Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1586
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Marcaine (Injection, Solution)
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The dose of any local anesthetic administered varies
with the anesthetic procedure, the area to be anesthetized, the vascularity
of the tissues, the number of neuronal segments to be blocked, the
depth of anesthesia and degree of muscle relaxation required, the
duration of anesthesia desired, individual tolerance, and the physical
condition of the patient. The smallest dose and concentration required
to produce the desired result should be administered. Dosages of MARCAINE
should be reduced for elderly and/or debilitated patients and patients
with cardiac and/or liver disease. The rapid injection of a large
volume of local anesthetic solution should be avoided and fractional
(incremental) doses should be used when feasible. For specific techniques and procedures, refer to standard textbooks. In recommended doses, MARCAINE produces complete sensory
block, but the effect on motor function differs among the three concentrations. 0.25%���when used for caudal, epidural, or peripheral
nerve block, produces incomplete motor block. Should be used for
operations in which muscle relaxation is not important, or when another
means of providing muscle relaxation is used concurrently. Onset of
action may be slower than with the 0.5% or 0.75% solutions. 0.5%���provides motor blockade for caudal, epidural,
or nerve block, but muscle relaxation may be inadequate for operations
in which complete muscle relaxation is essential. 0.75%���produces complete motor block. Most useful for
epidural block in abdominal operations requiring complete muscle relaxation,
and for retrobulbar anesthesia. Not for obstetrical anesthesia. The duration of anesthesia with MARCAINE is such that
for most indications, a single dose is sufficient. Maximum dosage limit must be individualized in each case after evaluating
the size and physical status of the patient, as well as the usual
rate of systemic absorption from a particular injection site. Most
experience to date is with single doses of MARCAINE up to 225 mg with
epinephrine 1:200,000 and 175 mg without epinephrine; more or less
drug may be used depending on individualization of each case. These doses may be repeated up to once every three hours.
In clinical studies to date, total daily doses have been up to 400
mg. Until further experience is gained, this dose should not be exceeded
in 24 hours. The duration of anesthetic effect may be prolonged by
the addition of epinephrine. The dosages in
Table 1 have generally proved satisfactory and are recommended as
a guide for use in the average adult. These dosages should be reduced
for elderly or debilitated patients. Until further experience is gained,
MARCAINE is not recommended for pediatric patients younger than 12
years. MARCAINE is contraindicated for obstetrical paracervical blocks,
and is not recommended for intravenous regional anesthesia (Bier Block). Use in 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. In obstetrics, only the 0.5%
and 0.25% concentrations should be used; incremental doses of 3 mL
to 5 mL of the 0.5% solution not exceeding 50 mg to 100 mg at any
dosing interval are recommended. Repeat doses should be preceded by
a test dose containing epinephrine if not contraindicated. Use only
the single-dose ampuls and single-dose vials for caudal or epidural
anesthesia; the multiple-dose vials contain a preservative and therefore
should not be used for these procedures. Test Dose for Caudal and Lumbar Epidural Blocks: The Test Dose of MARCAINE (0.5% bupivacaine with 1:200,000 epinephrine
in a 3 mL ampul) is recommended for use as a test dose when clinical
conditions permit prior to caudal and lumbar epidural blocks. This
may serve as a warning of unintended intravascular or subarachnoid
injection. (See PRECAUTIONS.) The pulse rate and other signs should
be monitored carefully immediately following each test dose administration
todetect possible intravascular injection, and adequate time for
onset of spinal block should be allotted to detect possible intrathecal
injection. 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 cardiovascular
effects from the epinephrine. (See WARNINGS and OVERDOSAGE.) Use in Dentistry: The 0.5% concentration with epinephrine is recommended for infiltration
and block injection in the maxillary and mandibular area when a longer
duration of local anesthetic action is desired, such as for oral surgical
procedures generally associated with significant postoperative pain.
