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.
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
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 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 quantities in areas of
the body supplied by end arteries or having otherwise compromised blood supply
such as digits, nose, external ear, or penis. Patients with hypertensive
vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic
injury or necrosis may result.
Because amide-local anesthetics such as MARCAINE are
metabolized by the liver, these drugs, especially repeat doses, should be used
cautiously in patients with hepatic disease. Patients with severe hepatic
disease, because of their inability to metabolize local anesthetics normally,
are at a greater risk of developing toxic plasma concentrations. Local
anesthetics should also be used with caution in patients with impaired
cardiovascular function because they may be less able to compensate for
functional changes associated with the prolongation of AV conduction produced
by these drugs.
Serious dose-related cardiac arrhythmias may occur if
preparations containing a vasoconstrictor such as epinephrine are employed in
patients during or following the administration of potent inhalation
anesthetics. In deciding whether to use these products concurrently in the same
patient, the combined action of both agents upon the myocardium, the
concentration and volume of vasoconstrictor used, and the time since injection,
when applicable, should be taken into account.
Many drugs used during the conduct of anesthesia are
considered potential triggering agents for familial malignant hyperthermia.
Because it is not known whether amide-type local anesthetics may trigger this
reaction and because the need for supplemental general anesthesia cannot be
predicted in advance, it is suggested that a standard protocol for management
should be available. Early unexplained signs of tachycardia, tachypnea, labile
blood pressure, and metabolic acidosis may precede temperature elevation.
Successful outcome is dependent on early diagnosis, prompt discontinuance of
the suspect triggering agent(s) and prompt institution of treatment, including
oxygen therapy, indicated supportive measures and dantrolene. (Consult
dantrolene sodium intravenous package insert before using.)
Use in Head and Neck Area: Small doses of local
anesthetics injected into the head and neck area, including retrobulbar,
dental, and stellate ganglion blocks, may produce adverse reactions similar to
systemic toxicity seen with unintentional intravascular injections of larger
doses. The injection procedures require the utmost care. Confusion,
convulsions, respiratory depression, and/or respiratory arrest, and
cardiovascular stimulation or depression have been reported. These reactions
may be due to intra-arterial injection of the local anesthetic with retrograde
flow to the cerebral circulation. They may also be due to puncture of the dural
sheath of the optic nerve during retrobulbar block with diffusion of any local
anesthetic along the subdural space to the midbrain. Patients receiving these
blocks should have their circulation and respiration monitored and be
constantly observed. Resuscitative equipment and personnel for treating adverse
reactions should be immediately available. Dosage recommendations should not be
exceeded. (See DOSAGE AND ADMINISTRATION.)
Use in Ophthalmic Surgery: Clinicians who perform
retrobulbar blocks should be aware that there have been reports of respiratory
arrest following local anesthetic injection. Prior to retrobulbar block, as
with all other regional procedures, the immediate availability of equipment,
drugs, and personnel to manage respiratory arrest or depression, convulsions,
and cardiac stimulation or depression should be assured (see also WARNINGS
and Use In Head and Neck Area, above). As with other anesthetic
procedures, patients should be constantly monitored following ophthalmic blocks
for signs of these adverse reactions, which may occur following relatively low
A concentration of 0.75% bupivacaine is indicated for
retrobulbar block; however, this concentration is not indicated for any other peripheral nerve block, including the facial nerve, and not indicated for local
infiltration, including the conjunctiva (see INDICATIONS AND USAGE and PRECAUTIONS,
General). Mixing MARCAINE with other local anesthetics is not
recommended because of insufficient data on the clinical use of such mixtures.
When MARCAINE 0.75% is used for retrobulbar block, complete corneal anesthesia usually precedes onset of clinically acceptable external
ocular muscle akinesia. Therefore, presence of akinesia rather than anesthesia
alone should determine readiness of the patient for surgery.
