BUPIVACAINE HYDROCHLORIDE AND EPINEPHRINE
bupivacaine hydrochloride and
epinephrine bitartrate injection, solution Hospira, Inc.
Bupivacaine HCl 0.5% with epinephrine 1:200,000 (as
bitartrate) (bupivacaine hydrochloride and epinephrine injection,
THIS SOLUTION IS INTENDED
FOR DENTAL USE.
Bupivacaine hydrochloride is (±) -1-Butyl-2´,6´-pipecoloxylidide
monohydro-chloride, 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
Epinephrine is (-)-3,4-Dihydroxy-α-[(methylamino)methyl]
benzyl alcohol. It has the following structural formula:
BUPIVACAINE HCl is available
in a sterile isotonic solution with epinephrine (as bitartrate) 1:200,000.
Solutions of BUPIVACAINE HCl containing epinephrine may not be autoclaved.
BUPIVACAINE HCl is related chemically and pharmacologically
to the aminoacyl local anesthetics. It is a homologue of mepivacaine
and is chemically related to lidocaine.
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 HCl stabilizes the neuronal membrane
and prevents the initiation and transmission of nerve impulses, thereby
effecting local anesthesia.
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.
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 analgesic is reduced.
injection of BUPIVACAINE HCl for caudal, epidural or peripheral nerve
block in man, peak levels of BUPIVACAINE HCl in the blood are reached
in 30 to 45 minutes, followed by a decline to insignificant levels
during the next three to six hours. Because of its amide structure,
BUPIVACAINE HCl is not detoxified by plasma esterases but is detoxified,
via conjugation with glucuronic acid, in the liver. When administered
in recommended doses and concentrations, BUPIVACAINE HCl does not
ordinarily produce irritation or tissue damage, and does not cause
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.
INDICATIONS AND USAGE
BUPIVACAINE HCl is indicated for the production of
local anesthesia for dental procedures by infiltration injection or
nerve block in adults.
BUPIVACAINE HCl is
not recommended for children.
BUPIVACAINE HCl 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 BUPIVACAINE HCl solutions.
LOCAL ANESTHETICS SHOULD BE EMPLOYED ONLY 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 and PRECAUTIONS .) 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.
doses of local anesthetics injected into the head and neck area, as
small as nine to eighteen milligrams, may produce adverse reactions
similar to systemic toxicity seen with unintentional intravascular
injections of larger doses. Confusion, convulsions, respiratory depression,
and/or respiratory arrest, cardiovascular stimulation or depression
and cardiac arrest have been reported. Reactions resulting in fatalities
have occurred on rare occasions. In a few cases, resuscitation has
been difficult or impossible despite apparently adequate preparation
and appropriate management. These reactions may be due to intra-arterial
injection of the local anesthetic with retrograde flow to the cerebral
circulation. 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 ).
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
injection. However, a negative aspiration does not ensure against
an intravascular injection.
in fatality have occurred on rare occasions with the use of local
anesthetics, even in the absence of a history of hypersensitivity.
This solution, which contains a vasoconstrictor, should
be used with extreme caution for patients whose medical history and
physical evaluation suggest the existence of hypertension, arteriosclerotic
heart disease, cerebral vascular insufficiency, heart block, thyrotoxicosis
and diabetes, etc., as well as patients receiving drugs likely to
produce alterations in blood pressure.
HCl 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
HCl containing a vasoconstrictor, such as epinephrine, should be used
with extreme caution in patients receiving monoamine oxidase inhibitors
(MAOI) or antidepressants of the triptyline or imipramine types, because
severe prolonged hypertension may result.
further experience is gained in children younger than 12 years, administration
of BUPIVACAINE HCl in this age group is not recommended.
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.
The safety and effectiveness of local anesthetics
depend upon proper dosage, correct technique, adequate precautions,
and readiness for emergencies.
dosage that gives effective anesthesia should be used in order to
avoid high plasma levels and serious systemic side effects. Injection
of repeated doses of BUPIVACAINE HCl may cause significant increase
in blood levels with each additional dose, due to accumulation of
the drug or its metabolites or due to slow metabolic degradation.
Tolerance varies with the status of the patient. Debilitated, elderly
patients and acutely ill patients should be given reduced doses commensurate
with age and physical condition.
of the long duration of anesthesia, when BUPIVACAINE HCl 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.
Changes in sensorium,
such as excitation, disorientation, drowsiness, may be early indications
of a high blood level of the drug and may occur following inadvertent
intravascular administration or rapid absorption of BUPIVACAINE HCl.
Solutions containing a vasoconstrictor should be used
cautiously in areas with limited blood supply, in the presence of
diseases that may adversely affect the patient's cardiovascular system,
or in patients with peripheral vascular disease.
Caution is advised in administration of repeat doses of BUPIVACAINE
HCl to patients with severe liver disease.
anesthetic procedures should be used with caution when there is inflammation
and/or sepsis in the region of the proposed injection.
See WARNINGS concerning solutions
containing a vasoconstrictor.
are employed to reduce patient apprehension, use reduced doses, since
local anesthetic agents, like sedatives, are central nervous system
depressants which in combination may have an additive effect.
