Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/43
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Bupivacaine Hydrochloride (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 physicalcondition of the patient. The smallest dose and concentration required
to produce the desired result should be administered. Dosages of Bupivacaine
Hydrochloride 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, Bupivacaine
Hydrochloride 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
Bupivacaine Hydrochloride 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 Bupivacaine Hydrochloride 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, Bupivacaine
Hydrochloride is not recommended for pediatric patients younger than
12 years. Bupivacaine Hydrochloride is contraindicated for obstetrical
paracervical blocks, and is not recommended for intravenous regional
anesthesia (Bier Block). Use in Epidural Anesthesia: During epidural
administration of Bupivacaine Hydrochloride, 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 Bupivacaine Hydrochloride (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 to detect 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.) 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.
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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: Bupivacaine Hydrochloride 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 Bupivacaine Hydrochloride
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. Bupivacaine Hydrochloride
Injection, USP is available in sterile, isotonic solutions containing
bupivacaine hydrochloride in water for injection with characteristics
as follows: May contain sodium hydroxide and/or hydrochloric
acid for pH adjustment. (See HOW SUPPLIED section for pH information.)
Multiple-dose vials contain methylparaben 1 mg/mL added as a preservative. Bupivacaine and Epinephrine Injection, USP is available
in sterile, isotonic solutions containing bupivacaine hydrochloride
and epinephrine 1:200,000 with characteristics as follows: Sodium metabisulfite 0.1 mg/mL added as antioxidant
and edetate calcium disodium, anhydrous 0.1 mg/mL added as stabilizer.
May contain sodium hydroxide and/or hydrochloric acid for pH adjustment.
(See HOW SUPPLIED section for pH information.) Multiple-dose vials
contain methylparaben 1 mg/mL added as a preservative. Single-dose solutions contain no added bacteriostat or
anti-microbial agent and unused portions should be discarded after
use.
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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 Bupivacaine
Hydrochloride, permitting the use of moderately larger total doses
and sometimes prolonging the duration of action. The onset of action with Bupivacaine Hydrochloride is rapid and anesthesiais long lasting. The duration of anesthesia is significantly longer
with Bupivacaine Hydrochloride 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. 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. Bupivacaine
Hydrochloride 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 Bupivacaine
Hydrochloride 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 Bupivacaine Hydrochloride 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 Bupivacaine
Hydrochloride 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 Bupivacaine Hydrochloride 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 Bupivacaine
Hydrochloride. 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,
Bupivacaine Hydrochloride does not ordinarily produce irritation or
tissue damage and does not cause methemoglobinemia.
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Bupivacaine Hydrochloride is contraindicated in obstetrical
paracervical block anesthesia. Its use in this technique has resulted
in fetal bradycardia and death. Bupivacaine
Hydrochloride is contraindicated in patients with a known hypersensitivityto it or to any local anesthetic agent of the amide-type or to other
components of Bupivacaine Hydrochloride 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.] Bupivacaine Hydrochloride���Solutions of Bupivacaine Hydrochloride that do not contain
epinephrine may be autoclaved. Autoclave at 15-pound pressure, 121��C
(250��F) for 15 minutes. Do not autoclave product packaged in
Abboject Syringes. Bupivacaine Hydrochloride
with epinephrine 1:200,000 (as bitartrate)���Solutions of Bupivacaine Hydrochloride 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: January, 2007
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THE 0.75% CONCENTRATION
OF BUPIVACAINE HYDROCHLORIDE IS NOT RECOMMENDED FOR OBSTETRICAL ANESTHESIA. THERE HAVE BEEN
REPORTS OF CARDIAC ARREST WITH DIFFICULT RESUSCITATION OR DEATH DURING
USE OF BUPIVACAINE HYDROCHLORIDE 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 Bupivacaine
Hydrochloride, 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 Bupivacaine Hydrochloride 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 Bupivacaine Hydrochloride 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 Bupivacaine Hydrochloride
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 theircirculation 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
Bupivacaine Hydrochloride with other local anesthetics is not recommended
because of insufficient data on the clinical use of such mixtures. When Bupivacaine Hydrochloride 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.<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 Bupivacaine Hydrochloride.<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
Bupivacaine Hydrochloride 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-controlled studies 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 Bupivacaine Hydrochloride at term for obstetrical anesthesia
or analgesia. (See Labor and Delivery.)<br/>Labor and Delivery:: SEE BOXED WARNING REGARDING OBSTETRlCAL USE OF 0.75%
BUPIVACAINE HYDROCHLORIDE. Bupivacaine Hydrochloride
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
highlyadvisable. 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.<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 Bupivacaine Hydrochloride
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 Bupivacaine Hydrochloride. (See ADVERSE REACTIONS.) Elderly patients may require lower doses of Bupivacaine
Hydrochloride. (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 mayavoid 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 of local anesthetic
solution may produce these same signs and also leadto 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
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| dailymed-instance:fullName |
Bupivacaine Hydrochloride (Injection, Solution)
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| dailymed-instance:adverseRe... |
Reactions to Bupivacaine Hydrochloride 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 vertebral
column (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 Bupivacaine Hydrochloride.
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 an adverse
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, or no 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 BUPIVACAINE HYDROCHLORIDE IS NOT RECOMMENDED FOR OBSTETRICAL ANESTHESIA. THERE HAVE BEEN
REPORTS OF CARDIAC ARREST WITH DIFFICULT RESUSCITATION OR DEATH DURING
USE OF BUPIVACAINE HYDROCHLORIDE 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. Bupivacaine Hydrochloride
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 Bupivacaine Hydrochloride
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 Bupivacaine Hydrochloride in this age group
is not recommended. Mixing or the prior or intercurrent
use of any other local anesthetic with Bupivacaine Hydrochloride 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 Bupivacaine Hydrochloride for intravenous regional
anesthesia (Bier Block). Information on safe dosages and techniques
of administration of Bupivacaine Hydrochloride in this procedure is
lacking. Therefore, Bupivacaine Hydrochloride is not recommended for
use in this technique. Bupivacaine Hydrochloride 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 Bupivacaine Hydrochloride without epinephrine do not contain sodium
metabisulfite.
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| dailymed-instance:indicatio... |
Bupivacaine Hydrochloride 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 Bupivacaine Hydrochloride in these patients. Bupivacaine Hydrochloride is not recommended for intravenous regional
anesthesia (Bier Block). (See WARNINGS.) The
routes of administration and indicated Bupivacaine Hydrochloride 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 Bupivacaine
Hydrochloride.
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| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Bupivacaine Hydrochloride
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