The average dose of 1.8 mL (9 mg) per injection site will usually
suffice; an occasional second dose of 1.8 mL (9 mg) may be used if
necessary to produce adequate anesthesia after making allowance for
2 to 10 minutes onset time. (See CLINICAL PHARMACOLOGY.) The lowest
effective dose should beemployed and time should be allowed between
injections; it is recommended that the total dose for all injection
sites, spread out over a single dental sitting, should not ordinarily
exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of
0.5% MARCAINE with epinephrine). Injections should be made slowly
and with frequent aspirations. Until further experience is gained,
MARCAINE in dentistry is not recommended for pediatric patients younger
than 12 years. Unused portions of solution not
containing preservatives, i.e., those supplied in single-dose ampuls
and single-dose vials, should be discarded following initial use. This product should be inspected visually for particulate
matter and discoloration prior to administration whenever solution
and container permit. Solutions which are discolored or which contain
particulate matter should not be administered. With continuous (intermittent) techniques,
repeat doses increase the degree of motor block. The first repeat
dose of 0.5% may produce complete motor block. Intercostal nerve block
with 0.25% may also produce complete motor block for intra-abdominal
surgery. For single-dose use, not
for intermittent epidural technique. Not for obstetrical anesthesia. See PRECAUTIONS. Solutions with or without epinephrine.
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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-��-[(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.
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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 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 thanwith 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 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 2.7hours 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.
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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.
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These solutions are not
for spinal anesthesia. Store at 20
to 25��C (68 to 77��F). [See USP Controlled Room Temperature.] MARCAINE���Solutions
of MARCAINE that do not contain epinephrine may be autoclaved. Autoclave
at 15-pound pressure, 121��C (250��F) for 15 minutes. MARCAINE with epinephrine
1:200,000 (as bitartrate)���Solutions of MARCAINE that contain epinephrine should not be autoclaved
and should be protected from light. Do not use the solution if its
color is pinkish or darker than slightly yellow or if it contains
a precipitate. Revised: October, 2004 ��Hospira 2004 EN-0664
Printed in USA HOSPIRA, INC., LAKE FOREST, IL 60045 USA
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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.
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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 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 significantincreases 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 andtingling 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 total doses. 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 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.<br/>Information for Patients:: When appropriate, patients should be informed in
advance that they may experience temporary loss of sensation and motor
activity, usually in the lower half of the body, following proper
administration of caudal or epidural anesthesia. Also, when appropriate,
the physician should discuss other information including adverse reactions
in the package insert of MARCAINE. Patients
receiving dental injections of MARCAINE should be cautioned not to
chew solid foods or test the anesthetized area by biting or probing
until anesthesia has worn off (up to 7 hours).<br/>Clinically Significant Drug Interactions:: The administration of local anesthetic solutions
containing epinephrine or norepinephrine to patients receiving monoamine
oxidase inhibitors or tricyclic antidepressants may produce severe,
prolonged hypertension. Concurrent use of these agents should generally
be avoided. In situations when concurrent therapy is necessary, careful
patient monitoring is essential. Concurrent
administration of vasopressor drugs and of ergot-type oxytocic drugs
may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse
the pressor effect of epinephrine.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: Long-term studies in animals of most local anesthetics
including bupivacaine to evaluate the carcinogenic potential have
not been conducted. Mutagenic potential or the effect on fertility
has not been determined. There is no evidence from human data that
MARCAINE may be carcinogenic or mutagenic or that it impairs fertility.<br/>Pregnancy Category C:: Decreased pup survival in rats and an embryocidal
effect in rabbits have been observed when bupivacaine hydrochloride
was administered to these species in doses comparable to nine and
five times respectively the maximum recommended daily human dose (400 mg).
There are no adequate and well-controlledstudies in pregnant women
of the effect of bupivacaine on the developing fetus. Bupivacaine
hydrochloride should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus. This does not exclude
the use of MARCAINE at term for obstetrical anesthesia or analgesia.
(See Labor and Delivery.)<br/>Labor and Delivery:: SEE BOXED WARNING REGARDING OBSTETRlCAL USE OF 0.75% MARCAINE. MARCAINE is contraindicated for obstetrical paracervical
block anesthesia. 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 Pharmacokinetics in CLINICAL PHARMACOLOGY.)
