MarcaineTM
Bupivacaine Hydrochloride Injection, USP
MarcaineTM
With Epinephrine 1:200,000 (as bitartrate)
Bupivacaine Hydrochloride and Epinephrine Injection, USP Rx only
DESCRIPTION
Bupivacaine hydrochloride is 2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-,
monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 95 percent ethanol,
soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula:
Epinephrine is (-)-3,4-Dihydroxy-α-[(methylamino)methyl] benzyl alcohol. It has the following structural
formula:
MARCAINE is available in sterile isotonic solutions with and without epinephrine (as bitartrate)
1:200,000 for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural
blocks. Solutions of MARCAINE may be autoclaved if they do not contain epinephrine. Solutions are
clear and colorless.
Bupivacaine is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a
homologue of mepivacaine and is chemically related to lidocaine. All three of these anesthetics contain an
amide linkage between the aromatic nucleus and the amino, or piperidine group. They differ in this
respect from the procaine-type local anesthetics, which have an ester linkage.
MARCAINE — Sterile isotonic solutions containing sodium chloride. In multiple-dose vials, each mL also
contains 1 mg methylparaben as antiseptic preservative. The pH of these solutions is adjusted to between
4 and 6.5 with sodium hydroxide or hydrochloric acid.
MARCAINE with epinephrine 1:200,000 (as bitartrate)—Sterile isotonic solutions containing sodium
chloride. Each mL contains bupivacaine hydrochloride and 0.0091 mg epinephrine bitartrate, with 0.5 mg
sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL
60% sodium lactate buffer, and 0.1 mg edetate calcium disodium as stabilizer. In multiple-dose vials, each
mL also contains 1 mg methylparaben as antiseptic preservative. The pH of these solutions is adjusted to
between 3.4 and 4.5 with sodium hydroxide or hydrochloric acid. The specific gravity of MARCAINE
0.5% with epinephrine 1:200,000 (as bitartrate) at 25°C is 1.008 and at 37°C is 1.008.
CLINICAL PHARMACOLOGY
Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing
the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and
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by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to
the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of
nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal
muscle tone.
Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous
systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac
conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal.
However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to
atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In
addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased
cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these
cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine.
Therefore, incremental dosing is necessary.
Following systemic absorption, local anesthetics can produce central nervous system stimulation,
depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering
progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest.
However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The
depressed stage may occur without a prior excited state.
Pharmacokinetics: The rate of systemic absorption of local anesthetics is dependent upon the total dose
and concentration of drug administered, the route of administration, the vascularity of the administration
site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of
epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and peak plasma
concentration of MARCAINE, permitting the use of moderately larger total doses and sometimes
prolonging the duration of action.
The onset of action with MARCAINE is rapid and anesthesia is long lasting. The duration of anesthesia is
significantly longer with MARCAINE than with any other commonly used local anesthetic. It has also
been noted that there is a period of analgesia that persists after the return of sensation, during which time
the need for strong analgesics is reduced.
The onset of action following dental injections is usually 2 to 10 minutes and anesthesia may last two or
three times longer than lidocaine and mepivacaine for dental use, in many patients up to 7 hours. The
duration of anesthetic effect is prolonged by the addition of epinephrine 1:200,000.
Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma
concentration of drug the higher the percentage of drug bound to plasma proteins.
Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is
governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of
lipid solubility. Fetal/ maternal ratios of local anesthetics appear to be inversely related to the degree of
plasma protein binding, because only the free, unbound drug is available for placental transfer.
MARCAINE with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The
extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug.
Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation.
Depending upon the route of administration, local anesthetics are distributed to some extent to all body
tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.
Pharmacokinetic studies on the plasma profile of MARCAINE after direct intravenous injection suggest a
three-compartment open model. The first compartment is represented by the rapid intravascular
distribution of the drug. The second compartment represents the equilibration of the drug throughout the
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highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment
represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. The
elimination of drug from tissue distribution depends largely upon the ability of binding sites in the
circulation to carry it to the liver where it is metabolized.
After injection of MARCAINE for caudal, epidural, or peripheral nerve block in man, peak levels of
bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels
during the next three to six hours.
Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence
of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the
route of drug administration, and the age of the patient. The half-life of MARCAINE in adults is 2.7 hours
and in neonates 8.1 hours.
In clinical studies, elderly patients reached the maximal spread of analgesia and maximal motor blockade
more rapidly than younger patients. Elderly patients also exhibited higher peak plasma concentrations
following administration of this product. The total plasma clearance was decreased in these patients.
Amide-type local anesthetics such as MARCAINE are metabolized primarily in the liver via conjugation
with glucuronic acid. Patients with hepatic disease, especially those with severe hepatic disease, may be
more susceptible to the potential toxicities of the amide-type local anesthetics. Pipecoloxylidine is the
major metabolite of MARCAINE.
The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion
is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted
unchanged in the urine.
When administered in recommended doses and concentrations, MARCAINE does not ordinarily produce
irritation or tissue damage and does not cause methemoglobinemia.
INDICATIONS AND USAGE
MARCAINE is indicated for the production of local or regional anesthesia or analgesia for surgery, dental
and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Only
the 0.25% and 0.5% concentrations are indicated for obstetrical anesthesia. (See WARNINGS.)
Experience with nonobstetrical surgical procedures in pregnant patients is not sufficient to recommend
use of 0.75% concentration of MARCAINE in these patients.
MARCAINE is not recommended for intravenous regional anesthesia (Bier Block). See WARNINGS.
The routes of administration and indicated MARCAINE concentrations are:
∙ local infiltration 0.25%
∙ peripheral nerve block 0.25% and 0.5%
∙ retrobulbar block 0.75%
∙ sympathetic block 0.25%
∙ lumbar epidural 0.25%, 0.5%, and 0.75%
(0.75% not for obstetrical anesthesia)
∙ caudal 0.25% and 0.5%
∙ epidural test dose 0.5% with epinephrine 1:200,000
∙ dental blocks 0.5% with epinephrine 1:200,000
(See DOSAGE AND ADMINISTRATION for additional information.)
Standard textbooks should be consulted to determine the accepted procedures and techniques for the
administration of MARCAINE.
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CONTRAINDICATIONS
MARCAINE is contraindicated in obstetrical paracervical block anesthesia. Its use in this technique has
resulted in fetal bradycardia and death.
MARCAINE is contraindicated in patients with a known hypersensitivity to it or to any local anesthetic
agent of the amide-type or to other components of MARCAINE solutions.
WARNINGS
THE 0.75% CONCENTRATION OF MARCAINE IS NOT RECOMMENDED FOR
OBSTETRICAL ANESTHESIA. THERE HAVE BEEN REPORTS OF CARDIAC ARREST
WITH DIFFICULT RESUSCITATION OR DEATH DURING USE OF MARCAINE FOR
EPIDURAL ANESTHESIA IN OBSTETRICAL PATIENTS. IN MOST CASES, THIS HAS
FOLLOWED USE OF THE 0.75% CONCENTRATION. RESUSCITATION HAS BEEN
DIFFICULT OR IMPOSSIBLE DESPITE APPARENTLY ADEQUATE PREPARATION
AND APPROPRIATE MANAGEMENT. CARDIAC ARREST HAS OCCURRED AFTER
CONVULSIONS RESULTING FROM SYSTEMIC TOXICITY, PRESUMABLY
FOLLOWING UNINTENTIONAL INTRAVASCULAR INJECTION. THE 0.75%
CONCENTRATION SHOULD BE RESERVED FOR SURGICAL PROCEDURES WHERE A
HIGH DEGREE OF MUSCLE RELAXATION AND PROLONGED EFFECT ARE
NECESSARY.
LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL
VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER
ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND
THEN ONLY AFTER INSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER
RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE
PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS
AND RELATED EMERGENCIES. (See also ADVERSE REACTIONS, PRECAUTIONS, and
OVERDOSAGE.) DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY,
UNDERVENTILATION FROM ANY CAUSE, AND/OR ALTERED SENSITIVITY MAY LEAD TO
THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH.