BUPIVACAINE HCl should be used cautiously in persons
with known drug allergies or sensitivities, particularly to the amide-type
cardiac arrhythmias may occur if preparations containing a vasoconstrictor
such as epinephrine are employed in patients during or following the
administration of chloroform, halothane, cyclopropane, trichloroethylene,
or other related agents. 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
Information for Patients:
When appropriate, the dentist should discuss information
including adverse reactions in the package insert for BUPIVACAINE
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.
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.
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 HCl may be carcinogenic or mutagenic or that it impairs
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 hydrochloride 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 HCl at term for obstetrical
anesthesia or analgesia.
It is not known whether local anesthetic drugs are
excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when local anesthetics are administered
to a nursing woman.
Until further experience is gained in children younger
than 12 years, administration of BUPIVACAINE HCl in this age group
is not recommended.
Reactions to BUPIVACAINE HCl are characteristic of
those associated with other amidetype local anesthetics. A major cause
of adverse reactions to this group of drugs is excessive plasma levels,
which may be due to overdosage, inadvertent intravascular injection,
or slow metabolic degradation.
plasma levels of the amide-type local anesthetics cause systemic reactions
involving the central nervous system and the cardiovascular system.
The central nervous system effects are characterized by excitation or depression. The first manifestation
may be nervousness, dizziness, blurred vision, or tremors, followed
by drowsiness, convulsions, unconsciousness, and possibly respiratory
arrest. Since excitement may be transient or absent, the first manifestation
may be drowsiness, sometimes merging into unconsciousness and respiratory
arrest. Other central nervous system effects may be nausea, vomiting,
chills, constriction of the pupils, or tinnitus. The cardiovascular manifestations of excessive
plasma levels may include depression of the myocardium, blood pressure
changes (usually hypotension), and cardiac arrest. Allergic reactions, which may be due
to hypersensitivity, idiosyncrasy, or diminished tolerance, are characterized
by cutaneous lesions (e.g., urticaria), edema, and other manifestations
of allergy. Detection of sensitivity by skin testing is of doubtful
Transient facial swelling and puffiness
may occur near the injection site.
Treatment of Reactions: Toxic effects
of local anesthetics require symptomatic treatment; there is no specific
cure. The dentist should be prepared to maintain an airway and to
support ventilation with oxygen and assisted or controlled respiration
as required. Supportive treatment of the cardiovascular system includes
intravenous fluids and, when appropriate, vasopressors (preferably
those that stimulate the myocardium). Convulsions may be controlled
with oxygen and intravenous administration, in small increments, of
a barbiturate, as follows: preferably, an ultra-short-acting barbiturate
such as thiopental or thiamylal; if this is not available, a short-acting
barbiturate (e.g., secobarbital or pentobarbital) or diazepam. Intravenous
barbiturates or anticonvulsant agents should only be administered
by those familiar with their use.
DOSAGE AND ADMINISTRATION
As with all local anesthetics, the dosage varies
and depends upon the area to be anesthetized, the vascularity of the
tissues, the number of neuronal segments to be blocked, individual
tolerance, and the technique of anesthesia. The lowest dosage needed
to provide effective anesthesia should be administered. For specific
techniques and procedures, refer to standard textbooks.
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 be employed 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% BUPIVACAINE HCl with epinephrine).
Injections should be made slowly and with frequent aspirations. Until
further experience is gained, BUPIVACAINE HCl in dentistry is not
recommended for children younger than 12 years.
Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration, whenever solution
and container permit.
Store at 20 to 25°C (68 to 77°F). [See
USP Controlled Room Temperature.] Protect from light.
0.5% Bupivacaine hydrochloride with
epinephrine 1:200,000 (as bitartrate) − Sterile isotonic
solutions containing sodium chloride. Each 1 mL contains 5 mg 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. The pH of these solutions is adjusted
with sodium hydroxide or hydrochloric acid. Solutions of BUPIVACAINE HCl 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. This product is latex-free.
NDC 0409–7600–01 1.8 mL cartridges,
containers of 50, to fit the Carpule®aspirator.
Revised: November, 2006
Printed in USA
Hospira, Inc., Lake Forest, IL 60045 USA
BUPIVACAINE HYDROCHLORIDE AND EPINEPHRINE
bupivacaine hydrochloride and epinephrine bitartrate injection, solution
HUMAN PRESCRIPTION DRUG
Item Code (Source)
Route of Administration
Name (Active Moiety)
Bupivacaine Hydrochloride (Bupivacaine)
5 MILLIGRAM In 1 MILLILITER
Epinephrine Bitartrate (Epinephrine)
0.0091 MILLIGRAM In 1 MILLILITER
0.5 MILLIGRAM In 1 MILLILITER
0.001 MILLILITER In 1 MILLILITER
2 MILLIGRAM In 1 MILLILITER
60% Sodium Lactate Buffer
0.0017 MILLILITER In 1 MILLILITER
Edetate Calcium Disodium
0.1 MILLIGRAM In 1 MILLILITER
contains a CAN
This package is contained within the CASE (0409-7600-01) and
contains a CARTRIDGE
This package is contained within a CAN and a CASE (0409-7600-01)