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 bemaintained 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.<br/>Nursing Mothers:: 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.<br/>Pediatric Use:: 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.)<br/>Geriatric Use:: 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
PHARMACOLOGY.) 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.)
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Acute emergencies from local anesthetics are generally
related to high plasma levels encountered during therapeutic use of
local anesthetics or to unintended subarachnoid injection of local
anesthetic solution. (See ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS.) Management of Local Anesthetic
Emergencies: The first consideration is prevention, best
accomplished by careful and constant monitoring of cardiovascular
and respiratory vital signs and the patient's state of consciousness
after each local anesthetic injection. At the first sign of change,
oxygen should be administered. The first step in the management of systemic toxic
reactions, as well as underventilation or apnea due to unintentional
subarachnoid injection of drug solution, consists of immediate attention
to the establishment and maintenance of a patent airway and effective
assisted or controlled ventilation with 100% oxygen with a delivery
system capable of permitting immediate positive airway pressure by
mask. This may prevent convulsions if they have not already
occurred. If necessary, use drugs to control
the convulsions. A 50 mg to 100 mg bolus IV injection of succinylcholine
will paralyze the patient without depressing the central nervous or
cardiovascular systems and facilitate ventilation. A bolus IV dose
of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental
will permit ventilation and counteract central nervous system stimulation,
but these drugs also depress central nervous system, respiratory,
and cardiac function, add to postictal depression and may result in
apnea. Intravenous barbiturates, anticonvulsant agents, or muscle
relaxants should only be administered by those familiar with their
use. Immediately after the institution of these ventilatory measures,
the adequacy of the circulation should be evaluated. Supportive treatment
of circulatory depression may require administration of intravenous
fluids, and when appropriate, a vasopressor dictated by the clinical
situation (such as ephedrine or epinephrine to enhance myocardial
contractile force). Endotracheal intubation,
employing drugs and techniques familiar to the clinician, may be indicated
after initial administration of oxygen by mask if difficulty is encountered
in the maintenance of a patent airway, or if prolonged ventilatory
support (assisted or controlled) is indicated. Recent clinical data from patients experiencing local anesthetic-induced
convulsions demonstrated rapid development of hypoxia, hypercarbia,
and acidosis with bupivacaine within a minute of the onset of convulsions.
These observations suggest that oxygen consumption and carbon dioxide
production are greatly increased during local anesthetic convulsions
and emphasize the importance of immediate and effective ventilation
with oxygen which may avoid cardiac arrest. If not treated immediately, convulsions with simultaneous hypoxia,
hypercarbia, and acidosis plus myocardial depression from the direct
effects of the local anesthetic may result in cardiac arrhythmias,
bradycardia, asystole, ventricular fibrillation, or cardiac arrest.
Respiratory abnormalities, including apnea, may occur. Underventilation
or apnea due to unintentional subarachnoid injection oflocal anesthetic
solution may produce these same signs and also lead to cardiac arrest
if ventilatory support is not instituted. If cardiac arrest should occur, successful outcome may require prolonged
resuscitative efforts. The supine
position is dangerous in pregnant women at term because of aortocaval
compression by the gravid uterus. Therefore during treatment of systemic
toxicity, maternal hypotension or fetal bradycardia following regional
block, the parturient should be maintained in the left lateral decubitus
position if possible, or manual displacement of the uterus off the
great vessels be accomplished. The mean seizure
dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg
with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous
and subcutaneous LDin mice is 6 mg/kg to 8 mg/kg and
38 mg/kg to 54 mg/kg respectively.
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| dailymed-instance:genericMe... |
Bupivacaine Hydrochloride
|
| dailymed-instance:fullName |
Marcaine (Injection, Solution)
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| dailymed-instance:adverseRe... |
Reactions to MARCAINE are characteristic of those
associated with other amide-type local anesthetics. A major cause
of adverse reactions to this group of drugs is excessive plasma levels,
which may be due to overdosage, unintentional intravascular injection,
or slow metabolic degradation. The most commonly
encountered acute adverse experiences which demand immediate counter-measures
are related to the central nervous system and the cardiovascular system.