Local anesthetic solutions containing antimicrobial preservatives, i.e., those supplied in multiple-dose
vials, should not be used for epidural or caudal anesthesia because safety has not been established with
regard to intrathecal injection, either intentionally or unintentionally, of such preservatives.
Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an
unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such
infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno
humeral chondrolysis have been described in pediatric and adult patients following intra-articular
infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is
insufficient information to determine whether shorter infusion periods are not associated with these
findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable,
but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for
chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic
procedures and some required arthroplasty or shoulder replacement.
It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting
any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or
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subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or
subarachnoid injection.
MARCAINE with epinephrine 1:200,000 or other vasopressors should not be used concomitantly with
ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of
MARCAINE containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in
patients receiving monoamineoxidase inhibitors (MAOI) or antidepressants of the triptyline or
imipramine types, because severe prolonged hypertension may result.
Until further experience is gained in pediatric patients younger than 12 years, administration of
MARCAINE in this age group is not recommended.
Mixing or the prior or intercurrent use of any other local anesthetic with MARCAINE cannot be
recommended because of insufficient data on the clinical use of such mixtures.
There have been reports of cardiac arrest and death during the use of MARCAINE for intravenous
regional anesthesia (Bier Block). Information on safe dosages and techniques of administration of
MARCAINE in this procedure is lacking. Therefore, MARCAINE is not recommended for use in this
technique.
MARCAINE with epinephrine 1:200,000 contains sodium metabisulfite, a sulfite that may cause allergic-
type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in
certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is
unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic
people. Single-dose ampuls and single-dose vials of MARCAINE without epinephrine do not contain
sodium metabisulfite.
PRECAUTIONS
General: The safety and effectiveness of local anesthetics depend on proper dosage, correct technique,
adequate precautions, and readiness for emergencies. Resuscitative equipment, oxygen, and other
resuscitative drugs should be available for immediate use. (See WARNINGS, ADVERSE
REACTIONS, and OVERDOSAGE.) During major regional nerve blocks, the patient should have IV
fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage
of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and
serious adverse effects. The rapid injection of a large volume of local anesthetic solution should be
avoided and fractional (incremental) doses should be used when feasible.
Epidural Anesthesia: During epidural administration of MARCAINE, 0.5% and 0.75% solutions should
be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic
manifestations of unintentional intravascular or intrathecal injection. Injections should be made slowly,
with frequent aspirations before and during the injection to avoid intravascular injection. Syringe
aspirations should also be performed before and during each supplemental injection in continuous
(intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood
are negative.
During the administration of epidural anesthesia, it is recommended that a test dose be administered
initially and the effects monitored before the full dose is given. When using a “continuous” catheter
technique, test doses should be given prior to both the original and all reinforcing doses, because plastic
tubing in the epidural space can migrate into a blood vessel or through the dura. When clinical conditions
permit, the test dose should contain epinephrine (10 mcg to 15 mcg has been suggested) to serve as a
warning of unintended intravascular injection. If injected into a blood vessel, this amount of epinephrine
is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in
heart rate and/or systolic blood pressure, circumoral pallor, palpitations, and nervousness in the unsedated
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patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15
or more seconds. Therefore, following the test dose, the heart rate should be monitored for a heart rate
increase. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring
can detect a transient rise in systolic blood pressure. The test dose should also contain 10 mg to 15 mg of
MARCAINE or an equivalent amount of another local anesthetic to detect an unintended intrathecal
administration. This will be evidenced within a few minutes by signs of spinal block (e.g., decreased
sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). The Test Dose
formulation of MARCAINE contains 15 mg of bupivacaine and 15 mcg of epinephrine in a volume of
3 mL. An intravascular or subarachnoid injection is still possible even if results of the test dose are
negative. The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced
cardiovascular effects.
Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each
repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation.
Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients and
acutely ill patients should be given reduced doses commensurate with their age and physical status. Local
anesthetics should also be used with caution in patients with hypotension or heartblock.
Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs
and the patient’s state of consciousness should be performed after each local anesthetic injection. It should
be kept in mind at such times that restlessness, anxiety, incoherent speech, lightheadedness, numbness
and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching,
depression, or drowsiness may be early warning signs of central nervous system toxicity.
Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully
restricted
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