Use in Dentistry: Because of the long duration of
anesthesia, when MARCAINE 0.5% with epinephrine is used for dental injections,
patients should be cautioned about the possibility of inadvertent trauma to
tongue, lips, and buccal mucosa and advised not to chew solid foods or test the
anesthetized area by biting or probing.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to evaluate the carcinogenic
potential of bupivacaine hydrochloride have not been conducted. The mutagenic
potential and the effect on fertility of bupivacaine hydrochloride have not
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant
women. MARCAINE should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus. Bupivacaine hydrochloride produced
developmental toxicity when administered subcutaneously to pregnant rats and
rabbits at clinically relevant doses. This does not exclude the use of MARCAINE
at term for obstetrical anesthesia or analgesia. (See Labor and Delivery)
Bupivacaine hydrochloride was administered subcutaneously to
rats at doses of 4.4, 13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8,
& 22.2 mg/kg during the period of organogenesis (implantation to closure of
the hard palate). The high doses are comparable to the daily maximum
recommended human dose (MRHD) of 400 mg/day on a mg/m2 body surface
area (BSA) basis. No embryo-fetal effects were observed in rats at the high
dose which caused increased maternal lethality. An increase in embryo-fetal
deaths was observed in rabbits at the high dose in the absence of maternal
toxicity with the fetal No Observed Adverse Effect Level representing
approximately 1/5th the MRHD on a BSA basis.
In a rat pre- and post-natal development study (dosing from
implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3,
& 40 mg/kg mg/kg/day, decreased pup survival was observed at the high dose.
The high dose is comparable to the daily MRHD of 400 mg/day on a BSA basis.
Labor and Delivery
SEE BOXED WARNING REGARDING OBSTETRlCAL USE OF 0.75%
MARCAINE is contraindicated for obstetrical paracervical
Local anesthetics rapidly cross the placenta, and when used
for epidural, caudal, or pudendal block anesthesia, can cause varying degrees
of maternal, fetal, and neonatal toxicity. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.)
The incidence and degree of toxicity depend upon the procedure performed, the
type, and amount of drug used, and the technique of drug administration.
Adverse reactions in the parturient, fetus, and neonate involve alterations of
the central nervous system, peripheral vascular tone, and cardiac function.
Maternal hypotension has resulted from regional anesthesia.
Local anesthetics produce vasodilation by blocking sympathetic nerves.
Elevating the patient's legs and positioning her on her left side will help
prevent decreases in blood pressure. The fetal heart rate also should be
monitored continuously and electronic fetal monitoring is highly advisable.
Epidural, caudal, or pudendal anesthesia may alter the
forces of parturition through changes in uterine contractility or maternal
expulsive efforts. Epidural anesthesia has been reported to prolong the second
stage of labor by removing the parturient's reflex urge to bear down or by
interfering with motor function. The use of obstetrical anesthesia may increase
the need for forceps assistance.
The use of some local anesthetic drug products during labor
and delivery may be followed by diminished muscle strength and tone for the
first day or two of life. This has not been reported with bupivacaine.
It is extremely important to avoid aortocaval compression by
the gravid uterus during administration of regional block to parturients. To do
this, the patient must be maintained in the left lateral decubitus position or
a blanket roll or sandbag may be placed beneath the right hip and gravid uterus
displaced to the left.
Bupivacaine has been reported to be excreted in human milk
suggesting that the nursing infant could be theoretically exposed to a dose of
the drug. Because of the potential for serious adverse reactions in nursing
infants from bupivacaine, a decision should be made whether to discontinue
nursing or not administer bupivacaine, taking into account the importance of
the drug to the mother.
Until further experience is gained in pediatric patients
younger than 12 years, administration of MARCAINE in this age group is not
recommended. Continuous infusions of bupivacaine in children have been reported
to result in high systemic levels of bupivacaine and seizures; high plasma
levels may also be associated with cardiovascular abnormalities. (See WARNINGS,
PRECAUTIONS, and OVERDOSAGE.)
Patients over 65 years, particularly those with hypertension,
may be at increased risk for developing hypotension while undergoing anesthesia
with MARCAINE. (See ADVERSE REACTIONS.)
Elderly patients may require lower doses of MARCAINE. (See PRECAUTIONS,
Epidural Anesthesia and DOSAGE AND ADMINISTRATION.)
In clinical studies, differences in various pharmacokinetic
parameters have been observed between elderly and younger patients. (See CLINICAL
This product is known to be substantially excreted by the
kidney, and the risk of toxic reactions to this drug may be greater in patients
with impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection, and it may be
useful to monitor renal function. (See CLINICAL PHARMACOLOGY.)