and debilitated patients
• Patients with partial or complete heart block, as local anesthetics may impair myocardial conduction.
• Patients with progressive liver disease or severe renal impairment.

Certain types of blocks, regardless of the local anesthetic used, may be associated with serious adverse reactions, for example

• Central blocks, especially against the background of hypovolemia, can lead to depression of cardiovascular activity.
• Large peripheral blocks may require the use of a large amount of local anesthetic in areas of high vascularity, often near large vessels, where the risk of intravascular injection and/or systemic absorption increases, which can lead to high plasma concentration of the drug.
• During retrobulbar injection, the drug may accidentally enter the cranial subarachnoid space, causing temporary blindness, apnea, convulsions, collapse and other side effects. Developed complications should be diagnosed and managed in a timely manner.
• During retrobulbar and peribulbar administration of local anesthetics, there is a slight risk of persistent impairment of ocular 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 trauma, 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 intensify tissue reactions and should be used only when indicated.
• During injections in the neck or head area, the drug may accidentally enter an artery, and in such cases, even when using low doses, the development of serious adverse reactions is possible.

Paracervical block sometimes leads to the appearance of fetal bradycardia/tachycardia, therefore careful monitoring of the fetal heart rate is mandatory.

Marcaine solution with epinephrine contains sodium metabisulfite. Sulfite can cause allergic-type reactions (including symptoms of anaphylaxis and asthmatic episodes up to life-threatening) in susceptible individuals. The prevalence of sulfite sensitivity in the general population is unknown and appears to be low. Sensitivity to sulfite is more common in asthmatics compared to individuals without asthmatic manifestations.

The solution does not contain preservatives and must be used immediately after opening the container. Any remaining solution must be discarded.

Overdose

Acute systemic intoxication

In case of accidental intravascular injection, a toxic reaction manifests within 1-3 minutes, whereas in case of overdose, peak plasma concentrations of the drug may 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 system and the cardiovascular system.

Against the background of high plasma concentration of bupivacaine, cases of ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse, and death have been recorded.

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, numbness of the tongue, pathologically heightened 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 these, loss of consciousness and the development of major convulsive seizures, which can last from a few seconds to several minutes, are possible. 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 subside due to the redistribution of the local anesthetic from the central nervous system and the metabolism of the drug. The cessation of toxic phenomena can occur quickly, unless the anesthetic was administered in a very large amount.

Cardiovascular System.

Toxic reactions manifesting from the cardiovascular system lead to the most severe consequences and usually precede the manifestation of toxic reactions from the central nervous system, which may be masked during general anesthesia or deep sedation with drugs such as benzodiazepines or barbiturates.

Against the background of high plasma concentrations of local anesthetics, the development of arterial hypotension, bradycardia, arrhythmias, and in some cases, cardiac arrest was noted.

Toxic reactions from the cardiovascular system are often associated with suppression of cardiac and myocardial conduction, which in turn can lead to a decrease in cardiac output, arterial hypotension, AV block, bradycardia, and in some cases to ventricular arrhythmia, including ventricular tachycardia and fibrillation, and cardiac arrest. These toxic manifestations often precede the manifestation of symptoms of acute toxicity from the central nervous system, for example, in the form of convulsions, however, in rare cases, cardiac arrest can occur without prior signs from the central nervous system. In the case of rapid intravenous bolus injection, a high plasma concentration of bupivacaine may be observed in the coronary vessels, affecting vascular circulation and leading to the development of independent cardiotoxic effects or preceding the development of toxic effects from the central nervous system. Therefore, myocardial depression may manifest as the first symptoms of intoxication. Particular attention should be paid to the early signs of intoxication development in children, since in this group of patients, a more pronounced block is most often achieved after the onset of anesthesia.

Treatment of acute intoxication

If signs of systemic intoxication appear, the 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 should be established (using a mask and bag). 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 thiopental quickly stops convulsions; alternatively, 5-10 mg of diazepam can be administered intravenously, although it acts more slowly. Succinylcholine quickly stops muscle convulsions, however, its use requires tracheal intubation and artificial lung ventilation, so this drug should be used only by those who are proficient in these methods.

With obvious depression of the cardiovascular system function (decreased BP and bradycardia), 5-10 mg of ephedrine is administered intravenously, repeating the administration after 2-3 minutes if necessary. In case of cardiac arrest, cardiopulmonary resuscitation should be started immediately. Optimization of oxygenation and ventilation and support of circulation along with correction of acidosis are vital, as hypoxia and acidosis will enhance the systemic toxic effects of the local anesthetic. Epinephrine (0.1-0.2 mg intravenously or intracardiac) should be administered as soon as possible, repeating the administration if necessary.

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 structurally similar to amide-type local anesthetics, such as antiarrhythmic drugs (e.g., lidocaine, mexiletine), due to the possibility of an additive toxic effect. The concomitant use of bupivacaine with class III antiarrhythmic drugs (e.g., amiodarone) has not been specifically studied, but caution is recommended when co-administering these drugs (see section “Special Instructions”).

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

Drugs containing oxytocin or ergotamine promote the development of 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 development.

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 CNS, local anesthetics enhance CNS depression.

Non-cardioselective beta-blockers, such as propranolol, enhance the pressor effect of epinephrine, which can lead to severe arterial hypertension and bradycardia.

Neuroleptics, such as phenothiazine and butyrophenone derivatives, may reduce the vasopressor effect of epinephrine.

When bupivacaine is used with narcotic analgesics during epidural anesthesia, an additive effect develops, but respiratory depression is enhanced.

Anticoagulants (ardeparin, dalteparin, danaparoid, enoxaparin, heparin, warfarin) increase the risk of bleeding.

Storage Conditions

List B. At a temperature not exceeding 15°C (59°F), protected from light, do not freeze. Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

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.