These adverse experiences are generally dose related and due to high
plasma levels which may result from overdosage, rapid absorption from
the injection site, diminished tolerance, or from unintentional intravascular
injection of the local anesthetic solution. In addition to systemic
dose-related toxicity, unintentional subarachnoid injection of drug
during the intended performance of caudal or lumbar epidural block
or nerve blocks near the vertebralcolumn (especially in the head
and neck region) may result in underventilation or apnea (���Total
or High Spinal���). Also, hypotension due to loss of sympathetic
tone and respiratory paralysis or underventilation due to cephalad
extension of the motor level of anesthesia may occur. This may lead
to secondary cardiac arrest if untreated. Patients over 65 years,
particularly those with hypertension, may be at increased risk for
experiencing the hypotensive effects of MARCAINE. Factors influencing
plasma protein binding, such as acidosis, systemic diseases which
alter protein production, or competition of other drugs for protein
binding sites, may diminish individual tolerance. Central Nervous System Reactions: These are characterized by excitation and/or depression. Restlessness,
anxiety, dizziness, tinnitus, blurred vision, or tremors may occur,
possibly proceeding to convulsions. However, excitement may be transient
or absent, with depression being the first manifestation of anadverse
reaction. This may quickly be followed by drowsiness merging into
unconsciousness and respiratory arrest. Other central nervous system
effects may be nausea, vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the use of
local anesthetics varies with the procedure used and the total dose
administered. In a survey of studies of epidural anesthesia, overt
toxicity progressing to convulsions occurred in approximately 0.1%
of local anesthetic administrations. Cardiovascular System Reactions: High doses
or unintentional intravascular injection may lead to high plasma levels
and related depression of the myocardium, decreased cardiac output,
heartblock, hypotension, bradycardia, ventricular arrhythmias, including
ventricular tachycardia and ventricular fibrillation, and cardiac
arrest. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE sections.) Allergic: Allergic-type
reactions are rare and may occur as a result of sensitivity to the
local anesthetic or to other formulation ingredients, such as the
antimicrobial preservative methylparaben contained in multiple-dose
vials or sulfites in epinephrine-containing solutions. These reactions
are characterized by signs such as urticaria, pruritus, erythema,
angioneurotic edema (including laryngeal edema), tachycardia, sneezing,
nausea, vomiting, dizziness, syncope, excessive sweating, elevated
temperature, and possibly, anaphylactoid-like symptomatology (including
severe hypotension). Cross sensitivity among members of the amide-type
local anesthetic group has been reported. The usefulness of screening
for sensitivity has not been definitely established. Neurologic: The incidences of
adverse neurologic reactions associated with the use of local anesthetics
may be related to the total dose of local anesthetic administered
and are also dependent upon the particular drug used, the route of
administration, and the physical status of the patient. Many of these
effects may be related to local anesthetic techniques, with or without
a contribution from the drug. In the practice
of caudal or lumbar epidural block, occasional unintentional penetration
of the subarachnoid space by the catheter or needle may occur. Subsequent
adverse effects may depend partially on the amount of drug administered
intrathecally and the physiological and physical effects of a dural
puncture. A high spinal is characterized by paralysis of the legs,
loss of consciousness, respiratory paralysis, and bradycardia. Neurologic effects following epidural or caudal anesthesia
may include spinal block of varying magnitude (including high or total
spinal block); hypotension secondary to spinal block; urinary retention;
fecal and urinary incontinence; loss of perineal sensation and sexual
function; persistent anesthesia, paresthesia, weakness, paralysis
of the lower extremities and loss of sphincter control all of which
may have slow, incomplete, orno recovery; headache; backache; septic
meningitis; meningismus; slowing of labor; increased incidence of
forceps delivery; and cranial nerve palsies due to traction on nerves
from loss of cerebrospinal fluid. Neurologic
effects following other procedures or routes of administration may
include persistent anesthesia, paresthesia, weakness, paralysis, all
of which may have slow, incomplete, or no recovery.
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| dailymed-instance:warning |
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. 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 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.
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| dailymed-instance:indicatio... |
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: (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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| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Marcaine
|